ibrx-20241231

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UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM 10-K

(Mark One)

For the fiscal year ended December 31, 2024

For the transition period from to

Commission file number: 001-37507

_____________________________________

IMMUNITYBIO, INC.

(Exact name of registrant as specified in its charter)

3530 John Hopkins CourtSan Diego, California 92121

(Address of principal executive offices) (Zip Code)

Registrant’s telephone number, including area code: (844) 696-5235

Securities registered pursuant to Section 12(b) of the Act:

Title of each class Trading Symbol(s) Name of each exchange on which registered

Common Stock, par value $0.0001 per share IBRX The Nasdaq Global Select Market

Securities registered pursuant to Section 12(g) of the Act:

None

Indicate by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yesþ No ̈

Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the Act. Yes ̈Noþ

Indicate by check mark whether the registrant (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days. Yesþ No ̈

Indicate by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T (§232.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant was required to submit such files). Yesþ No ̈

Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting company, or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company,” and “emerging growth company” in Rule 12b-2 of the Exchange Act.

Large accelerated filer þ Accelerated filer ̈

Non-accelerated filer ̈ Smaller reporting company þ

Emerging growth company ̈

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ̈

Indicate by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that prepared or issued its audit report. ☑

If securities are registered pursuant to Section 12(b) of the Act, indicate by check mark whether the financial statements of the registrant included in the filing reflect the correction of an error to previously issued financial statements. ̈

Indicate by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation received by any of the registrant’s executive officers during the relevant recovery period pursuant to §240.10D-1(b). ̈

Indicate by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Act). Yes ̈ No þ

The aggregate market value of the registrant’s voting and non-voting common equity held by non-affiliates, computed based on the closing price of shares of common stock on the Nasdaq Global Select Market on June 28, 2024 was approximately $980.3 million.

The number of shares of the registrant’s common stock outstanding as of February 27, 2025 was 853,442,137 (excluding 163,800 shares held by a majority owned subsidiary of ours that are treated as treasury shares for accounting purposes).

DOCUMENTS INCORPORATED BY REFERENCE

As noted herein, the information called for by Part III of this Annual Report is incorporated by reference to specified portions of the registrant’s definitive proxy statement to be filed in conjunction with the registrant’s 2025 Annual Meeting of Stockholders, which is expected to be filed not later than 120 days after the registrant’s fiscal year ended December 31, 2024.

IMMUNITYBIO, INC.

ANNUAL REPORT ON FORM 10-K

FOR THE YEAR ENDED DECEMBER 31, 2024

TABLE OF CONTENTS

Page

PART I

Item 1. Business. 1

Item 1A. Risk Factors. 54

Item 1B. Unresolved Staff Comments. 122

Item 1C. Cybersecurity. 123

Item 2. Properties. 125

Item 3. Legal Proceedings. 126

Item 4. Mine Safety Disclosures. 128

PART II

Item 6. Reserved. 130

Item 7A. Quantitative and Qualitative Disclosures About Market Risk. 154

Item 8. Financial Statements and Supplementary Data. 156

Item 9A. Controls and Procedures. 230

Item 9B. Other Information. 233

PART III

Item 10. Directors, Executive Officers and Corporate Governance. 234

Item 11. Executive Compensation. 234

Item 14. Principal Accountant Fees and Services. 234

PART IV

Item 15. Exhibits and Financial Statement Schedules. 235

Defined Terms

Unless expressly indicated or the context required otherwise, the terms “ImmunityBio,” “the company,” “we,” “us,” and “our” in this Annual Report refer to ImmunityBio, Inc., a Delaware corporation, and, where appropriate, its subsidiaries. We have also used several other terms in this Annual Report, the consolidated financial statements and accompanying notes included herein, most of which are defined below:

Term Definition

2014 Plan NantKwest, Inc. 2014 Equity Incentive Plan

2015 Plan ImmunityBio, Inc. 2015 Equity Incentive Plan

3M IPC 3M Innovative Properties Company

3PL Agent logistics agent

401(k) Plan 401(k) retirement and savings plan

AAHI Access to Advanced Health Institute

ACA Affordable Care Act

ADCC antibody-dependent cellular cytotoxicity

ALC absolute lymphocyte count

Altor Altor BioScience, LLC

America Invents Act Leahy-Smith America Invents Act

Amyris Amyris, Inc.

ANC absolute neutrophil count

aNK activated NK cells

Annual Report Annual Report on Form 10-K for the year ended December 31, 2024

Approved product ANKTIVA

ART anti-retroviral therapy

ASC Accounting Standards Codification

ASCO American Society of Clinical Oncology

ASU Accounting Standards Update

Athenex Athenex, Inc.

ATM “at-the-market” sales agreement

ATRA American Taxpayer Relief Act of 2012

BCG Bacillus Calmette-Guérin (TICE® BCG approved for use in the U.S.)

Beike Shenzhen Beike Biotechnology Co. Ltd.

BLA Biologics License Application

bNAbs broadly-neutralizing antibodies

BPCIA Biologics Price Competition and Innovation Act of 2009

Brink Brink Biologics, Inc.

Cambridge Cambridge Equities, LP

CAR chimeric antigen receptor

CCPA California Consumer Privacy Act of 2018

CEO chief executive officer

Term Definition

CFO chief financial officer

cGMP current Good Manufacturing Practice

CI confidence interval

CIO chief information officer

CIS carcinoma in situ

Clinic Immuno-Oncology Clinic, Inc.

Closing Date when used in connection with the RIPA, December 29, 2023

CMC Chemistry, Manufacturing and Controls

CMO contract manufacturing organization

CMS Centers for Medicare & Medicaid Services

Code Internal Revenue Code of 1986, as amended

CODM chief operating decision maker

CPI checkpoint inhibitor

CPRA California Privacy Rights Act

CR complete response

CRADA Cooperative Research and Development Agreement

CRL complete response letter

CRO contract research organization

CVR contingent value right

DAMPs damage-associated molecular patterns

DGCL Delaware General Corporation Law

DOD U.S. Department of Defense

DSCSA Drug Supply Chain Security Act

Duley Road Duley Road, LLC

EAP Expanded Access Program

EEA European Economic Area

EGFR epidermal growth factor receptor

EMA European Medicines Agency

ERM Enterprise Risk Management

EU European Union

Exchange Act Securities Exchange Act of 1934, as amended

Exyte Exyte U.S., Inc.

FASB Financial Accounting Standards Board

FCA False Claims Act

FCPA U.S. Foreign Corrupt Practices Act

FD&C Act Federal Food, Drug, and Cosmetic Act

FDA U.S. Food and Drug Administration

FDASIA Food and Drug Administration Safety and Innovation Act of 2012

FIFO First In First Out inventory method

Term Definition

FTC Federal Trade Commission

FTO freedom-to-operate

FVO fair value option

GBM glioblastoma multiforme

GCP Good Clinical Practice

GDPR General Data Protection Regulation

GlobeImmune GlobeImmune, Inc.

GLP Good Laboratory Practice

GMP Good Manufacturing Practice

hAd5 human adenovirus serotype 5

haNK high-affinity NK

Hatch-Waxman Act Drug Price Competition and Patent Term Restoration Act of 1984

HCW HCW Biologics, Inc.

HHS U.S. Department of Health and Human Services

HIPAA Health Insurance Portability and Accountability Act of 1996

HITECH Health Information Technology for Economic and Clinical Health Act

HIV human immunodeficiency virus

IDE Investigational Device Exemption

IgDraSol IgDraSol, Inc., a subsidiary of the company

IL-15 novel interleukin 15

IND investigational new drug

Infinity Infinity SA LLC, as purchaser agent for affiliates of Oberland

iNHL indolent non-Hodgkin lymphoma

IPR&D In-process research and development

IRA Inflation Reduction Act of 2022

IRB Institutional review boards

IRS Internal Revenue Service

LDMC low-dose metronomic chemotherapy

LMIC low- and middle-income countries

M-ceNK memory-like cytokine-enhanced NK

MAA Marketing Authorization Application

mAbs monoclonal antibodies

MCC Merkel cell carcinoma

mCRCP metastatic castration-resistant prostate cancer

MDSC myeloid-derived suppressor cells

MHC major histocompatability complex

MHC-I major histocompatability complex class I

MHC-II major histocompatability complex class II

iii

Term Definition

MHRA Medicines and Healthcare products Regulatory Agency

MTD maximum tolerated dose

NAI nogapendekin alfa inbakicept-pmln

NantBio NantBio, Inc.

Nant Capital Nant Capital, LLC

NantCell NantCell, Inc., a subsidiary of the company

NANTibody Immunotherapy NANTibody, LLC, a subsidiary of the company

NantKwest NantKwest, Inc.

NantMobile NantMobile, LLC

NantPharma NantPharma, LLC

NantWorks NantWorks, LLC, a related party

NC 2015 Plan NantCell, Inc. 2015 Stock Incentive Plan

NCI National Cancer Institute

NCV Nant Cancer Vaccine

NEO named executive officer

NHL non-Hodgkin lymphoma

NIAID National Institute of Allergy and Infectious Diseases

NIH National Institutes of Health

NIH Guidelines NIH Guidelines for Research Involving Recombinant DNA Molecules

NK natural killer

NMIBC non-muscle invasive bladder cancer

NOL net operating loss

NSCLC non-small cell lung cancer

OBA NIH Office of Biotechnology Activities

OFAC U.S. Treasury Department’s Office of Foreign Assets Control

PCAOB Public Company Accounting Oversight Board (United States)

PD-1 programmed death receptor 1

PD-L1 programmed death receptor ligand

PDMA U.S. Prescription Drug Marketing Act

PHI Protected Health Information

PHSA Public Health Service Act

PMA premarket approval

PREA Pediatric Research Equity Act

PRO Patient Recorded Outcomes

PSA prostate-specific antigen

QMSR Quality Management System Regulation

QSR Quality System Regulation

QUILT QUantum Integrative Lifelong Trial

R&E research and experimental expenditures

RAC Recombinant DNA Advisory Committee

Term Definition

rBCG recombinant BCG

RDO registered direct offering

RBCs red blood cells

RECIST response evaluation criteria in solid tumors

REMS Risk Evaluation and Mitigation Strategy

RIPA Revenue Interest Purchase Agreement

Riptide Riptide Bioscience, Inc.

RMAT regenerative medicine advanced therapy

RSU restricted stock unit

SAFE Simple Agreement for Future Equity

Sarbanes-Oxley Sarbanes-Oxley Act of 2002

SARS-CoV-2 novel strain of the coronavirus (COVID-19)

sBLA supplemental Biologics License Application

SEC U.S. Securities and Exchange Commission

Section 404 Section 404 of the Sarbanes-Oxley Act of 2002

Securities Act Securities Act of 1933, as amended

Serum Institute Serum Institute of India Private Limited

Sorrento Sorrento Therapeutics, Inc.

SPOA Stock Purchase and Option Agreement

SQ subcutaneous

SRLY separate return limitation year

TAA tumor-associated antigen

TCJA Tax Cuts and Jobs Act of 2017

Term SOFR Term Secured Overnight Financing Rate

Test Date when used in connection with the RIPA, December 31, 2029

TF Platform tissue factor-based fusion discovery platform

TGF-β transforming growth factor beta

t-haNK targeted high-affinity NK

TLR toll-like receptor

TME tumor microenvironment

TNBC triple-negative breast cancer

T-reg regulatory T cells

TriAd Triple Antigen (CEA, MUC1, Brachyury)

UK United Kingdom

UK GDPR UK Data Protection Act of 2018

USPTO U.S. Patent and Trademark Office

VA Veterans Affairs

VBC Holdings VBC Holdings, LLC, a subsidiary of the company

VIE variable interest entity

VivaBioCell VivaBioCell, S.p.A., a wholly-owned subsidiary of VBC Holdings

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PART I

ITEM 1. BUSINESS.

Forward-Looking Statements

This Annual Report contains forward-looking statements within the meaning of Section 27A of the Securities Act and Section 21E of the Exchange Act that are based on our management’s beliefs and assumptions and on information currently available to our management. Forward-looking statements include, but are not limited to:

•our ability to successfully commercialize ANKTIVA;

•our ability to obtain incremental approvals for ANKTIVA for new indications from the FDA or clearances or approvals from international regulatory agencies for the treatment of patients with NMIBC or other indications;

•potential future uses and applications of ANKTIVA, including as a lymphopenia rescue agent, and use in cancer vaccines and across multiple tumor types;

•our ability to develop next-generation therapies and vaccines that complement, harness, and amplify the immune system to defeat cancers and infectious diseases;

•our ability to obtain additional financing to fund our operations and complete the commercialization of our approved product and the development and commercialization of our other product candidates;

•our ability to meet our payment obligations under the RIPA and to service the interest on our related-party promissory note and repay such note, to the extent required;

•our ability to comply with the terms, conditions, covenants, restrictions, and obligations set forth in the RIPA and related transaction documents;

•our expectations regarding the potential benefits of our strategy and technology;

•our ability to forecast operating results and make period-to-period comparisons predictive of future performance due to fluctuations in warrant and derivative values;

•our expectations regarding the operation and effectiveness of our product candidates and related benefits;

•our ability to utilize multiple modes to induce cell death;

•our beliefs regarding the benefits and perceived limitations of competing approaches, and the future of competing technologies and our industry;

•details regarding our strategic vision and planned product candidate pipeline;

•our beliefs regarding the success, cost and timing of our product candidate development activities and current and future clinical trials and studies, including study design and the enrollment of patients;

•the timing of the development and commercialization of our other product candidates;

•our expectations regarding our ability to utilize the Phase 1/2 aNK and haNK® clinical trials data to support the development of our product candidates, including our taNK, t‐haNKTM, MSC, and M-ceNKTM product candidates;

•our expectations regarding the development, application, commercialization, marketing, prospects and use generally of our product candidates, including hAd5 constructs, and PD-L1 t‐haNK and M-ceNK;

•the timing or likelihood of regulatory filings or other actions and related regulatory authority responses in the U.S. and jurisdictions outside of the U.S., including any planned IND, BLA, NDA or MAA or similar filings or pursuit of accelerated regulatory approval pathways or orphan drug status and Breakthrough Therapy, Fast Track or RMAT designations and any designation’s eventual impact on BLA submission or approval timing and or approval probability;

•our ability to implement an integrated discovery ecosystem and the operation of that planned ecosystem, including being able to regularly add neoepitopes and subsequently formulate new product candidates;

•the ability and willingness of strategic collaborators to share our vision and effectively work with us to achieve our goals;

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•the ability and willingness of various third parties to engage in research and development activities involving our product candidates, and our ability to leverage those activities;

•our ability to attract additional third-party collaborators;

•our expectations regarding the ease of administration associated with our product candidates;

•our expectations regarding patient compatibility associated with our product candidates;

•our beliefs regarding the potential markets for our product candidates and our ability to serve those markets;

•our expectations regarding the timing of enrollment and submission of our clinical trials, and protocols and timing of data read-outs related to such trials;

•our ability to produce a cytokine fusion protein, a DNA or recombinant protein vaccine, or a cell therapy;

•our beliefs regarding the potential manufacturing and distribution benefits associated with our product candidates, and our third-party CMOs’ abilities to follow cGMP standards to scale up the production of our product candidates;

•our plans regarding our manufacturing facilities and our belief that our manufacturing is capable of being conducted in‐house;

•our belief in the potential of our cytokine fusion proteins, DNA or recombinant protein vaccines, or cell therapies, and the fact that our business is based upon the success individually and collectively of these platforms;

•our belief regarding the magnitude or duration for additional clinical testing of our cytokine fusion proteins, DNA or recombinant protein vaccines, or cell therapies, along with other product candidate families;

•even if we successfully develop and commercialize specific product candidates, our ability to develop and commercialize our other product candidates either alone or in combination with other therapeutic agents;

•the ability to obtain and maintain regulatory approval of our approved product and to obtain and maintain regulatory approval of any of our other product candidates, and any related restrictions, limitations and/or warnings in the label of any approved product candidate;

•our ability to successfully commercialize ANKTIVA or any future approved products;

•the rate and degree of market acceptance of any approved products;

•our ability to attract and retain key personnel;

•the accuracy of our estimates regarding our future revenue, as well as our future operating expenses, capital requirements and needs for additional financing;

•our ability to obtain, maintain, protect, and enforce patent protection and other proprietary rights for our approved product and our other product candidates and technologies;

•the terms and conditions of licenses granted to us and our ability to license additional intellectual property relating to our product, product candidates and technology;

•our expectations regarding the results of market access initiatives and coverage under medical reimbursement policies;

•shelf life of ANKTIVA drug substance and drug product and availability of product supply;

•our global expansion efforts;

•any government shutdown or budget disruption, which could adversely affect the U.S. and global economies, and materially and adversely affect our business and/or our future BLA submissions;

•the impact on us, if any, if the CVRs held by former Altor stockholders become due and payable in accordance with their terms; and

•regulatory developments in the U.S. and foreign countries.

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Forward-looking statements include statements that are not historical facts and can be identified by terms such as “anticipates,” “believes,” “continues,” “goal,” “could,” “estimates,” “scheduled,” “expects,” “intends,” “may,” “plans,” “potential,” “predicts,” “indicate,” “projects,” “seeks,” “should,” “will,” “would,” “strategy,” and variations of such words or similar expressions. and the negatives of those terms. In addition, statements that “we believe” and similar statements reflect our beliefs and opinions on the relevant subject. Statements of past performance, efforts, or results of our preclinical and clinical trials, about which inferences or assumptions may be made, can also be forward-looking statements and are not indicative of future performance or results. These statements are based upon information available to us as of the date of this Annual Report, and although we believe such information forms a reasonable basis for such statements, such information may be limited or incomplete, and our statements should not be read to indicate that we have conducted a thorough inquiry into, or review of, all potentially available relevant information. These statements are inherently uncertain, and investors are cautioned not to unduly rely upon these statements.

This Annual Report also contains estimates, projections and other information concerning our industry, our business, and the markets for certain diseases, including data regarding the estimated size of those markets, and the incidence and prevalence of certain medical conditions. Information that is based on estimates, forecasts, projections, market research or similar methodologies is inherently subject to uncertainties and actual events or circumstances may differ materially from events and circumstances reflected in this information. Unless otherwise expressly stated, we obtained this industry, business, market, and other data from reports, research surveys, studies, and similar data prepared by market research firms and other third parties, industry, medical and general publications, government data, and similar sources.

Forward-looking statements involve known and unknown risks, uncertainties, and other factors that may cause our actual results, performance, or achievements to be materially different from any future results, performance, or achievements expressed or implied by the forward-looking statements. We discuss these risks in greater detail in Item 1A. “Risk Factors” of this Annual Report. Given these uncertainties, you should not place undue reliance on these forward-looking statements as a representation or warranty by us or any other person that we will achieve our objectives and plans in any specified time frame. Also, forward-looking statements represent our management’s beliefs and assumptions only as of the date of this Annual Report.

Except as required by law, we assume no obligation to update these forward-looking statements, or to update the reasons actual results could differ materially from those anticipated in these forward-looking statements, even if new information becomes available in the future. You should read this Annual Report completely and with the understanding that our actual future results may be materially different from what we expect.

ImmunityBio, ImmunityBio Care, ANKTIVA, ThAnktiva, haNK, taNK, ceNK, NK-92, Nant Cancer Vaccine, NANT 001, NANT XL, NANT 001 and Design, QUILT, Outsmart Your Disease, Smart Therapies for Difficult Diseases, NantKwest, VivaBioCell, and Infacell are trademarks or registered trademarks of ImmunityBio, Inc., its subsidiaries and affiliates.

ANKTIVA has been approved by the U.S. FDA for use with BCG for the treatment of adult patients with BCG-unresponsive NMIBC with CIS with or without papillary tumors. Other than as set forth in such specific approved label, our product candidates, including N-803, are investigational agents that are restricted by federal law to investigational use only, and safety and efficacy have not been established by any agency, including the FDA.

This Annual Report contains references to our products and trademarks and products and trademarks belonging to other entities. Solely for convenience, trademarks and trade names referred to in this Annual Report, including logos, artwork, and other visual displays, may appear without the ® or TM symbols, but such references are not intended to indicate, in any way, that we will not assert, to the fullest extent under applicable law, our rights or the rights of the applicable licensor to these trademarks and trade names. We do not intend our use or display of other companies’ products or trade names or trademarks to imply a relationship with, or endorsement or sponsorship of us, by any other companies.

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Founder’s Vision for Next-Generation Immunotherapy

A Message from Patrick Soon-Shiong, M.D., Founder of ImmunityBio, Inc.

Founder’s Vision

My 35-Year Quest to Change the Paradigm of Cancer Care by Activating the Body’s Immune System and Natural Killer Cells.

Founder’s Hypothesis

cancer. In fact, a short-term battle would be won by observing a response rate, but the war lost because of the destruction of important cells called lymphocytes by our chemotherapy and radiation treatment, preventing the formation of memory T cells and long-term duration of response – duration matters, T cell memory matters. Thus began the hypothesis that if we could harness the activity of lymphocytes – specifically NK and killer T cells, the potential existed to outsmart the immuno-evasion of cancer and unleash the body’s immune system to treat cancer with immunotherapy for long-term overall survival and indeed even prevent cancer in patients with high risk.

However, I faced the challenge of 50 years of standards of care which relied on high-dose chemotherapy and radiotherapy. The notion that the standard-of-care would rapidly destroy these lymphocytes, the very cells needed to kill the tumor and establish T and NK cell memory, was difficult to convince the medical establishment and regulatory authorities. The possibility that our standard-of-care was indeed responsible for preventing long-term complete remissions by the inadvertent process of destroying the very system engineered in our bodies to protect against cancer and infectious disease, was the quest that required challenging. That is the mission of ImmunityBio and the recent recognition in 2025 by the FDA that ANKTIVA and PD-L1 t-haNK was granted a Regenerative Medicine Advanced Therapy (RMAT) designation for the reversal of lymphopenia in patients receiving chemotherapy and radiation therapy is a turning point for this paradigm change in cancer care.

The destruction of the NK and T cells resulting in lymphopenia (low levels of lymphocytes) correlated with poor prognosis of overall survival across multiple tumor types. With our increasing knowledge of the immune system, including the discovery of T cells, NK cells and dendritic cells, and their role in cancer suppression (immuno-surveillance) and cancer growth when the tumor develops mechanisms to hide from the cytotoxic effects of NK and T cells (immune evasion), it became time to re-visit immunotherapy. Most are familiar with the breakthrough of CPI therapy, represented by antibodies that target either PD-1, PD-L1, or other molecules that act to inhibit immune cell (specifically T cell) responses to cancer. But even the efficacy of CPI therapies can be undermined by lymphopenia (lack of T cells), making the rescue of lymphopenia an overarching goal of my approach to cancer therapy.

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This vision, which I have pursued for decades, is the transformation in the paradigm for cancer care by treating the host and activating the immune system (NK cell and killer T cell) resulting in immunogenic cell death and inducing long-term duration of response with the generation of memory T cells and memory NK cells. On the other hand, standards of care have been addressing the tumor itself (rather than the host immune system) with high-dose chemotherapy for short-term response gains. A paradigm change would be to address the host’s immune system by activating the host immune system by utilizing the tumor in the body as an antigenic source to generate a long-term durable response to the activated NK cell, T cell and memory T cell. In this way, a therapeutic cancer vaccine could be developed. Along this journey, it has been difficult to convince academia, medical cancer centers, the FDA and even the pharmaceutical industry that existing treatment paradigms for cancer are based on misplaced assumptions utilizing high-dose chemotherapy and radiotherapy by “winning the battle but losing the war.”

In 2017, I proposed a General Investigational Plan to study a potential therapeutic cancer vaccine applicable to all tumor types to the FDA and was given an audience with the Oncology Centers of Excellence by the FDA leadership. The hypothesis, including the request for RMAT designation presented in the plan was as follows:

“A paradigm change in cancer care is required in which a modernized treatment is based on the biology of the tumor independent of anatomy, utilizing molecular and immunological insights as to the dynamic state of the cancer in its evolution (elimination, equilibrium, and escape) and specifically tailored to the patient’s cancer altered genome, to reinstate the patient into equilibrium.

The notion that the tumor tissue itself could act as a source of both antigenicity and adjuvanticity is exploited by the NANT Cancer Vaccine – a universal therapeutic cancer vaccine that acts through the orchestration of the innate and adaptive immune system across all tumor types.

We hypothesize that the normal physiological protective immune system of Elimination can be reinstated by the NANT Cancer Vaccine, first by overcoming the immunosuppressed Escape state, followed by induction of immunogenic cell death and activation of effector immune cells, with restoration of the patient to a state of Equilibrium, a paradigm change in cancer care.”

The leadership at the FDA listened to this presentation and subsequently while denying RMAT designation, authorized my request to pursue this hypothesis by performing Phase 1 and Phase 2 clinical trials I termed “QUILT” QUantum Integrative Lifelong Trial across certain indications including first-line and second-line NMIBC, second-line and third-line MCC, second-line and third-line metastatic pancreatic cancer, second-line or greater GBM, third-line metastatic TNBC and third-line metastatic head & neck cancer. I also coined the term “Quantum Oncotherapeutics” to highlight the concept that the TME is dynamic and very rapid changes occur based on the therapy we administer.

This authorization was seminal in my journey to prove the importance of NK and T cells and the need to orchestrate molecules which would induce the innate and adaptive immune system to result in durable overall survival and complete remissions. Over the course of the past 8 years, the findings I describe below provide support that my hypothesis was correct and a universal therapeutic cancer vaccine may be possible.

For the first time in 50 years, oncologists may now have a reason to pay more attention to a complete blood count analysis of lymphocytes (NK & T cells) as the RMAT designation – granted on February 27, 2025 for ANKTIVA and PD-L1 t-haNK in combination with standard-of-care chemotherapy/radiotherapy indicated for the reversal of lymphopenia and treatment of multiply relapsed locally advanced or metastatic pancreatic cancer – is developed. Below is a summary of this journey. It is my hope that the concept of ALC will begin to be recognized by oncologists and the ratio of ANC to ALC will become a key biomarker of the current status of a patient with cancer and a predictor of outcome.

The Breakthrough of NK and T Cell Rescue by IL-15 Receptor Superagonist – Overcoming Lymphopenia

The standard analysis performed by oncologists following chemotherapy is the evaluation of the CBC with the differential subset of cells that make up the circulating blood levels. The focus of oncologists today in the review of the differential are red blood cells, platelet count and neutrophils. Remarkably, very little to no attention is given to lymphocyte count – the very cells (killer T cells and NK cells) that are critical for killing the tumor. Instead, in addition to platelet counts, oncologists today focus on the following subset of cells in the CBC:

•Red Blood Cells (RBCs) – to determine anemia as a consequence of the chemotherapy

•Neutrophils (ANC) – to determine the neutrophil level to avoid infection as a consequence of the chemotherapy

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Oncologists are familiar with monitoring RBCs and neutrophils since therapies are available to mitigate the consequences of anemia and neutropenia by administration of, for example, EPOGEN to manage anemia and NEUPOGEN to manage neutropenia. Yet there is little focus on the cells of importance in the blood system that are directly involved in the killing of the tumor, lymphocytes (NK and T cells), as reflected by the lymphocyte count and percentage of lymphocytes relative to the neutrophils. It is likely that attention was rarely given to the lymphocyte count and the neutrophil to lymphocyte ratio (NLR) by caregivers managing cancer patients because no therapy existed to mitigate lymphopenia. Now, we believe our IL-15 receptor superagonist ANKTIVA (also known as N-803; molecular name nogapendekin alfa inbakicept-pmln, which has been approved for the treatment of adult patients with BCG-unresponsive NMIBC with CIS with or without papillary tumors), provides a potential treatment for lymphopenia.

We believe that NAI may be the answer to the challenge oncologists have faced for the last 50 years, that is, how to address lymphopenia. The efficacy of immune CPIs, while a major step forward in cancer care, depends on the presence of T cells as well as the presence of the receptor to T cells on tumors (MHC-I and MHC-II). It stands to reason that with lymphopenia (low T cells) or MHC-I loss, T cell activity would be inhibited, and CPI therapy would fail. However reversing lymphopenia and overcoming low NK and T cell activity could result in the rescue of T cells and CPI failures. Just as EPOGEN and NEUOPOGEN are used across all tumor types regardless of the anatomy, we believe that NAI (proposed as ANKTIVOGEN in this potential indication), due to its ability to rescue lymphopenia by proliferation and activation of NK and T cells, has the potential to, if approved, overcome lymphopenia across all tumor types.

We believe the FDA authorization of RMAT designation for NAI and PD-L1 t-haNK in combination with standard-of-care chemotherapy/radiotherapy indicated for the reversal of lymphopenia and treatment of multiply relapsed locally advanced or metastatic pancreatic cancer places ImmunityBio on the path to a potential paradigm change in cancer care.

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Lymphopenia in cancer and its effects on response rates to chemo and immunotherapy have been studied in detail. Studies performed in large patient populations with advanced cancers confirm that regardless of histological subtype and treatment, global and CD4+ lymphopenia are powerful independent predictors of risk of high-grade toxicity to chemotherapy. In addition, peripheral lymphopenia, pre-existing or induced by therapies in patients with metastatic solid tumors, strongly impacts their survival and CD4+ lymphopenia is a powerful marker of reduced survival. Different published studies exploring the impact of global lymphopenia or NK and T cell subsets on relapse-free survival and overall survival in patients with solid tumors show lymphocyte thresholds (% lymphopenia) generally <1,000 per microliter of blood leading to elevated relative risk scores for both relapse-free survival (1.35-3.81) and overall survival (1.25-7.70).

We believe the FDA approval of ANKTIVA with BCG for treatment of adult patients with BCG-unresponsive NMIBC with CIS with or without papillary tumors in 2024 and the recent RMAT designation with ANKTIVA and PD-L1 t-haNK provides the opportunity for the first FDA-approved cancer therapy (ANKTIVA in BCG Unresponsive NMIBC CIS) to be extended in patients receiving standard-of-care chemotherapy and radiotherapy, that has the potential to reverse lymphopenia – meaning the ability to resuscitate and rescue NK and T cells – the very cells of critical importance for immunogenic cell death and long-term memory against the tumor. Through its mechanisms of action to proliferate NK and T cells (as described on its label) and therefore rescue lymphopenia, I believe ANKTIVA has the potential to be the backbone of my vision for ‘Immunotherapy 2.0’ that could launch a new era and paradigm change in the treatment of cancer across all tumor types by driving memory T and NK cells with durable remission of the disease.

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ANKTIVA overcomes tumor evasion by mitigating both the loss of T cells (lymphopenia) and the loss of the ligand to T cells on the tumor (MHC-I loss). The mechanism of potentially overcoming cold tumors will be discussed in detail further below.

ABRAXANE – Immunogenic Cell Death in the Tumor Microenvironment (2005: FDA Approval)

As the first step in my quest to change the paradigm of cancer care previously based on toxic high-dose chemotherapy and/or radiation, I left academia (UCLA) to develop the nation’s first albumin-bound nanoparticle of paclitaxel (nab-paclitaxel), ABRAXANE, and to institute the concept of LDMC to elicit a vaccine-like effect. LDMC is chemotherapy not used at the MTD to kill the tumor, but rather to stress the tumor and elicit release of antigens to allow the killer cells surrounding the tumor (macrophages, T cells and NK cells), to induce immunogenic cell death.

Even today, the concept of albumin-bound therapy to concentrate drug at the tumor site is not always fully appreciated by the oncology community. ABRAXANE was developed to exploit the biology of the concept of transcytosis whereby the transport of albumin-bound paclitaxel across the endothelial blood vessel layer to the TME is accomplished through the gp60 receptor and the Caveolin pathway leading to entry of paclitaxel in the TME and the production of stress molecules in the tumor (DAMPs), while at the same time activating the killer macrophages (M2 suppressive macrophages to M1 killer macrophages). ABRAXANE was approved by the FDA in 2005 for the treatment of breast cancer after failure of combination chemotherapy for metastatic diseases or relapse within six months of adjuvant chemotherapy and now also has FDA approval for patients with lung and pancreatic cancer in certain indications.

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ANKTIVA – IL-15 Receptor Superagonist Rescuing Lymphocytes and Overcoming MHC-I Loss (2024: FDA Approval)

With ABRAXANE as the first pillar in this quest to change the paradigm of care, I then turned my attention to addressing lymphopenia and unleashing the “triangle offense” via the IL-15 receptor superagonist ANKTIVA.

In 2024, ANKTIVA with BCG for the treatment of adult patients with BCG-unresponsive NMIBC with CIS with or without papillary tumors was approved by the FDA, who authorized the description of the mechanism of action in the label as:

I believe this potentially universal therapeutic vaccine, sometimes referred to as NCV (U.S. Patent #US11071774-B2), could be able to coordinate the release of antigens from tumor cells (DAMPs/neoantigens and/or shared tumor-associated antigens, TAAs) or provision of vaccine antigens with support for immune-cell activity, including cells of both the innate and adaptive immune systems, to achieve a vaccine-like effect. ANKTIVA, due to its mechanism of proliferating and activating innate (macrophages, NK cells, dendritic cells) and adaptative (T cells, iNKT cells, and memory T cells) immune cells provides the vital stimulus needed to establish immune memory.

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Thus, I believe ANKTIVA has the potential to become the backbone for a cancer vaccine not only to potentially cure cancer (long-term duration free of disease) but also to prevent cancer. An example of the possibility of prevention is in subjects with Lynch Syndrome, a genetic condition that puts them at significantly higher risk for cancer, and with an earlier age of onset. Currently, ANKTIVA plus vaccines that deliver tumor associated antigens via adenovirus, relevant to Lynch Syndrome are being tested in clinical trials with subjects with Lynch Syndrome for their ability to prevent cancer onset. If efficacious, this novel treatment could help support that a universal cancer vaccine is indeed possible.

Quantum Oncotherapeutics – A Potential Universal Therapeutic Cancer Vaccine

Changing the paradigm and convincing oncologists of the need to avoid high-dose chemotherapy and implement a treatment protocol that activates the patient’s immune system rather than destroying the NK cells and T cells remains a difficult task even today.

In 2017, the FDA allowed ImmunityBio (formerly NantKwest and NantCell) to initiate a series of transformative clinical trials in which the concept of inducing immunogenic cell death (ICD) was pursued. These trials entitled “QUILT” QUantum Integrative Lifelong Trials were seminal in the pursuit of a universal cancer vaccine. The clinical protocols shared an approach that followed my vision of inducing DAMPs, avoiding high-dose chemotherapy, educating T cell via dendritic cell activation and inducing NK, CD4+ and CD8+ T cell proliferation in combination with off-the-shelf CAR-NK cell therapy to overcome immunosuppressive T-reg cells and myeloid-derived suppressive cells (MDSCs). The findings from the QUILT trials have confirmed the validity of the NCV approach.

In 2022, I was honored to present the concept of “Quantum Oncotherapeutics” providing updates and receiving authorization to proceed with the QUILT trials and by 2025 met with the FDA to present the update of these trials.

The Challenges of Checkpoint Failure Facing Oncologists: Immunotherapy 2.0 Beyond Checkpoints

By 2024, the FDA had approved the use of CPIs (pembrolizumab, nivolumab, etc.) across 17 different tumor types. However, at the 2024 ASCO Annual Meeting I believe it became apparent that responses to CPIs were frequently fleeting and that CPIs were not effective in so-called “cold tumors.” The cold tumor is defined as lacking sufficient T-cell infiltration or activity of the T cells, even with use of a CPI, in the TME, and the loss of MHC-I, the binding site on the tumor for the T-cell receptor. Thus, the lack of effect in cold tumors is driven by fewer T cells (lymphopenia) and selection of cancer cell clones without the receptor for T cells to bind to MHC-I (MHC-I loss). Given these dynamics, it is not surprising that CPIs alone often fail or elicit only transient responses.

Overcoming Tumor Evasion and Converting a Cold Tumor to a Hot Tumor

The addition of ANKTIVA not only rescues T cells, but also activates NK cells that have the ability to recognize tumor cells without MHC-I expression and, as a result of increased interferon-γ (IFN-γ) secretion by the activated NK cells, also has the potential to restore MHC-I expression. All of these activities act to rescue CPIs. Thus, the combination of ANKTIVA plus a CPI represents Immunotherapy 2.0. A depiction of how ANKTIVA has the potential to convert a cold tumor to a hot tumor and rescues CPIs is provided below.

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The loss of MHC-I molecules serves as a mechanism for tumor evasion and progression during CPI therapy. This phenomenon can be understood through the lens of Darwinian selection, where tumors that are resistant to either chemotherapy or chemo-immunotherapy emerge due to the loss of MHC-I receptors on tumor cells, which are essential for T cell recognition. These highly selected resistant cells, characterized by MHC-I loss, subsequently become targets for NK cells. NK cells are specifically designed to identify and eliminate cells that lack MHC-I expression, a process known as “missing-self” recognition.

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The evasion of tumors from checkpoint therapy through the loss of MHC-I molecules leads to the generation of MHC-I negative, or “cold” tumors. Initially, the tumor cells are “hot” and recognized by T cells activated by CPIs. However, with the loss of MHC-I, these tumor cells evade T cell detection, becoming “cold” and resulting in checkpoint therapy failure and subsequent tumor progression.

An MHC negative cold tumor cell which has evaded T cell detection and hence led to progression despite treatment with CPIs is now the target of NK cells. NK cells cytotoxicity is independent of MHC-I status and independent of PD-L1 status on the tumor cell. Thus, if NK cells could be activated and proliferated, NK cells could kill these Darwinian-selected resistant cancer cells and rescue CPIs.

The NK cell recognizes the MHC negative cold tumor and converts the tumor from hot to cold through IFN-γ stimulation. As a consequence, MHC-I and MHC-II are re-expressed on the tumor cell, making the cell recognizable by T cells. This dynamic activity can be enhanced by proliferation of NK, CD4+ and CD8+ T cells through IL-15 stimulation of the IL-15 receptor on NK, CD4+ and CD8+ T cells.

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ANKTIVA, an IL-15 receptor superagonist, stimulates the IL-15 receptor on natural killer cells resulting in proliferation of the NK cell and conversion of the cold tumor to hot by the NK cell recognizing the MHC negative tumor and converting the cold tumor to hot. This activity of reactivating T cells allows the rescue of CPIs against PD-1.

SUMMARY: ANKTIVA rescues and restores CD8+ killer T cells and memory T cells by converting MHC negative (cold) to MHC positive (hot) tumors through IL-15 stimulated NK cell activation and IFN-γ secretion with durable response and prolonged overall survival.

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QUILT Studies Validate NCV with ANKTIVA as the Backbone

I presented findings from completed QUILT studies during a 2025 program review meeting with the FDA, including the achievement of complete remissions in late-stage and advanced tumors of many types, such as NMIBC, MCC, TNBC, pancreatic cancer and head & neck cancer, validating the concept of eliciting immunogenic cell death rather than the tolerogenic cell death induced by current standards of care. A summary of the complete remissions is shown in the image below.

ImmunityBio Platforms - The Development of a Universal Therapeutic Cancer Vaccine

Based on the vision of activating the patient’s immune system, the company continues its efforts to demonstrate that a universal cancer vaccine that leverages the power of its platforms – backbone ANKTIVA, off-the-shelf and autologous NK-cell-based therapies, adenovirus-vectored delivered vaccines, and other technologies – provide benefit and hope not only for patients with cancer but also for those with a high risk of developing cancer.

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Select Clinical Development Program 2025+

The future of immunotherapy appears bright and I continue my quest to drive towards a therapeutic vaccine across multiple tumor types where patients do not suffer the adverse events of high-dose chemotherapy and high-dose radiotherapy. We have made and are targeting multiple submissions to the FDA in 2025 and beyond. In February 2025, the FDA authorized an EAP allowing us to provide rBCG developed by Serum Institute to urologists to address the TICE BCG shortage in all settings where TICE BCG is approved.

In addition, as announced on February 27, 2025, the FDA has granted ImmunityBio RMAT designation for ANKTIVA and PD-L1 t-haNK in combination with standard-of-care chemotherapy/radiotherapy indicated for the reversal of lymphopenia and treatment of multiply relapsed locally advanced or metastatic pancreatic cancer. This RMAT designation follows clinical data of ALC and significant overall survival correlations in QUILT trials across multiple tumor types including third-line or greater metastatic pancreatic cancer, checkpoint relapsed NSCLC, and supportive data from healthy volunteers. The reversal of lymphopenia by ImmunityBio’s IL-15 receptor superagonist is consistent with the mechanism of action of ANKTIVA demonstrating proliferation and activation of NK cells, CD4+ T cells, CD8+ T cells, and memory T cells without upregulation of suppressive T reg cells and approved in the ANKTIVA label (approved for the treatment of adult patients with BCG-unresponsive NMIBC with CIS with or without papillary tumors). ImmunityBio intends to submit a BLA for the indication of reversal of lymphopenia in patients receiving standard-of-care chemotherapy and/or radiation and for the treatment of locally advanced or metastatic pancreatic cancer which includes the first-in-class CAR-NK (PD-L1 t-haNK), and to provide data from fully enrolled clinical trials in metastatic pancreatic cancer (QUILT 88) and in checkpoint relapsed NSCLC (QUILT 3055, NSCLC Cohort) patients, as well as lymphopenia reversal across multiple tumor types (QUILT 3055, all Cohorts), with supportive data of lymphocyte proliferation in healthy volunteers (QUILT 1004). In addition, ImmunityBio intends to file an EAP for ANKTIVA and PD-L1 t-haNK in combination with standard-of-care chemotherapy/radiotherapy and submit the protocol to the FDA.

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ImmunityBio Business, Strategy and Products

Our Business

ImmunityBio is a vertically-integrated commercial stage biotechnology company developing next-generation therapies that bolster the natural immune system to defeat cancers and infectious diseases. The company’s range of immunotherapy platforms, alone and together, act to drive an immune response with the goal of creating durable immune memory generating safe protection against disease. We are applying our science and platforms to treating cancers, including the development of potential cancer vaccines, as well as developing immunotherapies and cell therapies that we believe sharply reduce or eliminate the need for standard high-dose chemotherapy. These platforms and their associated product candidates are designed to be more effective, accessible, and easily administered than current standards of care in oncology and infectious diseases.

Our Strategy

We seek to become a leading global immunological therapeutics company by creating next-generation therapies to address serious unmet needs within urologic and other cancers as well as infectious diseases. To achieve this goal, the key elements of our strategy include:

•advancing the commercialization of ANKTIVA as an integral component of immunotherapy combinations, including those with CPIs and cell therapy;

•accelerating product candidates generated from our immunotherapy platforms with registrational intent to address difficult-to-treat oncological and infectious disease indications in large market segments;

•continuously refining our pipeline and investing in high-value discovery, development, and manufacturing capabilities for our next generation product candidates;

•continuing to prospect, license, and acquire technologies to complement and strengthen our platforms and product candidates, both as single agent and combination therapies, in order to optimize responses of the innate and adaptive immune systems to generate cellular memory against multiple tumor types and infectious diseases; and

•cultivating new and expanding existing collaborations for our multi-stage pipeline to reach global scale efficiently.

Our Approved Product – ANKTIVA

Our lead biologic product ANKTIVA is a novel first-in-class IL-15 receptor superagonist antibody-cytokine fusion protein. On April 22, 2024, the FDA approved our product, ANKTIVA with BCG for the treatment of adult patients with BCG-unresponsive NMIBC with CIS with or without papillary tumors (the “approved product”). ANKTIVA was approved with a label indicating an immunological mechanism of action which proliferates and activates NK, CD8+ and memory T cells without the proliferation of immunosuppressive T-reg cells leading to the establishment of memory T cells. We began commercial distribution of our approved product in May 2024.

We believe there is potential for ANKTIVA to become a therapeutic foundation across all phases of treatment, including in adjunctive therapy, to amplify, reactivate or extend the efficacy of standard of care.ANKTIVA is being clinically evaluated in multiple oncology indications. We believe that other oncology indications with registration potential for ANKTIVA include other types of NMIBC (BCG-unresponsive papillary, BCG-naïve CIS and BCG-naïve papillary), lung, colorectal, pancreatic, prostate and ovarian cancers, and GBM and NHL.

Data from multiple clinical trials suggest ANKTIVA has potential to enhance the activity of therapeutic mAbs, including CPIs (e.g., pembrolizumab/Keytruda), across a wide range of tumor types, including lung cancer. Further, ANKTIVA has been observed to increase lymphocyte count in healthy adults, making it a potential therapy to rescue lymphopenia. We believe that the FDA authorization of RMAT designation for ANKTIVA and PD-L1 t-haNK in combination with standard-of-care chemotherapy/radiotherapy indicated for the reversal of lymphopenia and treatment of multiply relapsed locally advanced or metastatic pancreatic cancer may lead to a potential paradigm change in cancer care. We are also exploring or pursuing several other studies of ANKTIVA in combination with our other product candidates, including in prostate cancer (ANKTIVA in combination with hAd5 PSA), colon cancer (ANKTIVA in combination with hAd5 TriAd), and NHL (ANKTIVA in combination with rituximab). We are also exploring ANKTIVA in infectious diseases, including HIV and long COVID.

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Key Catalysts for ANKTIVA

The following is a summary of selected significant developments affecting our business that occurred since the filing of our Quarterly Report dated September 30, 2024 with the SEC on November 12, 2024:

•ANKTIVA received a J-code (J9028) assigned by the CMS in the U.S. for ANKTIVA (Injection, nogapendekin alfa inbakicept-pmln, for intravesical use, 1 microgram), which became effective on January 1, 2025.

•With a permanent J-code awarded in January 2025, our February 2025 ANKTIVA unit sales volume grew 97% over unit sales volume in December 2024 and 67% over unit sales volume in January 2025.

•ANKTIVA is now widely accessible to patients through commercial and government insurance programs (VA, DoD, Medicare). To date, commercial and governmental insurance cover over 240 million lives for ANKTIVA.

•We completed the submission of MAAs for the treatment of patients with BCG-unresponsive NMIBC with CIS with or without papillary tumors for ANKTIVA in combination with BCG to the MHRA in the UK in November 2024 and to the EMA in the EU in December 2024. The MHRA validated and accepted the MAA for review in February 2025, while the EMA accepted the MAA for review in January 2025. We are in continued dialogue for requests for information from both the MHRA and EMA, with the potential for approval in the UK and EU by 2026.

•In collaboration with Serum Institute, and in connection with our exclusive global supply arrangement that we announced during 2024, in February 2025 the FDA authorized an EAP allowing us to provide rBCG developed by Serum Institute to urologists to address the TICE BCG shortage in all settings where TICE BCG is approved, and we are also testing rBCG in an FDA-approved clinical trial in the U.S. Serum Institute’s GMP capacity to manufacture large-scale volumes of rBCG, already tested for safety and efficacy in clinical trials in Europe in subjects with NMIBC, aims to address the shortage of TICE BCG, which we believe will help to ensure a reliable supply for patients in need. This initiative underscores our commitment to addressing critical supply issues and expanding the opportunity for patients and physicians to have access to high quality and quantities of BCG to initialize and maintain treatments for bladder cancer, subject to regulatory approvals. We expect to begin shipments of rBCG pursuant to the EAP during the first quarter of 2025.

•In January 2025, we announced a collaboration and supply agreement with BeiGene, Ltd. (to be renamed to BeOne Medicines, Ltd.), a global oncology company, to conduct a confirmatory randomized Phase 3 clinical trial (ResQ201A-NSCLC), combining BeOne’s tislelizumab, a PD-1 CPI, and our ANKTIVA (nogapendekin alfa inbakicept-pmln) product. The Phase 3 ResQ201A-NSCLC study aims to confirm the efficacy and safety of combination ANKTIVA plus CPI therapy previously demonstrated in the QUILT 3055 trial and provide evidence of the potential for these two immunotherapeutic agents to improve overall survival in patients with advanced or metastatic NSCLC who have acquired resistance to immune CPI therapy.

•On February 27, 2025, the FDA granted us RMAT designation for ANKTIVA and CAR-NK (PD-L1 t-haNK) in combination with standard-of-care chemotherapy/radiotherapy indicated for the reversal of lymphopenia and treatment of multiply relapsed locally advanced or metastatic pancreatic cancer. This RMAT designation follows clinical data of ALC and significant overall survival correlations in QUILT trials across multiple tumor types including third-line or greater metastatic pancreatic cancer, checkpoint relapsed NSCLC, and supportive data from healthy volunteers. The reversal of lymphopenia by our IL-15 receptor superagonist is consistent with the mechanism of action of ANKTIVA demonstrating proliferation and activation of NK cells, CD4+ T cells, CD8+ T cells, and memory T cells without upregulation of suppressive T-reg cells and approved in the ANKTIVA label (approved for the treatment of adult patients with BCG-unresponsive NMIBC with CIS with or without papillary tumors). We intend to submit a BLA for the indication of reversal of lymphopenia in patients receiving standard of care chemotherapy and/or radiation and for the treatment of locally advanced or metastatic pancreatic cancer which includes the first-in-class CAR-NK (PD-L1 t-haNK), and to provide data from fully enrolled clinical trials in metastatic pancreatic cancer (QUILT 88) and in checkpoint relapsed NSCLC (QUILT 3055, NSCLC Cohort) patients, as well as lymphopenia reversal across multiple tumor types (QUILT 3055, all Cohorts), with supportive data of lymphocyte proliferation in healthy volunteers (QUILT 1004). In addition, we intend to file an EAP for ANKTIVA and PD-L1 t-haNK in combination with standard of care chemotherapy/radiotherapy and to submit the protocol to the FDA.

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2025 Platforms and Indications

Our proprietary platforms for the development of biologic products and product candidates include:

Our Next-Generation Platforms

i. Cytokine Fusion Proteins

a.ANKTIVA

ii. DNA and Vaccine Vectors

a.hAd5 (PSA, Brachyury, CEA, MUC1, HPV [E6/E7], neoantigens, nucleocapsid)

iii. Cell Therapies

a.CD19 t-haNK

b.PD-L1 t-haNK

c.M-ceNK (autologous, allogeneic)

Indications (Current Prioritized Studies)

i. BCG-Unresponsive NMIBC with CIS (approved)

ii. BCG-Unresponsive NMIBC Papillary

iii. BCG-Naïve NMIBC with CIS

iv. rBCG in NMIBC

v. Non-Small Cell Lung Cancer

vi. Pancreatic Cancer

vii. Chemotherapy Radiation Lymphopenia

viii. Lynch Syndrome

ix. Hematological Malignancies (Liquid Tumors)

x. Colon Cancer

xi. Glioblastoma Multiforme

xii. Non-Hodgkin Lymphoma

xiii. Ovarian Cancer

xiv. Prostate Cancer

xv. HIV

xvi. Universal Nucleocapsid Vaccine

xvii. Long COVID

Our Pipeline

Our proprietary platforms for the development of biologic products and product candidates include: (i) cytokine fusion proteins, (ii) vaccine vectors, and (iii) cell therapies. As of December 2024, our platforms have generated nine first-in-human therapeutic agents (including one agent approved by the FDA) that are currently or planned to be studied in clinical trials in liquid and solid tumors. The indications in the table above are among the most frequent and lethal cancer types and where there are high failure rates for existing standards of care or no available effective treatment. We are constantly monitoring and prioritizing clinical development based upon the availability of our resources and the efficacy and market developments of our competitors’ products and product candidates, among other factors.

Our platforms and their associated approved product and product candidates are designed to attack cancer and infectious pathogens by activating both the innate immune system, including NK cells, dendritic cells, and macrophages, as well as the adaptive immune system comprising B and T cells, in an orchestrated manner. The goal of this potentially best-in-class approach is to generate immunogenic cell death thereby eliminating rogue cells from the body whether they are cancerous or virally-infected. Our ultimate goal is to overcome the limitations of current treatments, such as CPIs, by turning immunologically cold, MHC-deficient tumors into hot tumors, and/or reducing the need for standard high-dose chemotherapy in cancer by employing a coordinated approach to establish “immunological memory” that confers long-term benefit for the patient.

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Our Next-Generation Platforms

Cytokine Fusion Proteins

Cytokine fusion proteins, such as ANKTIVA, represent a novel class of biologics that improve immune responses by enhancing the therapeutic potential of cytokines and promoting lymphocyte infiltration at a site of disease. The cytokine interleukin-15 (IL-15) plays a crucial role in the immune system by affecting the development, maintenance, and function of key immune cells—NK and CD8+ killer T cells—that are involved in killing cancer cells. ANKTIVA is a first-in-class IL-15 receptor superagonist IgG1 fusion complex, consisting of an IL-15 mutant (IL-15N72D) fused with an IL-15Rα, which binds with high affinity to IL-15 receptors on NK, CD4+, and CD8+ T cells. This fusion complex of ANKTIVA, which confers stability and longer half-life than recombinant or native IL-15, mimics the natural biological properties of the membrane-bound IL-15Rα, delivering IL-15 by dendritic cells and drives the activation and proliferation of NK cells with the generation of memory killer T cells that have retained immune memory against these tumor clones. By activating NK cells, ANKTIVA overcomes the tumor escape phase of clones resistant to T cells without stimulating immunosuppressive T-reg cells and restores memory T cell activity with resultant prolonged duration of CR. Further, by stimulating the release of interferon-γ, ANKTIVA restores MHC-I expression, making more tumor cells targets for T-cell killing. As evidenced by its ability to increase lymphocyte counts in healthy adults in Phase 1 testing, ANKTIVA also has the potential to rescue lymphopenia, which is associated with poor prognosis in cancer before treatment or as a consequence of chemo- or radiation therapy.

ANKTIVA’s mechanisms-of-action make it an ideal ‘backbone’ for combination therapy with the company’s platforms, such as second-generation hAd5 vaccines, off-the-shelf CAR-engineered NK cells, and M-ceNK cells, as well as other therapeutics including BCG, targeted antibodies, and CPIs.

Leveraging our success with ANKTIVA, we are developing multi-functional cytokine fusion proteins targeting TGF-ß, PD-L1, CD16, CD20, and comprising IL-12, IL-15, and IL-21, amongst others, to further enhance NK and T cell activation directed to the TME or virally infected cells and to modulate the systemic and local immune response to accelerate immunogenic cell death.

DNA and Vaccine Vectors

We have developed and/or acquired rights to multiple vaccine delivery technologies for oncology to deliver common TAAs, and neoepitopes (expressed only by cancer cells) and for infectious diseases to target key viruses. These technologies can deliver DNA and protein subunits to induce B and T cell memory through activation of both CD4+ and CD8+ T cells along with antibody (humoral) responses.

Adenovirus is a well-established viral vector that can be utilized as a vaccine platform to stimulate the immune system, however there is risk for a treated person to develop adenovirus immunity. Our second generation hAd5 vector has unique deletions in the early 1, (E1), early 2 (E2b) and early 3 (E3) regions (hAd5 [E1-, E2b-, E3-]), which allows it to be effective in the presence of pre-existing adenovirus immunity and lowers the risk of generating de novo vector-directed immunity. We have developed several hAd5 product candidates that have been evaluated in multiple clinical trials as potential vaccines for and treatments of certain cancers and infectious diseases. Importantly, these product candidates have shown an ability to overcome previous adenovirus immunity in preclinical models and in cancer patients. In oncology, we are clinically evaluating hAd5 product candidates in combination with ANKTIVA to yield immunological immunity in colon cancer (hAd5 TAAs CEA, MUC1, Brachyury; collectively the TriAd) and prostate cancer (hAd5 PSA), and as a single agent in HPV-associated cancers (hAd5 TAA [E6/E7]).

Cell Therapies

We believe that we have one of the most comprehensive clinical-stage cell-based platforms in development. Our engineered NK cells have demonstrated the ability to induce cell death in cancers and virally-infected cells through a variety of concurrent mechanisms including innate killing, antibody-mediated killing, and CAR-directed killing.

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Off-The-Shelf Targeted High-Affinity NK Cells

NK cells are a type of cytotoxic lymphocyte critical to the innate immune system. NK cells show spontaneous cytolytic activity against cells under stress such as tumor cells and virally-infected cells. After activation, NK cells secrete several cytokines such as interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), granulocyte macrophage colony-stimulating factor (GM‐CSF), and chemokines that can modulate the function of other innate and adaptive immune cells. Our proprietary NK-92 cytotoxic cell line (also referred to as aNK) was established from a patient with clonal NK-cell lymphoma. aNK cells can be expanded in culture in the presence of cytokines (IL-2, IL-15). Our “off-the-shelf” aNK cell platform has been molecularly engineered in a variety of ways to boost its killing capabilities against cancers and virally-infected cells. Unlike normal NK cells, our aNK cells do not express the key inhibitory receptors that diseased cells often exploit to turn off the killing function of NK cells thereby escaping elimination. Further, we have genetically engineered our aNK cell platform to generate haNK cells engineered to express the high-affinity variant of the Fcγ receptor (FcγRIIIA/CD16a 158V) as well as endoplasmic reticulum-retained IL-2 that bind to antibodies with demonstrated enhanced ADCC-mediated antitumor activity (Jochems 2016). These antibody-targeted haNK cells are designed to directly bind to IgG1-type antibodies, such as avelumab, trastuzumab, cetuximab, and rituximab, with the intention of enhancing the cancer-killing efficacy of these antibodies by boosting the population of competent NK cells that can kill cancer cells through ADCC.

Our most advanced off-the-shelf NK cell platform, CAR-targeted t-haNK cells, enables innovative, bioengineered cell lines that incorporate all the features of our haNK platform together with a CAR, such as PD-L1. Product candidates under this platform have three modes of killing: innate, antibody-mediated, and CAR-directed killing. These product candidates also include one or more additional expression elements such as functional cytokines, chemokines, and trafficking factors. These product candidates are intended to be combined with commercially-available therapeutic antibodies to effectively target either two different epitopes of the same cancer-specific protein or two entirely different cancer-specific proteins. A number of t-haNK cell lines that express CARs have been developed.

Findings from a preclinical study performed in collaboration with the NCI demonstrated our PD-L1 t-haNK cells exert potent antitumor effects against MDSC and overcome T cell escape in multiple types of resistant tumors. The contribution of PD-L1 t‐haNK to antitumor efficacy is further evidenced by data reported at the ASCO meeting in June 2022 and updated at ASCO GI in January 2023 from the QUILT 88 trial of patients with advanced pancreatic cancer who were administered PD-L1 t-haNK, and ANKTIVA. The multi-modal therapy resulted in a median overall survival of 6.3 months (95% CI: 5.0, 7.2 months) in patients who had progressed after two prior lines of therapy, more than doubling the historical survival rate.

haNK cells engineered with CARs targeting CD19 have shown to be effective against in vitro/in vivo models of lymphoblastic leukemia and lymphoma (Boissel 2013, Muller 2008, Romanski 2016). The CD19 t-haNK cell line combines the engineered enhancements of haNK cells with the expression of a CAR targeting CD19 and thus has potential to demonstrate robust ADCC antitumor activity against cancerous B cells and provide clinical benefit to patients with R/R NHL.

Clinical trials to assess our t‐haNK product candidates have been initiated: PD-L1 t-haNK in a Phase 1 trial in TNBC and a Phase 2 trial in pancreatic cancer; and CD19 t-haNK in a Phase 1 trial in R/R B-Cell NHL. In addition, the FDA recently granted us RMAT designation for ANKTIVA and PD-L1 t-haNK in combination with standard-of-care chemotherapy/radiotherapy indicated for the reversal of lymphopenia and treatment of multiply relapsed locally advanced or metastatic pancreatic cancer.

Autologous and Allogeneic M-ceNK

NK persistence and function can be enhanced with cytokine stimulation. Our M-ceNK cells are generated from lymphocytes collected from donors that are then pre-activated ex-vivo by exposure to interleukins -12 (IL-12), -15 (N-803) and -18 (IL-18), which results in differentiation and acquisition of enhanced responses to cytokine re-stimulation. M-ceNK have increased antitumor characteristics, including enhanced IFN-γ production and cytotoxicity against leukemic cell lines. M-ceNK cells are further distinguished by their unique cell-surface marker profile and their highly desirable feature of immune-memory, marked by their pronounced anti-cancer activity for weeks to months in duration, which has made these cells a research focus for more than a decade.We have developed a unique ability to generate a portfolio of distinct M-ceNK cell products through the application of our proprietary technology and cytokines. Also, we can manufacture these cell products for clinical delivery using our proprietary methods and overall expertise in scale manufacturing of NK cell-based products. A Phase 1 first-in-human trial is open and actively enrolling patients to study the M-ceNK platform in solid tumors (QUILT 3076). In addition, M-ceNK is being evaluated in combination with ANKTIVA and gemcitabine in patients with recurrent platinum-resistant high-grade ovarian cancer (ResQ209) and in combination with ANKTIVA and hAd5-PSA in high-risk prostate cancer (ResQ110A-B).

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Indications (Current Prioritized Studies)

Bladder Cancer

In the U.S., bladder cancer was the sixth most commonly-diagnosed cancer and the fourth most commonly-diagnosed solid malignancy in men in 2024. The American Cancer Society estimates there will be 84,870 new cases and 17,420 deaths from bladder cancer in 2025. NMIBC represents approximately 75% of all bladder cancers. Radical cystectomy is a treatment to control the disease for unresponsive NMIBC; however, the procedure introduces compromise to the quality of life and additional costs. There is an urgent, unmet need to treat NMIBC and avoid radical cystectomy of the bladder in an attempt to control the disease.

ANKTIVA received Breakthrough Therapy and Fast Track designations from the FDA for the treatment of BCG-unresponsive NMIBC with CIS (Cohort A) with or without papillary tumors for which we received approval from the FDA in April 2024. ANKTIVA also received Fast Track designation for BCG-unresponsive NMIBC papillary and BCG-naïve NMIBC with CIS. The receipt of such designations may not lead to a faster development process or regulatory review and may not increase the likelihood that our product candidates will receive marketing approval.

In our QUILT 3032 trial, as we reported in November 2022 in NEJM Evidence, the primary end points were met for both BCG-unresponsive NMIBC with CIS with a CR rate of 71%, and BCG-unresponsive NMIBC papillary with a 12-month disease-free rate of 55%. As presented at ASCO 2022, the combination of BCG plus ANKTIVA (as measured in BCG-unresponsive NMIBC patients, Cohorts A and B combined) was well-tolerated with 1% treatment-related serious adverse events, 0% immune-related serious adverse events, and 100% bladder cancer-specific overall survival at 24 months. Low-grade treatment-related adverse events include dysuria (22%), pollakiuria (20%), hematuria (17%), fatigue (16%), and urgency (12%), and all other treatment-related adverse events were seen at 7% or less. Seminal patents covering intravesical administration of BCG and ANKTIVA were issued providing term coverage until 2035.

BCG-Unresponsive NMIBC with CIS (Cohort A) – QUILT 3032

In our Phase 2/3 open-label multi-center trial of BCG-unresponsive high-grade NMIBC patients with CIS, the patients receive BCG plus ANKTIVA weekly for six consecutive weeks during induction. The patients also receive additional treatment including three weekly maintenance instillations every three months for up to 12 months and then at month 18. Patients with no disease or low-grade Ta disease at months 24, 30, and 36 are eligible for continued BCG plus ANKTIVA (Cohort A) or ANKTIVA alone (Cohort C) treatment (3 weekly instillations), at the principal investigators’ discretion.

The primary endpoint of the BCG-unresponsive NMIBC with CIS trial is a CR rate at any time equal to or greater than 30% and the lower bound of the 95% CI must be greater than or equal to 20% for success. CR, or the disappearance of measurable disease in response to treatment, is evaluated at three months or six months following initial administration of BCG plus ANKTIVA (and every three months thereafter until 24 months). This endpoint would be achieved once at least 24 of the 80 patients in the trial achieve a CR.

A data cut-off occurred in January 2022, which provided a median follow-up in Cohort A of approximately 24 months. Data published in NEJM Evidence in November 2022 showed a CR in 58 of 82 patients with a 71% CR rate (95% CI: 59.6, 80.3) and a median duration of CR of 26.6 months (95% CI: 9.9, [upper bound not reached]). At 24 months in patients with a CR, the probability of avoiding cystectomy and disease-specific survival was 91.4% and 100%, respectively. Also, at 24 months in all patients in Cohort A, the probability of avoiding cystectomy and of disease-specific survival was 84.1% and 100%, respectively. In December 2024, we provided an update on the full enrollment of 100 patients with BCG-unresponsive NMIBC with CIS as of November 2024 that have been treated with ANKTIVA in combination with BCG, with a 71% CR rate. In these responders, the range of durable response extended to 54 months. This data was submitted to the EMA in an MAA for ANKTIVA in the EU in December 2024.

As part of planned analyses, BCG-unresponsive patients in the QUILT 3032 trial of ANKTIVA plus BCG completed PRO questionnaires, which revealed stability of both mean physical function and global health from baseline to 24 months on-study for those participants who had reached the 24-month assessment. Further, at month 6, Cohort A (CIS disease) patients that achieved a CR reported higher physical function scores than those without a CR (P=0.0659). Summary scores for the NMIBC-specific questionnaire also remained stable. These PROs, taken together with efficacy findings from both the NEJM Evidence report and subsequent follow-up, suggest a favorable risk-benefit ratio for the novel therapeutic combination.

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In May 2022, we submitted a BLA to the FDA for our product candidate, ANKTIVA in combination with BCG for the treatment of adult patients with BCG-unresponsive NMIBC with CIS with or without papillary tumors.In May 2023, we received a CRL from the FDA, indicating that the FDA had determined it could not approve the original BLA submission in its initial form, citing deficiencies related to the FDA’s pre-license inspection of our third-party CMOs, among other items and made recommendations to address the issues raised.

The CRL that we received in response to our initial BLA submission required us to resubmit the BLA to the FDA addressing the issues in the CRL. On April 22, 2024, the FDA approved our product, ANKTIVA with BCG for the treatment of adult patients with BCG-unresponsive NMIBC with CIS with or without papillary tumors. We are required to comply with certain post-marketing commitments, including completion of our QUILT 3032 clinical trial and annual reporting for up to four years, with a final report submission to the FDA by the end of 2029. We began commercial distribution of our approved product in May 2024.

BCG-Unresponsive NMIBC Papillary (Cohort B) – QUILT 3032

In our Phase 2, open-label multi-center trial of BCG-unresponsive high-grade NMIBC papillary patients (Cohort B), the patients are receiving BCG plus ANKTIVA weekly for six consecutive weeks during induction. The patients also receive additional treatment including three weekly maintenance instillations every three months for up to 12 months and then every nine months for up to 24 months. The primary endpoint of the trial is a 12-month disease free rate greater than or equal to 30% and the lower bound of the 95% CI must be greater than or equal to 20% for success. To meet the primary endpoint, 24 out of 80 patients must be disease free at 12 months.

A data cut-off occurred in January 2022, which provided a median follow-up in Cohort B of approximately 21 months. Data published in NEJM Evidence in November 2022 showed a 12-month disease-free survival rate of 55% (95% CI: 42.0, 66.8), with median disease-free survival of 19.3 months (95% CI: 7.4, [upper bound not reached]). At the cutoff date 67 of 72 patients, 93.1%, had not progressed to radical cystectomy and the 24-month disease-free survival rate was 97.7%.

We are preparing to submit an sBLA in 2025 for our innovative treatment targeting BCG-unresponsive NMIBC in the papillary indication. This immunotherapy of rescuing BCG with ANKTIVA represents a step towards providing therapeutic options in patients with BCG unresponsive NMIBC in papillary disease who currently have limited treatment choices and face radical total cystectomy (removal of bladder). The addition of the BCG-unresponsive NMIBC papillary indication could expand the potential patient population benefiting from this therapy and may allow patients to avoid the high morbidity and mortality associated with radical total cystectomy.

BCG-Naïve NMIBC with CIS – QUILT 2005

As discussed above, ANKTIVA received Fast Track designation from the FDA for the treatment of BCG-naïve NMIBC with CIS. We are currently enrolling patients in our Phase 2b blinded, randomized, two-cohort, open-label, multi-center trial of intravesical BCG plus ANKTIVA vs. BCG alone, in BCG-naïve patients with high-grade NMIBC with CIS (Cohort A) and NMIBC papillary (Cohort B). Planned enrollment for Cohort A (CIS) and Cohort B (papillary) is 366 patients and 230 patients, respectively. As part of our BLA resubmission for ANKTIVA in combination with BCG for the treatment of adult patients with BCG-unresponsive NMIBC with CIS with or without papillary tumors, we provided an update on the long-term follow-up of BCG-naïve patients in QUILT 2005 receiving ANKTIVA plus BCG for CIS± Ta/T1 in the Phase 1b trial, examining the survival of the 9 subjects who entered the trial since 2014. As initially reported in 2021, all 9 patients (100%) achieved a CR, and in an 8-year follow up, the 6 evaluable patients remain disease-free (two were deceased from causes other than bladder cancer and one was lost to follow-up) with bladder preservation over a median survival period of 8.8 years.

As part of our Breakthrough Therapy designation submission for BCG-unresponsive NMIBC with CIS with or without papillary tumors described above, the FDA requested an interim analysis of 43 patients in our QUILT 2005 trial which showed an 84% CR rate at nine months in patients receiving ANKTIVA plus BCG. We continue to enroll patients and expect full enrollment in late 2025 to early 2026 with a data readout from the pivotal clinical trial in the second half of 2026. We are targeting a BLA submission to the FDA in late 2026 to early 2027.

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NMIBC – Recombinant BCG as Alternative Source of BCG

In May 2024, we announced an exclusive global arrangement with Serum Institute, the world’s largest manufacturer of vaccines by number of doses produced, to supply ImmunityBio with rBCG for use exclusively in combination with ANKTIVA, subject to regulatory approvals. We are responsible, in part, for regulatory submissions, clinical trials and commercialization efforts, and our exclusive rights under the arrangement extend to the scope of the FDA’s approval obtained by us for Serum Institute’s rBCG product in the U.S. Serum Institute’s GMP capacity to manufacture large-scale volumes of rBCG, already tested for safety and efficacy in clinical trials in Europe in subjects with NMIBC, aims to address the shortage of TICE BCG, which we believe will help to ensure a reliable supply for patients in need. In February 2025, the FDA authorized an EAP allowing us to provide rBCG developed by Serum Institute to urologists to address the TICE BCG shortage in all settings where the TICE BCG label is approved, and shipments of rBCG pursuant to the EAP are expected to begin during the first quarter of 2025. In addition, we are testing rBCG in an FDA-approved clinical trial (ResQ133A) of intravesical rBCG in participants with NMIBC eligible to receive TICE BCG. This initiative underscores our commitment to addressing critical supply issues and expanding the opportunity for patients and physicians to have access to high quality and quantities of BCG to initialize and maintain treatments for bladder cancer, subject to regulatory approvals.

Lung Cancer

According to the American Cancer Society, lung cancer is the second most common cancer in the U.S. In 2025, it is estimated that 226,650 new cases of lung cancer will be diagnosed in the U.S. and 124,730 deaths will be attributed to the disease. NSCLC accounts for about 87% of all lung cancer diagnoses and there are very few successful treatment options for these patients once the cancer spreads beyond the lungs.

The development of CPIs in NSCLC has been revolutionary, doubling the median overall survival in some settings; however, patient response may be short lived, due to late response and/or disease progression after achieving an initial response. As with bladder cancer, ANKTIVA enhances the proliferation and activation of NK and T cells critical for targeting and killing lung cancer cells. There is therefore a strong rationale to evaluate ANKTIVA in addition to a PD-1 or PD-L1 CPI for patients with NSCLC who have relapsed after achieving an initial response to PD-1 or PD-L1 CPI therapy.

Analysis of pooled data from a Phase 1/2 trial conducted from January 2016 to June 2017 in 23 patients and a subsequent investigator-initiated Phase 2 trial conducted by the Medical University of South Carolina, yielded confirmation of activity of the combination of CPIs and ANKTIVA in relapsed NSCLC relative to historical response rates. In 15 patients with PD-L1 greater than 50%, the overall response rate was 38% and the median overall survival rate was 17.1 months. These preliminary findings were favorable relative to the historical response rates seen in this patient population in the first-line setting with CPI therapy.

Non-Small Cell Lung Cancer – QUILT 3055

On the basis of these findings discussed above, we initiated a single-arm Phase 2b multi-cohort basket trial of ANKTIVA and CPI combinations in patients who have previously received treatment with PD-1/PD-L1 immune CPIs per an FDA-approved indication. Patients enrolled in this trial were eligible if actively progressing on CPI therapy. Upon enrollment, patients continued on the same CPI but with the addition of ANKTIVA. Despite progressing on CPI therapy upon entry into the trial, the majority of patients reverted to stable disease and demonstrated durability of stable disease, some extending as long as nine months. Data presented at the ASCO Annual Meeting in 2021 showed that despite the patients’ prior progression on CPI therapy alone, upon entry into the trial the majority of patients experienced clinical benefit either as stable disease (49%) or a partial response (9%).

Among 140 patients enrolled in QUILT 3055, the common ANKTIVA attributed grade 1 and 2 adverse events included: injection-site reaction (71%), chills (34%), fatigue (27%), pyrexia (24%), flu-like illness (13%), and decreased appetite (10%). A total of 18 grade 3 and 4 adverse events attributed to ANKTIVA have been reported among 16 patients (12%) in the trial as of February 2021. All reported grade 3 and 4 adverse events occurred at a frequency of 5% or less; two patients reported increased alanine amino transferase, increased aspartate amino transferase or increased blood alkaline phosphatase, anemia, injection-site reaction, or injection-site pain. All other occurrences of grade 3 or 4 adverse events that the clinical trial site investigators reported as suspected as being due to ANKTIVA include: decreased lymphocyte count; weight loss; influenza-like illness; injection-site pruritus; cellulitis; injection-site cellulitis; sepsis; deep vein thrombosis; hypovolemic shock; colitis; diarrhea; delirium; respiratory failure; and maculopapular rash. Based on this relatively well-tolerated adverse event profile, coupled with NK and CD8+ T cell stimulatory effects, we believe that ANKTIVA has the potential to become a standard in combination with other immunotherapies for multiple indications.

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In September 2024, Dr. John Wrangle gave an oral presentation of the updated QUILT 3055 NSCLC pooled data at the World Conference on Lung Cancer, with data through February 2024 from several cohorts of NSCLC patients who have progressed after CPI therapy. These cohorts are:

•Cohort 1a – NSCLC patients with initial response on single-agent CPI therapy and subsequently progressed on or after that therapy.

•Cohort 2 – NSCLC patients having high PD-L1 expression (tumor proportion score ≥50%) and disease progression on a PD-1/PD-L1 CPI after experiencing an initial response when received CPI as a single-agent for first-line treatment.

•Cohort 3 – NSCLC patients with initial response but subsequently relapsed on maintenance PD-1/PD-L1 CPI therapy when initially received CPI therapy in combination with chemotherapy as first-line treatment.

•Cohort 4 – NSCLC patients currently receiving PD-1/PD-L1 CPI therapy that progressed after experiencing stable disease for at least 6 months during previous treatment with PD-1/PD-L1 CPI therapy.

These results showed a median overall survival of 14.1 months in the 86 patients in the pooled analysis. This is in contrast to the overall survival of 6.1 months (Freeman et al. 2020) for patients who received any therapy post-CPI therapy progression or an overall survival of 7.5 months (Brueckl et al. 2021) for patients who received docetaxel plus ramucirumab after initial failure of first-line chemotherapy plus a CPI.

The Phase 2b study demonstrated prolonged overall survival when ANKTIVA was combined with the same CPIs on which patients were progressing, validating the rescue potential of ANKTIVA for T cells and CPIs. The combination of ANKTIVA plus a CPI represents an immunotherapeutic advance for this disease, when compared to the most frequently used chemotherapy docetaxel in this setting, which has an overall survival ranging from 7 to 10 months and which is associated with high toxicities as a chemotherapeutic agent.

Overall survival in checkpoint relapsed patients ranged up to 58 months. The long duration of survival is potentially a result of ANKTIVA’s mechanism of action to stimulate and proliferate memory T cells and overcome immune exhaustion or immune escape mediated by MHC-loss in checkpoint relapse via stimulation of NK cells. We plan to submit a BLA in 2025 for second-line and third-line treatment of patients with NSCLC, who are progressing on CPIs.

Non-Small Cell Lung Cancer – ResQ201A

Following a meeting with the FDA, we launched a pivotal, randomized, open-label Phase 3 clinical trial of ANKTIVA plus tislelizumab (anti-PD-1) and docetaxel vs. docetaxel monotherapy in participants with advanced or metastatic NSCLC who have acquired resistance to immune CPI therapy.A total of 462 patients will be enrolled 1:2 either in a control arm or an experimental arm.

•Control arm:Docetaxel (standard of care) N=154. Repeated 3-week cycles with docetaxel.

•Experimental arm: ANKTIVA, tislelizumab, N=308. Two 3-week cycles of ANKTIVA, tislelizumab plus docetaxel followed by repeated 3-week cycles of ANKTIVA and tislelizumab (no docetaxel).

Participant randomization to either the control or experimental arm will be stratified by geographical region (North America vs. Europe vs. Asia), NSCLC histology (squamous vs. nonsquamous), and actionable genomic alterations.

The primary outcome is the comparison of overall survival between the experimental and the control arms. We expect full enrollment in early 2026 and a data readout in the second half of 2027.

Colorectal Cancer

According to the American Cancer Society, colorectal cancer is the third-leading cause of cancer-related deaths in the U.S. in men and the fourth-leading cause in women, but it is the second most common cause of cancer deaths when numbers for men and women are combined. Colorectal cancer is expected to cause about 52,900 deaths during 2025.

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Lynch Syndrome – QUILT 5015 (NCI)

Lynch Syndrome is the most common cause of hereditary colorectal cancer. People with this syndrome harbor mutations in mismatch repair genes that put them at high risk of developing colorectal cancer. Lynch Syndrome causes about 4,300 colorectal cancers per year. These cancers are more likely to develop at earlier ages, often before the age of 50. If someone has Lynch Syndrome, it means that their close relatives (parents, siblings, and children) have a 50% chance of having the mutation that causes it too.

A Phase 2 trial sponsored by the NCI evaluates the ability of ANKTIVA in combination with our TriAd5–a combination of three vaccines targeting TAAs CEA, MUC1, and Brachyury– to reduce the incidence of cancer onset in people with Lynch Syndrome. The trial recently reached full accrual of participants in the first two open-label phases. The randomized controlled portion of the trial is now recruiting with plans to enroll up to 138 participants.

Pancreatic Cancer

According to the American Cancer Society, pancreatic cancer is the third-leading cause of cancer-related deaths in the U.S. in men and the fourth-leading cause in women, and is also the third most common cause of cancer deaths when numbers for men and women are combined. Pancreatic cancer is expected to cause about 52,000 deaths during 2025, with a five-year survival rate for late-stage cases of only 3%.

Advanced Pancreatic Cancer – QUILT 88

Exploratory Phase 1b/2 trials in patients with second-line or greater metastatic pancreatic cancer in which ANKTIVA was combined with off-the-shelf haNK cells, other agents, and SBRT showed encouraging results in patients with advanced disease. The primary endpoints of the Phase 1b and 2 portions of the trials were safety and objective response rate, respectively. In aggregate, 82% of patients (14/17) with advanced pancreatic cancer achieved disease control following combination therapy including ANKTIVA. There were no ANKTIVA-related grade 3 or 4 adverse events reported.

On the basis of these exploratory trials, together with the preclinical findings that PD-L1 t-haNK is as active as haNK + anti-PD-L1 mAbs, we initiated a first-line through third-line pancreatic cancer clinical trial that uses PD-L1 t-haNK as described below:

•First-line advanced pancreatic cancer (Cohort A). Combination of ANKTIVA with low-dose chemotherapy plus SBRT with or without PD-L1 t-haNK vs. gemcitabine/Abraxane® as the standard-of-care control arm in this randomized trial.

•Second-line advanced pancreatic cancer (Cohort B). Combination of ANKTIVA with low-dose chemotherapy plus SBRT + PD-L1 t-haNK vs. 5FU/Onivyde® as the standard-of-care control arm in this randomized trial.

•Third-line and beyond (Cohort C). Combination of ANKTIVA with low-dose chemotherapy plus SBRT + PD-L1 t-haNK in a single arm cohort of this trial with a primary endpoint of overall survival.

In October 2021, we announced that the trial’s Cohort C was fully enrolled. Based on the strength of earlier data and the significant unmet medical need, we submitted an amendment to the FDA to increase enrollment in Cohort C. As of January 2023, as reported at ASCO GI, the median overall survival in this highly advanced group of patients (who failed two to six prior lines of treatment) was 5.8 months (95% CI: 4.9, 6.4 months) exceeding the approximately two- to three-month historical median overall survival. Of the 83 patients, 41 (49.4%) had progressed after two prior lines of therapy. Median overall survival in this group was 6.3 months (95% CI: 5.0, 7.2 months), more than doubling the historical overall survival (survival of three months as reported by Manax et al. ASCO GI 2019). In Cohort C, grade 3 or greater treatment-related adverse events included anemia (32%), neutropenia (25%), thrombocytopenia (13%) and fatigue (7%) while all other grade 3 or greater treatment-related adverse events occurred at a frequency of less than 5%.

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On February 27, 2025, the FDA granted us RMAT designation for ANKTIVA and CAR-NK (PD-L1 t-haNK) in combination with standard-of-care chemotherapy/radiotherapy indicated for the reversal of lymphopenia and treatment of multiply relapsed locally advanced or metastatic pancreatic cancer. We intend to submit a BLA for the indication of reversal of lymphopenia in patients receiving standard-of-care chemotherapy and/or radiation and for the treatment of locally advanced or metastatic pancreatic cancer which includes the first-in-class CAR-NK (PD-L1 t-haNK), and to provide data from fully enrolled clinical trials in metastatic pancreatic cancer (QUILT 88) and in checkpoint relapsed NSCLC (QUILT 3055, NSCLC Cohort) patients, as well as lymphopenia reversal across multiple tumor types (QUILT 3055, all Cohorts), with supportive data of lymphocyte proliferation in healthy volunteers (QUILT 1004). There can be no assurance that we will be successful in targeting the indication.

Prostate Cancer

According to the American Cancer Society, one in eight men will be diagnosed with prostate cancer with an estimated 313,780 new diagnoses in 2025. Prostate cancer is the second leading cause of cancer death in men with 35,770 deaths expected in 2025.

hAd5 PSA has been evaluated in combination with related recombinant hAd5-based cancer vaccines (hAd5 Brachyury and hAd5 MUC1) in a Phase 1 study in participants with mCRPC who had not responded to standard therapies (Bilusic 2021). A total of 18 patients with mCRPC were enrolled and received at least one vaccination. A total of 62 vaccinations were given. The vaccine regimen was found to be well tolerable and safe with no DLTs. The most common adverse events were grade 1 or grade 2 and included injection-site reaction (94.4% of participants), flu-like symptoms (58.8%), and fatigue (38.9%). Treatment-related toxicities were uncommon and included grade 3 decreased lymphocyte count (n=2), grade 2 injection-site reaction (n=7), and grade 2 decreased lymphocyte count (n=1). The recommended Phase 2 dose was determined to be 5×1011 viral particles per dose. Grade 3 significant adverse events included anemia, dehydration, hypotension, and lung infection. No significant adverse events were related to study treatment.

We believe the combination of ANKTIVA, hAd5 PSA, M-ceNK cells, and standard-of-care in prostate cancer offers a unique opportunity to overcome resistance mediated by more than one mechanism, specifically, T cell exhaustion and human leukocyte antigen modulation. The overall goals of the treatment regimen are to maximize immune cell death and augment and maintain the innate and adaptive immune responses against cancer cells.

High-Risk Prostate Cancer – ResQ110A

We have initiated a clinical trial to evaluate a new immunotherapy combination of ANKTIVA, hAd5 PSA, and M-ceNK in men with high-risk prostate cancer who have not had prostatectomy. Participants will receive immunotherapy pre- and post-surgery. This open-label study will enroll 20 patients and assess primary endpoints of event-free survival and biochemical recurrence-free survival post-surgery immunotherapy.

High-Risk Prostate Cancer – ResQ110B

We have also initiated a clinical trial to evaluate the immunotherapy combination of ANKTIVA, hAd5 PSA, and M-ceNK in men with high-risk prostate cancer who are ineligible for prostate surgery and receiving external beam radiation therapy. This open-label study will enroll 20 patients and deliver the combination regimen prior to and after radiation therapy. Primary outcomes are complete pathologic response after pre-radiation immunotherapy and prostate-specific antigen levels following post-radiation immunotherapy.

Glioblastoma Multiforme

According to the American Association of Neurological Surgeons, GBM is the most common malignant brain tumor accounting for approximately 48% of all primary brain tumors. GBM has a low survival rate of approximately 40% in the first year after diagnosis and only 17% in the second year. In a preclinical study, we evaluated the activity of ANKTIVA alone and in combination with an anti-PD-1 antibody or stereotactic radiosurgery in a murine GL261-luc GBM model and demonstrated that ANKTIVA as a monotherapy or combination therapy with an anti-PD-1 antibody exhibits a robust antitumor immune response resulting in prolonged survival including complete remission in tumor bearing mice. In addition, treatment with ANKTIVA resulted in long-term immune memory against GBM tumor rechallenge.

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Recurrent or Progressive GBM – QUILT 3078

A multi-center, open-label Phase 2/3 trial has been initiated to evaluate the safety and efficacy of combination therapy with ANKTIVA, PD-L1 t-haNK, and bevacizumab in patients with recurrent or progressive GBM. In Phase 2, safety of the combination will be assessed prior to Phase 3 wherein participants will be randomized to either combination therapy or bevacizumab monotherapy as the current standard of care.

•Pilot (Part A). Enrollment will be initiated with a single-arm study of 10 patients to receive ANKTIVA, PD-L1 t-haNK, and bevacizumab combination therapy. Continued development of the experimental arm in Part B will be based on the overall risk/benefit of the combined treatment regimen observed in Part A.

•Randomized Comparison of Combination Therapy vs. Bevacizumab Monotherapy (Part B). Part B will enroll patients to be randomly assigned (1:1) to the experimental arm or to the control arm.

The trial has enrolled patients with plans to enroll up to 20 patients.

Non-Hodgkin Lymphoma

The American Cancer Society estimates that 80,350 people will be diagnosed with NHL and 19,390 deaths will be attributed to the disease in 2025. A Phase 1 trial evaluating ANKTIVA in combination with rituximab, an anti-CD20 mAb therapy, in patients with iNHL, who had relapsed or were refractory after two lines of therapy, was published in Clinical Cancer Research in 2021. The combination regimen of ANKTIVA with rituximab was well tolerated with a single reported grade 4 adverse event and no reported grade 5 adverse events. For patients with anti-CD20 mAb sensitive disease, the overall response rate in the SQ cohort was 78% (7 of 9) with 7 of 7 (100%) responses as complete remission.

NHL types can start in B cells or T cells with B cell lymphomas being more common. Most B cell malignancies express high levels of CD19, including the majority of NHLs, such as diffuse large B cell lymphoma, follicular lymphoma, and mantle cell lymphoma. In addition, many leukemias express high levels of CD19, including B cell precursor acute lymphoblastic leukemia, chronic lymphocytic leukemia, and hairy cell leukemia. As such, two CD19-directed CAR-T cell therapeutics are FDA-approved for use in a variety of indications including NHL and ALL. Like T cells, NK cells can be genetically modified to express CARs that recognize tumor-associated cell-surface antigens and mediate specific recognition and lysis of cancer cells. The CD19 t-haNK cell line combines the engineered enhancements of haNK cells with the expression of a CAR targeting CD19 and thus has the potential to demonstrate robust antibody-dependent cellular cytotoxicity antitumor activity against cancerous B cells and provide clinical benefit to patients with relapsed/refractory NHL.

Relapsed/Refractory Non-Hodgkin Lymphoma – QUILT 3092

We have initiated an open-label, Phase 1, first-in-human trial to evaluate the safety of CD19 t-haNK as a single agent and the safety and preliminary efficacy of CD19 t-haNK in combination with rituximab only and in combination with rituximab and ANKTIVA in subjects with relapsed/refractory NHL.

Ovarian Cancer

The American Cancer Society estimates that 20,890 women will be diagnosed with ovarian cancer and 12,730 deaths will be attributed to the disease in 2025. A woman’s risk of getting ovarian cancer in her lifetime is about 1 in 91 and her chance of dying from ovarian cancer is about 1 in 143.

Platinum-Resistant Ovarian Cancer – ResQ209

Platinum-based chemotherapy is the standard-of-care for ovarian cancer; however, 20-30% of patients have cancer recurrence following treatment and are considered platinum-resistant. An open-label Phase 2 trial of ANKTIVA plus M-ceNK in patients with platinum-resistant ovarian cancer has been initiated. In this trial, patients with platinum-resistant high-grade ovarian cancer will receive M-ceNK adoptive cell therapy in combination with ANKTIVA and gemcitabine. Participants will undergo mononuclear cell collection for M-ceNK generation, day 8 induction and every 28-day (if M-ceNK are available) maintenance dosing, along with ANKTIVA. Estimated enrollment is 20 participants. Primary endpoints are progression-free survival using RECIST 1.1 criteria, overall survival, overall response rate, duration of response, disease control rate, and CA-125 levels. Safety endpoints are adverse events, treatment-emergent adverse events and significant adverse events, graded using NCI Common Terminology Criteria for Adverse Events Version 5.0.

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Other Oncology Indications

In addition to the indications above, findings from completed QUILT studies, including the achievement of complete remissions in late-stage and advanced tumors of many types, such as MCC, TNBC, pancreatic cancer and head & neck cancer, validate the concept of eliciting immunogenic cell death rather than the tolerogenic cell death induced by current standards of care.

In addition to the trials listed above, we are exploring or pursuing several other company-sponsored and investigator-initiated studies of our product candidates including in colon cancer (hAd5 CEA, ANKTIVA), prostate cancer (ANKTIVA, hAd5 PSA), head and neck cancer (ANKTIVA, hAd5 CEA, hAd5 MUC1, hAd5 Brachyury), among others.

Infectious Disease Indications

In addition to the trials listed above in oncology, our approved product and other product candidates are being evaluated in several other company-sponsored and investigator-initiated studies in infectious diseases.

HIV

HIV affects tens of millions of people globally and while ART has increased the survival of infected HIV individuals, there is currently no cure. One strategy for curing HIV is known as the “kick and kill” approach. The “kick” is to induce HIV out of its latent resting state in T cells, revealing infected cells to the immune system, and the “kill” is to eliminate the infected cells via an immune response or immunotherapy. ANKTIVA is a promising molecule to elicit “kick and kill” because of its ability to activate viral transcription in CD4+ T cells (“kick”) while strongly activating CD8+ effector memory cells and NK cells important for recognizing and killing HIV infected cells (“kill”), as well as directing these cells to sites of viral reservoirs. ANKTIVA is being evaluated in investigator-initiated trials as a single agent and in combination with broadly neutralizing antibodies to control HIV in persons living with HIV and persons with acute HIV infection.

Active HIV Infection – University of Minnesota, National Institute of Allergy and Infectious Diseases

Based on the hypothesis that CD8+ T cells will migrate to B cell follicles and reduce the frequency of cells with an inducible HIV provirus in HIV-infected individuals treated with ANKTIVA, a Phase 1 proof-of-concept non-randomized, open-label dose-escalation clinical trial sponsored by the University of Minnesota in collaboration with the NIAID was conducted. The primary assessment is the safety of ANKTIVA in ART-suppressed people living with HIV, along with exploratory analysis of effects on the HIV reservoir. In a 2022 report, no significant laboratory adverse events attributable to ANKTIVA were recorded, and ANKTIVA was associated with proliferation and/or activation of CD4+ and CD8+ T cells and NK cells, with a small but significant decrease in the frequency of peripheral blood mononuclear cells with an inducible HIV provirus.

A separate small HIV Cure Phase 1 trial evaluating ANKTIVA in combination with haploidentical NK cells in HIV-infected patients was completed in 2023. Reported data from the study validate the hypothesis that ANKTIVA combined with NK cells has the potential to reduce viral load in people living with HIV, showing a marked decrease in HIV-producing cells in lymph nodes. The trial is complete, and results were published in May 2024. The approach was well tolerated with no unexpected adverse events. A follow-on trial is being planned to further investigate the above regimen in additional patients.

Active HIV Infection – National Institute of Allergy and Infectious Diseases, Rockefeller University

In June 2021, we announced the opening of a Phase 1 clinical trial sponsored by the AIDS Clinical Trials Group and the NIAID (the HIV Cure Study) that will evaluate whether ANKTIVA alone or together with bNAbs can control HIV following interruption of ART. The Phase 1 open-label, randomized trial will enroll 46 people living with HIV whose virus has been suppressed by ART for approximately two years, including at least 30% cisgender women or transgender men. This trial is actively enrolling as of January 2025.

An additional and companion Phase 1 trial utilizing ANKTIVA and 2 different bNAbs sponsored by The Rockefeller University opened in December 2022. This trial completed enrollment as of January 2025.

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