UNITED

STATES

SECURITIES

AND EXCHANGE COMMISSION

Washington,

D.C. 20549

Form

10-K

(Mark

One)

For

the fiscal year ended July 31, 2022

For

the Transition Period from [●] to [●]

Commission

File Number: 001-40101

BRIACELL THERAPEUTICS CORP.

(Exact

name of registrant as specified in its charter)

(Address of principal executive offices) (Zip Code)

(604)921-1810

(Registrant’s telephone number, including area code)

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

Title of each class Name of each exchange on which registered

Common Shares, no par value The NASDAQ Capital Market

Warrants to purchase common shares, no par value The NASDAQ Capital 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. Yes ☐ 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 ☐ No ☒

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. Yes ☒ No ☐

Indicate

by check mark whether the registrant has submitted electronically and posted on its corporate Web site, if any, every Interactive Data

File required to be submitted and posted 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 and post such files). Yes ☒ No ☐

Indicate

by check mark if disclosure of delinquent filers pursuant to Item 405 of Regulation S-K (§229.405 of this chapter) is not contained

herein, and will not be contained, to the best of registrant’s knowledge, in definitive proxy or information statements incorporated

by reference in Part III of this Form 10-K or any amendment to this Form 10-K. ☒

Indicate

by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, or a smaller reporting

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.

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. ☐

Indicate

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

The

aggregate market value of the voting and non-voting common equity held by non-affiliates based on a closing sale price of $6.32 per share,

which was the last sale price of the common shares as of January 31, 2022, the last business day of the registrant’s most recently

completed second fiscal quarter, was $88,633,205.

of October 27, 2022, 15,518,018 shares of the registrant’s common shares, no par value per share, were issued and outstanding.

TABLE

OF CONTENTS

Page

PART I

Item 1 Business 5

Item 1A Risk Factors 40

Item 1B Unresolved Staff Comments 58

Item 2 Properties 58

Item 3 Legal Proceedings 58

Item 4 Mine Safety Disclosures 58

PART II

Item 6 [Reserved] 59

Item 7A Quantitative and Qualitative Disclosures About Market Risk 67

Item 8 Financial Statements and Supplementary Data 67

Item 9A Controls and Procedures 67

Item 9B Other Information 67

Item 9C Disclosure Regarding Foreign Jurisdictions that Prevent Inspections. 67

PART III

Item 10 Directors, Executive Officers, and Corporate Governance 68

Item 11 Executive Compensation 77

Item 14 Principal Accountant Fees and Services 81

PART IV

SIGNATURES 84

Forward-Looking

Statements

This

Annual Report on Form 10-K contains forward-looking statements which are made pursuant to the safe harbor provisions of Section 27A of

the Securities Act of 1933, as amended (the “Securities Act”), and Section 21E of the Securities Exchange Act of 1934, as

amended (the “Exchange Act”). These statements may be identified by such forward-looking terminology as “may,”

“should,” “expects,” “intends,” “plans,” “anticipates,” “believes,”

“estimates,” “predicts,” “potential,” “continue” or the negative of these terms or other

comparable terminology. Our forward-looking statements are based on a series of expectations, assumptions, estimates and projections

about our company, are not guarantees of future results or performance and involve substantial risks and uncertainty. We may not actually

achieve the plans, intentions or expectations disclosed in these forward-looking statements. Actual results or events could differ materially

from the plans, intentions and expectations disclosed in these forward-looking statements. Our business and our forward-looking statements

involve substantial known and unknown risks and uncertainties, including the risks in the section

titled “Risk Factors” beginning on page 40, that may cause our or our industry’s actual results, levels of activity,

performance or achievements to be materially different from any future results, levels of activity, performance or achievements expressed

or implied by these forward-looking statements. In addition, you are directed to factors discussed in the “Business”

section beginning on page 5 and the “Management’s Discussion and Analysis of Financial Condition and Results of Operations”

section beginning on page 59, as well as those discussed elsewhere in this Annual Report on Form 10-K.

All

of our forward-looking statements are as of the date of this Annual Report on Form 10-K only. In each case, actual results may differ

materially from such forward-looking information. We can give no assurance that such expectations or forward-looking statements will

prove to be correct. An occurrence of, or any material adverse change in, one or more of the risk factors or risks and uncertainties

referred to in this Annual Report on Form 10-K or included in our other public disclosures or our other periodic reports or other documents

or filings filed with or furnished to the U.S. Securities and Exchange Commission (the “SEC”) could materially and

adversely affect our business, prospects, financial condition and results of operations. Except as required by law, we do not undertake

or plan to update or revise any such forward-looking statements to reflect actual results, changes in plans, assumptions, estimates or

projections or other circumstances affecting such forward-looking statements occurring after the date of this Annual Report on Form 10-K,

even if such results, changes or circumstances make it clear that any forward-looking information will not be realized. Any public statements

or disclosures by us following this Annual Report on Form 10-K that modify or impact any of the forward-looking statements contained

in this Annual Report on Form 10-K will be deemed to modify or supersede such statements in this Annual Report on Form 10-K.

This

Annual Report on Form 10-K may include market data and certain industry data and forecasts, which we may obtain from internal company

surveys, market research, consultant surveys, publicly available information, reports of governmental agencies and industry publications,

articles and surveys. Industry surveys, publications, consultant surveys and forecasts generally state that the information contained

therein has been obtained from sources believed to be reliable, but the accuracy and completeness of such information is not guaranteed.

While we believe that such studies, clinical trials and publications are reliable, we have not independently verified market and industry

data from third-party sources.

Risk

Factor Summary

Our

business is subject to significant risks and uncertainties that make an investment in us speculative and risky. Below we summarize what

we believe are the principal risk factors but these risks are not the only ones we face, and you should carefully review and consider

the full discussion of our risk factors in the section titled “Risk Factors”, together with the other information

in this Annual Report on Form 10-K. If any of the following risks actually occurs (or if any of those listed elsewhere in this Annual

Report on Form 10-K occur), our business, reputation, financial condition, results of operations, revenue, and future prospects could

be seriously harmed. Additional risks and uncertainties that we are unaware of, or that we currently believe are not material, may also

become important factors that adversely affect our business.

● We are an early stage development company;

● We are developing novel technologies which may not be effective or safe;

● We have an unproven market for our product candidates;

● We must obtain additional capital to continue our operations;

● We are highly dependent on our key personnel;

PART

ITEM

1. BUSINESS

BUSINESS

Overview

of the Company

BriaCell

(the “Company”) is an immuno-oncology biotechnology company with a strong focus on cancer immunotherapy.

Immunotherapies have come to the forefront in the fight against cancer since they harness the body’s own immune system to recognize

and destroy cancer cells. BriaCell owns the U.S. patent to SV-BR-1-GM (“Bria-IMTTM”), a whole-cell targeted immunotherapy

for cancer (U.S. Patent No. 7,674,456), as well as patents related to PKCδ inhibitors (U.S. Patent Nos. 9,364,460 and 9,572,793).

The Company is currently advancing our targeted immunotherapy program by prioritizing a Phase I/IIa clinical trial with Bria-IMTTM

in combination with an immune checkpoint inhibitor and a companion diagnostic test, BriaDxTM, to identify patients most likely to

benefit from Bria-IMTTM. The Bria-IMTTM regimen was evaluated in four patients in a prior study in 2004-2006 by Dr. Charles

Wiseman, the scientific founder, former member of the board of directors of the Company (the “Board”) and principal

scientific advisor. Encouraging results were obtained, especially in a patient who matched Bria-IMTTM at HLA-DR alleles and had

a grade II tumor. In 2017-2018 BriaCell evaluated 23 patients with advanced breast cancer with the Bria-IMTTM regimen and obtained

confirmation of the ability of the Bria-IMTTM regimen to induce regression of metastatic breast cancer in patients who match Bria-IMTTM

at least at one HLA allele and/or if they had grade I or grade II tumors. A combination study with the immune checkpoint inhibitor pembrolizumab

(KEYTRUDA®) was initiated and the first patient dosing in the “combination therapy” clinical trial occurred in September

2018. BriaCell purchased the KEYTRUDA® for this study as BriaCell does not have an agreement with Merck & Co., Inc. for the supply

of KEYTRUDA®. Eleven patients were dosed in the combination therapy trial with Bria-IMTTM and the immune checkpoint inhibitor

KEYTRUDA® and subsequently dosing with this combination was discontinued. The study was modified under an amended protocol which

evaluates the combination of the Bria-IMTTM regimen with Incyte Corporation experimental drugs retifanlimab (anti-PD-1 antibody

similar to pembrolizumab). The study is ongoing.

Market

is estimated by the National Cancer Institute that in 2022, approximately 287,500 women will be diagnosed with breast cancer in the United

States. That means that every two minutes an American woman is diagnosed with breast cancer and more than 43,000 are projected to die

in 2022. Although about 100 times less common than in women, breast cancer also affects men. It is estimated that the lifetime risk of

men getting breast cancer is about 1 in 1,000, and the American Cancer Society estimates that approximately 2,710 new cases of invasive

male breast cancer will be diagnosed and approximately 530 men will die from breast cancer in 2022.

According

to the May 2019 “Global Oncology Trends 2021” report by the IQVIA Institute, the global market for cancer drugs (including

immunotherapy drugs) is expected to reach nearly $269 billion by the end of 2025, growing at a compound annual growth rate (“CAGR”)

of 10% between 2021 and 2025, of which about 20% is expected to be immuno-oncology drugs.

About 12.9% percent of women will be diagnosed

with breast cancer at some point during their lifetime. In 2018, there were an estimated 3,676,262 women living with female breast cancer

in the United States. Approximately 81% of cases present as invasive breast cancer. Approximately 6% of new breast cancer diagnoses are

Stage IV (metastatic breast cancer (“MBC”), which has already spread to other organs). Twenty to thirty percent of

all women diagnosed with breast cancer will develop MBC. Breast cancer can be subdivided based on receptor status – the hormone

receptors for estrogen (ER) and progesterone (PR), collectively referred to as hormone receptors (HR), and the Her2/neu growth factor

receptor (HER2). Based on the latest SEER statistics, 74.6% were found to be HR+/HER2−, 10.8% were triple-negative (HR−/HER2−),

10.5% were HR+/HER2+, and 4.0% were HR−/HER2+.1

is estimated that over 150,000 women in the US are living with MBC.2 For those with metastatic disease at diagnosis, their

5-year survival rate is 27%.3 For patients who develop MBC after initially having localized disease, if they had a good response

to treatment (i.e. a disease-free interval of more than 24 months), their survival rate is similar to that of patients with MBC at initial

diagnosis, but if their disease-free interval is less than 24 months, their prognosis is worse.4 We currently propose that

Bria-IMT’sTM indication will be for the treatment of patients with MBC who have failed at least two lines of therapy. Similarly,

another study showed that the median overall survival among patients with de novo stage IV MBC was 39.2 months, while for patients with

relapsed disease it was 27.2 months.5 Median progression free survival after first-line therapy is only 9 months and the survival

benefit decreases with subsequent lines of therapy.6 One study showed that of 386 patients with MBC, 374 (97%) received first-line

therapy, 254 (66%) received second-line therapy, 175 (45%) received third-line therapy, and 105 (27%) received therapy beyond third-line.7

See https://seer.cancer.gov/statfacts/html/breast.html

Mariotto AB, Etzioni R, Hurlbert M, Penberthy L, Mayer M. Estimation of the Number of Women Living with Metastatic Breast Cancer

in the United States. Cancer Epidemiol Biomarkers Prev. 2017 Jun;26(6):809-815.

Breast Cancer Facts & Figures 2017-2018. Atlanta: American Cancer Society, Inc. 2017.

Lobbezoo, D. J. A. et al. Prognosis of metastatic breast cancer subtypes: the hormone receptor/HER2-positive subtype is associated

with the most favorable outcome. Breast Cancer Res. Treat. 141, 507–514 (2013).

Dawood S, Broglio K, Ensor J, Hortobagyi GN, Giordano SH. Survival differences among women with de novo stage IV and relapsed breast

cancer. Ann Oncol. 2010 Nov; 21(11):2169–74.

Bonotto M, Gerratana L, Iacono D, Minisini AM, Rihawi K, Fasola G, Puglisi F. Treatment of Metastatic Breast Cancer in a Real-World

Scenario: Is Progression-Free Survival With First Line Predictive of Benefit From Second and Later Lines? Oncologist.

Kotsakis A, Ardavanis A, Koumakis G, Samantas E, Psyrri A, Papadimitriou C. Epidemiological characteristics, clinical outcomes

and management patterns of metastatic breast cancer patients in routine clinical care settings of Greece: Results

Figure

A: Overview of current drugs for breast cancer, demonstrating the pattern of novel therapeutic introductions and significant market

uptake. These precedents demonstrate a strong market pull for Bria-IMTTM.

The

best response to Bria-IMTTM to date is in patients who matched Bria-IMTTM at one or more HLA alleles, with higher response

rates for patients with 2+ HLA allele matches. If one HLA allele match is found to be sufficient, we will be able to treat ~50-60% of

the patient population, while patients with 2+ HLA matches constitutes ~15-35% of cases.8 We also saw higher clinical benefit

rates for patients with grade I/II tumors. Tumor differentiation in breast cancer cell lines is often described by their classification

as Luminal, Basal A and Basal B subtypes, with Luminal representing well differentiated tumors, Basal B poorly differentiated tumors,

and Basal A an intermediate stage tumor (“moderately” differentiated).2

Yao and colleagues in 2005 identified a 9-gene signature (AURKB, CENPI, DEPDC1, DEPDC1B, FAM83D, FGD3, NCAPH, TNFRSF18, FCGR1A)

discriminating poorly (grade 3) from moderately (grade 2) differentiated tumors.3

To understand the place of SV-BR-1-GM in this model, we compared its RNA expression profile with those of three other cell lines

representing Luminal (MCF-7), Basal A (MDA-MB-468) and Basal B (MDA-MB-231), using a 10-gene signature (AURKB, CENPI, DEPDC1, DEPDC1B,

FAM83D, FGD3, NCAPH, DLGAP, KIF2C, VAV3) derived from those by Yao and colleagues. The results, shown in the figure below, demonstrate

that Bria-IMTTM most closely clusters with MDA-MB-468 and as such is considered a grade II “moderately differentiated”

cell line.

Greece:

Results from the EMERGE multicenter retrospective chart review study. BMC Cancer. 2019 Jan 18;19(1):88.

Gragert, Loren, Abeer Madbouly, John Freeman, and Martin Maiers. 2013. “Six-Locus High Resolution HLA Haplotype Frequencies

Derived from Mixed-Resolution DNA Typing for the Entire US Donor Registry.” Human Immunology.

Neve RM, Chin K, Fridlyand J, et al. A collection of breast cancer cell lines for the study of functionally distinct

cancer subtypes. Cancer Cell. 2006;10(6):515-527. doi:10.1016/j.ccr.2006.10.008)

Yao F, Zhang C, Du W, Liu C, Xu Y. Identification of gene-expression signatures and protein markers for breast cancer

grading and staging. PLoS One. 2015;10(9). doi:10.1371/journal.pone.0138213)

Based

on a recent publication of patients with relapsed breast cancer, we estimate that this will account for ~40% of relapsed metastatic breast

cancer cases (33% grade II and 7% grade I) (Sundquist M, Brudin L, Tejler G. Improved survival in metastatic breast cancer 1985-2016.

Breast. 2017 Feb;31:46-50. doi: 10.1016/j.breast.2016.10.005. Epub 2016 Nov 2). In patients with relapsed disease, the overall survival

following relapse appears similar for those with grade II and grade III tumors.9 The market for breast cancer drugs is a multibillion-dollar

market with new drugs being approved on an ongoing basis, indicating the shortage of safe and effective treatments for this deadly disease.

Figure A summarizes current drugs on the market utilized in combination therapy along with their reported market sales, which further

supports market potential for Bria-IMTTM to be used for combination therapy for breast cancer patients.

propose the following calculation in order to show the rationale behind the number of patients that we anticipate can be currently treated

by SV-BR-1-GM:

● There are 150,000 women with metastatic breast cancer in the U.S.10

● ~45% will receive third line therapy11 = 68,000 patients available

● 40% have grade I/II tumors14 = 13,600 patients available for treatment

See note 5, above.

Mariotto AB, Etzioni R, Hurlbert M, Penberthy L, Mayer M. Estimation of the Number of Women Living with Metastatic Breast Cancer

in the United States. Cancer Epidemiol Biomarkers Prev. 2017 Jun;26(6):809-815.

Kotsakis A, Ardavanis A, Koumakis G, Samantas E, Psyrri A, Papadimitriou C. Epidemiological characteristics, clinical outcomes

and management patterns of metastatic breast cancer patients in routine clinical care settings of Greece: Results from the EMERGE multicenter

retrospective chart review study. BMC Cancer. 2019 Jan 18;19(1):88.

Gragert, Loren, Abeer Madbouly, John Freeman, and Martin Maiers. 2013. “Six-Locus High Resolution HLA Haplotype Frequencies

Derived from Mixed-Resolution DNA Typing for the Entire US Donor Registry.” Human Immunology.

Momenimovahed Z, Salehiniya H. Epidemiological characteristics of and risk factors for breast cancer in the world. Breast Cancer

(Dove Med Press). 2019 Apr 10;11:151-164. SEER Cancer Statistics Factsheets: Female Breast Cancer. National Cancer Institute. Bethesda,

MD; American Cancer Society. Breast Cancer Facts & Figures 2017-2018. Atlanta: American Cancer Society, Inc. 2017.

See note 5, above.

Competition

Currently

available therapeutic options for breast cancer offer some hope for patients, but there is much room for improvement. Comparable studies

looking primarily at second line or later treatment are shown in Table “A”, below. Evaluating response rates (partial and

complete responses = ORR), progression free survival (“PFS”) and overall survival (“OS”) from clinical

trials in similar subjects with metastatic or recurrent breast cancer indicate that response rates range from 6.9% up to 59%, depending

on the population studied and the intervention (median 24%). PFS ranges from 8 weeks to 12 months (median 5 months) and OS from 6 months

to 31 months (median 13 months).

Table

A: Studies evaluating second-line or later treatment options. Data depict an unpredictable response rate to treatment ranging from

6.9-59%, therefore establishing and confirming the opportunity for Bria-IMTTM.

Study Treatment & Design # of Pts ORR PFS/TTP OS

Seidman16 Gemcitabine Monotherapy 160 26 %

Zelek17 Vinorelbine Monotherapy 40 25 % 6 mo

Licchetta18 Cyclophosphamide and megestrol acetate 29 31 % 7.4 mo 13.4 mo

Leyland-Jones23 Trastuzumab with paclitaxel 32 59 % 12.2 mo

von Minckwitz24 Trastuzumab with capecitabine 78 48.1 % 8.2 mo 25.5 mo

Geyer26 Lapatinib plus capecitabine 163 22 % 8.4 mo

Capecitabine Monotherapy 161 14 % 4.4 mo

Bartsch27 Capecitabine and trastuzumab 40 20 % 8 mo 24 mo

MBC

treated with second or higher lines of therapy has a very poor prognosis and few effective therapies that consistently induce long-term

remission,29 which indicates the market demand and clinical need for new and improved therapeutic drugs and treatment options

in order to improve these response outcomes and patient survival rates. Thus, Bria-IMTTM has the potential to induce long-term remission,

especially in combination with immunotherapies. Current treatment of MBC is outlined in Figure “B”, below, which illustrates

different therapeutic treatment options and drugs used upon diagnoses from biopsy and identification of breast cancer biomarkers.30

Perez, E. A., Vogel, C. L., Irwin, D. H., Kirshner, J. J. & Patel, R. Multicenter Phase II Trial of Weekly Paclitaxel in Women

With Metastatic Breast Cancer. J. Clin. Oncol. 19, 4216–4223 (2001).

Seidman, A. D. Gemcitabine as single-agent therapy in the management of advanced breast cancer. Oncology (Williston Park). 15,

11–4 (2001).

Zelek, L. et al. Weekly vinorelbine is an effective palliative regimen after failure with anthracyclines and taxanes in metastatic

breast carcinoma. Cancer 92, 2267–72 (2001).

Licchetta A, Correale P, Migali C, Remondo C, Francini E, Pascucci A, Magliocca A, Guarnieri A, Savelli V, Piccolomini A, Carli

AF, Francini G. Oral metronomic chemo-hormonal-therapy of metastatic breast cancer with cyclophosphamide and megestrol acetate. J Chemother.

2010 Jun;22(3):201-4.

Harvey, V. et al. Phase III Trial Comparing Three Doses of Docetaxel for Second-Line Treatment of Advanced Breast Cancer. J. Clin.

Oncol. 24, 4963–4970 (2006).

Rivera, E. et al. Phase 3 study comparing the use of docetaxel on an every-3-week versus weekly schedule in the treatment of metastatic

breast cancer. Cancer 112, 1455–1461 (2008).

Gradishar WJ. Taxanes for the treatment of metastatic breast cancer. Breast Cancer (Auckl). 2012;6:159-71.

Perez, E. A. et al. Efficacy and Safety of Ixabepilone (BMS-247550) in a Phase II Study of Patients With Advanced Breast Cancer

Resistant to an Anthracycline, a Taxane, and Capecitabine. J. Clin. Oncol. 25, 3407–3414 (2007).

Leyland-Jones, B. et al. Pharmacokinetics, Safety, and Efficacy of Trastuzumab Administered Every Three Weeks in Combination With

Paclitaxel. J. Clin. Oncol. 21, 3965–3971 (2003). Only 41% of patients had prior systemic chemotherapy.

von Minckwitz G et el. Trastuzumab beyond progression: overall survival analysis of the GBG 26/BIG 3-05 phase III study in HER2-positive

breast cancer. Eur J Cancer. 2011 Oct;47(15):2273-81. Prior therapy limited to trastuzamab alone or in combination with a taxane.

Verma, S. et al. Trastuzumab Emtansine for HER2-Positive Advanced Breast Cancer. N. Engl. J. Med. 367, 1783–1791 (2012).

Geyer, C. E. et al. Lapatinib plus Capecitabine for HER2-Positive Advanced Breast Cancer. N. Engl. J. Med. 355, 2733–2743

(2006).

Bartsch, R. et al. Capecitabine and Trastuzumab in Heavily Pretreated Metastatic Breast Cancer. J. Clin. Oncol. 25, 3853–3858

(2007).

Blackwell, K. L. et al. Randomized Study of Lapatinib Alone or in Combination With Trastuzumab in Women With ErbB2-Positive, Trastuzumab-Refractory

Metastatic Breast Cancer. J. Clin. Oncol. 28, 1124–1130 (2010).

Dawood S, Broglio K, Ensor J, Hortobagyi GN, Giordano SH. Survival differences among women with de novo stage IV and relapsed breast

cancer. Ann Oncol. 2010 Nov; 21(11):2169–74; Bonotto M, Gerratana L, Iacono D, Minisini AM, Rihawi K, Fasola G, Puglisi F. Treatment

of Metastatic Breast Cancer in a Real-World Scenario: Is Progression-Free Survival With First Line Predictive of Benefit From Second

and Later Lines? Oncologist. 2015 Jul;20(7):719-24; Kotsakis A, Ardavanis A, Koumakis G, Samantas E, Psyrri A, Papadimitriou C. Epidemiological

characteristics, clinical outcomes and management patterns of metastatic breast cancer patients in routine clinical care settings of

Greece: Results from the EMERGE multicenter retrospective chart review study. BMC Cancer. 2019 Jan 18;19(1):88.

Figure

B: Current treatment paradigm for metastatic breast cancer including between different treatment strategies and combination therapies

dependent upon biomarker identification and activity within the breast cancer signaling pathway.

patients treated with trastuzumab for MBC, one study showed that 241/331 (72%) progressed within 27 months (32% per year) with median

survival of 13-14 months (CI 10-15 months).31 This indicates the high unmet need in this patient population which should facilitate

regulatory review of novel therapies such as Bria-IMTTM.

While

there are approximately 36 different biotech companies working to create an effective breast cancer vaccine, a significant gap remains

in the effectiveness and safety of second or higher lines of therapy. The most studied targeted immunotherapy, Neuvax (Galena), a HER2

peptide vaccine, failed a Phase III trial, but there is encouraging data to support at least three ongoing clinical trials combining

trastuzumab with HER2 epitope immunogens.32 The National Cancer Institute (“NCI”) randomized trial adding

PANVAC (a poxviral-based immunogen) to docetaxel increased the median PFS from 3.9 months to 7.9 months and is to be used as a basis

for larger, more sophisticated clinical trials.33 An immunogen targeting a carbohydrate antigen, globo-H, was associated with

improved PFS, but only in the subset able to mount antibody responses.34 A Johns Hopkins breast cancer trial using a breast

cancer cell line transfected with the gene for GM-CSF has not been positive but, using the same cell line with trastuzumab, 40% of patients

enjoyed clinical benefit (CR+PR+stable) at one year.35 Finally, the study of targeted cancer immunotherapies in combination

with other therapies is receiving much attention, particularly combination with checkpoint inhibitors.36

Rossi, V.; Nole, F.; Redana, S.; Adamoli, L.; Martinello, R.; Aurilio, G.; Verri, E.; Sapino, A.; Viale, G.; Aglietta, M.; Montemurro,

F., Clinical outcome in women with HER2-positive de novo or recurring stage IV breast cancer receiving trastuzumab-based therapy. Breast

2014, 23 (1), 44-9.

Mittendorf, E. A.; Peoples, G. E., Injecting Hope—A Review of Breast Cancer Vaccines. Oncology (Williston Park) 2016, 30

(5), 475-81, 485.

Heery, C. R.; Ibrahim, N. K.; Arlen, P. M.; Mohebtash, M.; Murray, J. L.; Koenig, K.; Madan, R. A.; McMahon, S.; Marte, J. L.;

Steinberg, S. M.; Donahue, R. N.; Grenga, I.; Jochems, C.; Farsaci, B.; Folio, L. R.; Schlom, J.; Gulley, J. L., Docetaxel Alone or in

Combination With a Therapeutic Cancer Vaccine (PANVAC) in Patients With Metastatic Breast Cancer: A Randomized Clinical Trial. JAMA Oncol

2015, 1 (8), 1087-95.

Huang, C.; Yu, A.; Tseng, L., Randomized phase II/III trial of active immunotherapy with OPT-822/OPT-821 in patients with metastatic

breast cancer. J Clin Oncol 2016, 34 (15).

Chen, G.; Gupta, R.; Petrik, S.; Laiko, M.; Leatherman, J. M.; Asquith, J. M.; Daphtary, M. M.; Garrett-Mayer, E.; Davidson, N.

E.; Hirt, K.; Berg, M.; Uram, J. N.; Dauses, T.; Fetting, J.; Duus, E. M.; Atay-Rosenthal, S.; Ye, X.; Wolff, A. C.; Stearns, V.; Jaffee,

E. M.; Emens, L. A., A feasibility study of cyclophosphamide, trastuzumab, and an allogeneic GM-CSF-secreting breast tumor vaccine for

HER2+ metastatic breast cancer. Cancer Immunol Res 2014, 2 (10), 949-61.

McArthur, H. L.; Page, D. B., Immunotherapy for the treatment of breast cancer: checkpoint blockade, cancer vaccines, and future

directions in combination immunotherapy. Clin Adv Hematol Oncol 2016, 14 (11), 922-933.

There

are several other approaches to developing targeted breast cancer immunotherapies. These include using peptide cocktails, a triple peptide

regimen, recombinant HER2, antigen-pulsed dendritic cells, DNA immunogens, whole cell allogeneic GM-CSF secreting SKBR3 or T47D cells,

an (HLA)-A2/A3-restricted immunogenic peptide derived from the HER2 protein, oxidized mannan-MUC1, and personalized peptide immunogens.

Among

the most promising results in patients with advanced disease have been using whole-cell preparations, particularly if the cells are engineered

to express GM-CSF. We are taking this approach and capitalizing on positive initial results with Bria-IMTTM monotherapy in difficult

to treat patients using a regimen that both limits regulatory T cell activity (using low dose cyclophosphamide pre-treatment) and boosts

the immune response (using post-dose alpha interferon in the inoculation sites). The combination with PD-1 inhibitors is a logical extension

of our findings where 21 of 23 MBC patients had demonstrable PD-L1 expression on the circulating tumor cells (“CTCs”)

and/or circulating cancer-associated macrophage-like cells (“CAMLs”). The overall strategy, once the initial milestones

have been met, to enroll additional patients for product registration, will allow rapid progression of the best therapeutic option to

a Biologics License Application (“BLA”).

Products/Pipeline

Bria-IMTTM

Bria-IMTTM,

BriaCell’s lead candidate, is a whole-cell immunotherapy undergoing clinical testing in patients with MBC who have failed prior

lines of therapy. BriaCell has been conducting a Phase I/IIa clinical trial of Bria-IMTTM, in combination with immune checkpoint

inhibitors such as pembrolizumab (KEYTRUDA®; manufactured by Merck & Co., Inc.). The combination study is listed in ClinicalTrials.gov

as NCT03328026 under FDA-approved BB-IND 10312 under protocol BRI-ROL-001 at three clinical sites: St. Joseph Heritage Healthcare in

Santa Rosa, California, United States; University of Miami/Sylvester at Plantation, in Plantation, Florida, USA; Cancer Center of Kansas,

in Wichita, Kansas, USA. Subsequent to the establishment of a collaboration with Incyte Corporation, this study has been modified to

evaluate the combination of the Bria-IMTTM with retifanlimab (also referred to as INCMGA00012 ,a PD-1 inhibitor).

BriaCell

has achieved proof of concept based on data from a Phase I/IIa study of Bria-IMTTM in advanced breast cancer patients. In essence,

BriaCell obtained evidence that patients with certain HLA molecules also present in Bria-IMTTM have a higher likelihood of responding

to the Bria-IMTTM regimen with tumor regression (“shrinkage”), which is consistent with results from a molecular

analysis of Bria-IMTTM conducted by BriaCell.

Positive

Proof of Concept

X.;

Wolff, A. C.; Stearns, V.; Jaffee, E. M.; Emens, L. A., A feasibility study of cyclophosphamide, trastuzumab, and an allogeneic GM-CSF-secreting

breast tumor vaccine for HER2+ metastatic breast cancer. Cancer Immunol Res 2014, 2 (10), 949-61.

About

Bria-IMTTM

Developed

and characterized by a team of dedicated scientists and clinicians, Bria-IMTTM (SV-BR-1-GM) is a targeted immunotherapy being developed

for the treatment of breast cancer. Bria-IMTTM is a genetically engineered human breast cancer cell line with features of immune

cells and clinically applied as a targeted immunotherapy.

short, Bria-IMTTM immunotherapy is a genetically engineered human breast cancer cell line derived from a grade II tumor which activates

the immune system to attack and destroy breast cancer tumors.

Mechanism

of Action of Bria-IMTTM

The

mechanism of action of Bria-IMTTM is currently under investigation. It is likely that the expression of certain breast cancer antigens

(proteins expressed in breast cancer cells) in Bria-IMTTM generates strong T cell and potentially antibody responses – resulting

in recognition and destruction of cancerous cells.37

Bria-IMTTM

is designed to secrete GM-CSF, a factor that stimulates components of the immune system. Specifically, GM-CSF activates dendritic cells,

the cells that start immune responses. These activated dendritic cells then activate T cells, a key component of the immune system, to

recognize the tumor cells as foreign, and eliminate them. To amplify this action, we have combined Bria-IMTTM with other immune

system activators including cyclophosphamide (used in low doses to reduce immune suppression), and interferon-α, a cytokine that

further activates the immune system. We believe this approach of simultaneous activation of the immune system via different pathways

will improve the immune system response to attack and destroy cancer cells.

Bria-OTSTM

Using

BriaCell’s novel technology platform and our strong research and development capabilities, BriaCell plans to develop Bria-OTSTM,

a personalized off-the-shelf immunotherapy for breast cancer, and similar immunotherapy cell lines for other cancer indications.

BriaDxTM

is a diagnostic test that BriaCell is developing to identify the patients most likely to respond to Bria-IMTTM. Currently, BriaDxTM

includes HLA typing of the patients, as patients having HLA alleles also present in Bria-IMTTM appear to have a higher likelihood

of responding to the Bria-IMTTM regimen with tumor shrinkage. Additional markers of potential diagnostic use are being developed

based on the expression of specific biomarkers in the responder (i.e. biomarkers which identify the patients for which Bria-IMTTM

immunotherapy appears more effective) vs the non-responder patients from clinical studies of Bria-IMTTM in advanced breast cancer

patients.

Blood

and tumor samples from the patients are analyzed using cutting-edge technologies including gene expression analysis and assessment of

the levels of antibodies predicted to bind to Bria-IMTTM.

The

insights gained from biomarker studies conducted to date have provided us with a solid basis for the development of Bria-OTSTM,

an off-the-shelf personalized immunotherapy which would match over 99% of patients with advanced breast cancer.

Lacher M.D., Bauer G. Fury B., Graeve S., Fledderman E.L., Petrie T.D., Coleal-Bergum D.P., Hackett T., Perotti N.H., Kong Y.Y.,

Kwok W.W., Wagner J.P., Wiseman C.L., and Williams W.V. SV-BR-1-GM, a Clinically Effective GM-CSF- Secreting Breast Cancer Cell Line,

Expresses an Immune Signature and Directly Activates CD4+ T Lymphocytes. Frontiers in Immunology 2018; 9: Article 776.

BriaDxTM

is being developed to help understand which patients are most likely to respond to Bria-IMTTM targeted immunotherapy. Based on the

proposed mechanism of action of Bria-IMTTM, HLA molecules play a key role inducing cellular immune responses to Bria-IMTTM

which boosts the patient’s immune response to their cancer.

HLA

molecules are polymorphic, in that they are different in different individuals, but shared by some individuals (similar to eye color).

Based on our clinical data to date, we hypothesize that patients with HLA alleles also present in Bria-IMTTM have a higher likelihood

of responding to the Bria-IMTTM regimen with tumor regression. Therefore, BriaDxTM, a companion diagnostic test, determines

the patients’ HLA types.

Available

Clinical Data for Treatment with the Bria-IMTTM Regimen

BriaCell

conducted three Proof of Concept clinical trials, one using parental SV-BR-1 cells and the other two using Bria-IMTTM (i.e. genetically

engineered SV-BR-1 cells – producing GM-CSF also called SV-BR-1-GM), in metastatic (i.e. Stage IV) breast cancer patients who had

failed prior treatments. The patients were treated with the Bria-IMTTM regimen according to the following schedule, and the results

are summarized below.

Treatment

schedule:

First

Proof of Concept Trial

● N = 14 late stage, treatment-refractory breast cancer patients.

● No significant adverse treatment-associated events, well tolerated.

● Median Overall Survival = 12.1 months.

Second

Proof of Concept Trial

● No significant adverse treatment-associated events, well tolerated.

● Median Overall Survival = 35 months.

Third

Proof of Concept Trial

Thirty

patients were screened, 24 enrolled and 23 dosed in the Phase I/IIa study (2017-2018).

● Patients were treated with a median of three cycles of therapy (range 1-8).

● There were no serious, unexpected, drug-related AEs.

Most

patients who withdrew from the trial did so due to the worsening of their underlying disease. Specifically, 14 patients terminated participation

due to progressive disease, four withdrew, three terminated participation due to mortality (unrelated to study drug), and two terminated

participation due to adverse events (both judged unrelated to study drug).

the combined experience of the second and third studies (which both use the same Bria-IMTTM regimen), disease control (i.e. stable

disease or partial response) was evaluated.

Disease

Control* in Studies SVMC #01-026 and WRI-GEV-007 Based on HLA Matching to Bria-IMTTM and Immune Response to Treatment

Patients HLA Match Disease Control Disease Control in Immune Responders

Disease

Control in Studies SVMC #01-026 and WRI-GEV-007 Based on Tumor Grade

Patients Grade I/II Disease Control

Immune Responders (as measured by DTH)

Immune Responders N=22 7 71 %

● Bria-IMTTM has been very well tolerated (over 100 doses given to date).

Development

of Additional Immunotherapy Cell Lines

Protein

Kinase C Delta (PKCδ) Inhibitors

Overview

The

delta isoform of the Protein Kinase C family (PKCδ) is implicated in a multitude of cellular responses to external and internal

stimuli, playing both pro- and anti-tumorigenic roles. In contrast to PKCα, PKCδ does not seem to be required for survival

of normal cells. In PKCδ knockout mice, mild lymphoproliferation was observed, but overall, PKCδ inhibition is well tolerated

at the organismal level. BriaCell scientists develop small-molecule PKCδ inhibitors for use in those situations where PKCδ

carries out pro-tumorigenic functions. Preliminary data suggest that PKCδ inhibition may be particularly beneficial in a subset

of cancers with oncogenic Ras or with otherwise activated Ras signaling, for instance in endometrial cancers with estrogen-induced K-Ras

stabilization. In particular, PKCδ inhibition may be of therapeutic use in cancers dependent on Ras signaling for proliferation,

as shown in vitro for lung cancer. BriaCell, through our subsidiary Sapientia, uses structural information of Rottlerin, a PKCδ

inhibitor with modest activity, and Staurosporine, a potent but nonspecific PKC inhibitor, to develop a series of “hybrid”

compounds. This rational design approach is envisioned to yield molecules with, compared to Rottlerin, enhanced activity yet retained

PKC δ-selectivity.

Strategy

and Results

PKCδ

inhibition was achieved with small molecules using a pharmacophore model based on Staurosporine and Rottlerin. One of the most promising

molecules based on this approach, BC106 (BJE6-106), presents an IC50 for PKCδ inhibition of approximately 50 nM and

is approximately 1000-fold more selective for PKCδ than for PKCα. In cellular and animal model studies, BC106 shows effective

anti-proliferative and anti-tumor activity, but this molecule is not water soluble, hence not appropriate as a drug candidate. Efforts

to improve water solubility have been initiated, with a series of compounds undergoing testing in in vitro kinase and cell-based

assays.

develop PKCδ inhibitors, BriaCell affiliates started with two molecules known to have PKC-inhibitory properties: Staurosporine

and Rottlerin. Multiple chemical manipulations and testing resulted in BC106, one of the Company’s most effective compounds to-date.

Staurosporine is a well-known PKC inhibitor with anti-cancer activity, while Rottlerin, also known as Mallotoxin, opens potassium channels

that have been used to induce apoptosis. Rottlerin has also been shown to be an immunosuppressive agent, affecting multiple oncogenic

pathways. Although some reports claim that Rottlerin does not act primarily via PKCδ inhibition, BriaCell’s data supports

Rottlerin-derived molecules as viable tumor suppressors.

The

Company’s strategy for compound synthesis is based on a hitherto unexplored design concept, wherein functional moieties of two

natural products known to strongly inhibit PKCδ – Rottlerin and Staurosporine – have been “intellectually cut”

from each natural product and then covalently joined to make a novel, chimeric scaffold. The Company’s synthetic analogs, in essence,

combine the bottom benzopyran moiety of Rottlerin and chemically join that to the indolyl carbazole moiety of Staurosporine. Further,

new chimeric scaffolds are synthesized in a novel, convergent modular fashion, allowing for the rapid assembly and testing of many derivatives.

Rottlerin

was initially used because this molecule inhibits purified PKCδ at an IC50 of 3-5 μM in vitro, and in cultured

cells with an IC50 of 5 μM. Rottlerin is relatively more selective for PKCδ than for PKCα (PKCδ IC50:PKCα

IC50 ≈ 1:30). BriaCell further advanced our pharmacophore model using the Rottlerin-based prototype chimeric structure

in combination with Staurosporine by incorporating protein structural data for the novel class PKCs. This strategy produced a second

generation of PKCδ inhibitors with the “head” group resembling that of Staurosporine and the other domains conserved

from the Rottlerin scaffold to preserve isozyme specificity. A second generation successful product is represented by BC128, which has

an IC50 of 4 μM for PKCδ (similar to Rottlerin), and better isozyme selectivity (IC50 of >120 μM

for PKCα). BC128 showed anti-tumor cell activity in vitro and in vivo.

BC106,

BriaCell’s most-recent “lead” compound, produces substantial cytotoxicity against multiple human tumor lines at nM

concentrations (10-40 times lower than Rottlerin or BC128). BC106 dramatically inhibited the clonogenic capacity of RAS-mut tumor cell

lines after as little as 12 hours of exposure. BC106 is 1000-fold more selective for PKCδ than for PKCα. The latter is an

important finding because inhibition of PKCα is generally toxic to all cells (normal and malignant) and would make BC106 non-tumor-targeted.

Approximately

40% of melanomas harbor NRAS mutations and there is no effective RAS-targeted treatment available for this subgroup. BriaCell affiliates

have demonstrated that NRAS-mutant melanoma cells were highly sensitive to PKCδ siRNA knock-down and to BC106 at nM concentrations.

Clonogenic assays demonstrated that irreversible inhibition of proliferation required as little as 12 hours of exposure to Rottlerin

or BC106.

BriaCell

affiliates also assessed the effects of PKCδ inhibition on breast tumor growth and survival in a xenograft human breast cancer

stem cell model. PKCδ inhibition prevented tumor grown and promoted the survival of the animals evaluated over the course of 300

days (note that the vehicle treated animals all died within the first 20 days of the study).

Furthermore,

PKCδ inhibition also inhibited the growth of neuroendocrine cells.

Summary

and Outlook – Early Stage Preclinical Program

● Candidate selection is anticipated in 2022.

Prior IA, Lewis PD, Mattos C. A comprehensive survey of Ras mutations in cancer. Cancer Res. 2012 May 15; 72(10): 2457–2467.

Xia, S., Forman, L. W. & Faller, D. V. Protein Kinase Cδ Is Required for Survival of Cells Expressing Activated p21RAS.

J. Biol. Chem. 282, 13199–13210 (2007); Chen, Z. et al. Protein kinase Cδ inactivation inhibits cellular proliferation and

decreases survival in human neuroendocrine tumors. Endocr. Relat. Cancer 18, 759–71 (2011); Xia, S., Chen, Z., Forman, L. W. &

Faller, D. V. PKCδ survival signaling in cells containing an activated p21Ras protein requires PDK1. Cell. Signal. 21, 502–508

(2009); Liou, J. S., Chen, C.-Y., Chen, J. S. & Faller, D. V. Oncogenic Ras Mediates Apoptosis in Response to Protein Kinase C Inhibition

through the Generation of Reactive Oxygen Species. J. Biol. Chem. 275, 39001–39011 (2000); Liou, J. S., Chen, J. S. & Faller,

D. V. Characterization of p21Ras-mediated apoptosis induced by protein kinase C inhibition and application to human tumor cell lines.

J. Cell. Physiol. 198, 277–294 (2004); Chen, C. Y., Liou, J., Forman, L. W. & Faller, D. V. Differential regulation of discrete

apoptotic pathways by Ras. J. Biol. Chem. 273, 16700–9 (1998); Chen, C. Y. & Faller, D. V. Direction of p21ras-generated signals

towards cell growth or apoptosis is determined by protein kinase C and Bcl-2. Oncogene 11, 1487–98 (1995); Chen, C. Y. & Faller,

D. V. Phosphorylation of Bcl-2 protein and association with p21Ras in Ras-induced apoptosis. J. Biol. Chem. 271, 2376–9 (1996);

Chen, C.-Y., Liou, J., Forman, L. W. & Faller, D. V. Correlation of genetic instability and apoptosis in the presence of oncogenic

Ki-Ras. Cell Death Differ. 5, 984–995 (1998); Chen, C. Y. et al. The recruitment of Fas-associated death domain/caspase-8 in Ras-induced

apoptosis. Cell Growth Differ. 12, 297–306 (2001).

Miyamoto A, Nakayama K, Imaki H, Hirose S, Jiang Y, Abe M, Tsukiyama T, Nagahama H, Ohno S, Hatakeyama S, Nakayama KI. Increased

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