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Thursday, September 22, 2016

Recent News From BriaCell Points To Meaningful Progress

BriaCell Therapeutics Corp. (TSXV: BCT.V) is one of my favorite under-the-radar micro-cap immuno-oncology stories. The company is developing BriaVax™, a proprietary allogeneic whole tumor cell vaccine for the treatment of late-stage breast cancer. Management is preparing to initiate a Phase I/II clinical study with BriaVax in the fourth quarter 2016. The company is currently completing manufacturing of the vaccine for the clinical study.

BriaCell has announced some positive incremental news over the past few months since I first started following the story about a year ago. For instance, BriaCell recently appointed NY-based RK Equity Advisors LLC and TrueNorth Lifesciences LLC for the provision of corporate advisory services. Pursuant to the Agreement, RK and TruthNorth will assist BriaCell in engaging select members of the international investment community, with a focus on increasing awareness of BriaCell and its unique growth strategy, as well as assisting with the commercialization of its product and other market opportunities.

The start of the Phase I/II clinical study initiates a meaningful catalyst for the shares. And given that BriaCell is now actively out and talking with investors, as well as engaging with advisory and investor relations firms to increase awareness, I thought it made sense for me to do a quick review of the story and highlight why I'm a fan of the company.

Quick Refresher on BriaVax

BriaVax™ is a proprietary allogeneic whole tumor cell vaccine isolated from a chest wall lesion of a 39-year-old woman with metastatic breast cancer. The irradiated cells are ER/PR negative and overexpress HER-2/neu, a clinically validated target of effective monoclonal antibody therapeutics. BriaVax has been genetically engineered to release sargramostim (granulocyte macrophage - colony-stimulating factor [GM-CSF]) for up-regulation of professional antigen-presenting cells. GM-CSF has been shown to be the most potent immunostimulatory secreted molecule for inducing tumor immunity (1) and is believed to provide an antitumor effect that prolongs survival and disease-free survival in subjects with stage III and IV melanoma (2) and metastatic non-small cell lung cancer (3). Also, part of the treatment regimen is the addition of low-dose cyclophosphamide (CY) 2-3 days prior to inoculation to down-regulate the activity of regulatory T cells and the use of interferon (IFN) alpha to boost differentiation of dendritic cells.

Treatment with BriaVax is the result of decades of clinical investigation and research into therapeutic cancer vaccines and the use of an allogeneic whole cell breast tumor line that overexpresses a clinically validated tumor antigen. The cells have been genetically engineered to secrete GM-CSF, which has multiple effects on the tumor-immune response equilibrium, including activating dendritic cell recruitment and maturation. The protocol employs a novel use of CY to take the "foot off the brake" with respect to regulatory T cell response and then follows with a local injection of IFN-alpha to "step on the gas" and evoke prolonged immune response.

- BriaVax Mechanism of Action - 

BriaVax is believed to work by increasing expression of CD40 Ligand (CD40L), a costimulatory protein found on antigen presenting cells, such as T cell, B cell, and natural killer (NK) cells, that is required for their activation (4). Activation of CD40L has a variety of downstream effects, including dendritic cell maturation and an increase in serum levels of CD4+, CD8+, and NK cells known for their anti-tumor activities (5). BriaVax has shown that CD40L levels increase following administration of BriaVax, with one subject demonstrating tumor regression.

 

 - Predictors of Response - 

BriaCell believes that they have identified a gene signature predictive of response to BriaVax. For example, following the successful completion of the second Phase I study (n=4) (6), the scientists at BriaCell observed potentially prolonged overall survival among three of the four patients (median OS: ~35 months); in addition, one patient, with an OS of 33.7 months, demonstrated clinically significant (>90%) tumor) regression. Focusing more closely on these patients, BriaCell conducted a molecular analysis of both the BriaVax cell line and blood cells obtained from the Phase I patients. This "gene signature" analysis informed the company about a putative BriaVax mechanism of action and paved the way for the development of a potential companion diagnostic for both patient selection as well as monitoring during human clinical trials.

The basic findings, which were presented at AACR in April 2016 (Poster #2369), show that BriaVax expresses several genes known to encode tumor-associated antigens, such as PRAME, a Cancer/Testis Antigen (CTA), which trigger immune stimulatory roles and activation of tumor-specific T cells via mechanisms of direct antigen presentation, cross-presentation, and/or cross-dressing. Simply, BriaVax stimulates both a cell-mediated and a humoral immune response, which is believed to result in robust clinical response to the vaccine. More about this topic can be found in my article from April 2016.

The Planned Phase I/II Program

BriaCell expects to initiate a Phase I/II program with BriaVax in the fourth quarter 2016. The company is currently completing manufacturing of the vaccine for the clinical trial. The trial is expected to enroll up to 24 late-stage cancer patients with metastatic breast cancer. Enrollment is expected to take place at several university hospitals in the U.S. Below is a schematic of the planned protocol, although management is in discussion with the U.S. FDA about amending the trial to allow for extended dosing beyond six vaccines in patients that show response and to potentially allow for the enrollment of earlier-stage cancer patients. The company is also looking at the potential to use BriaVax in combination with other treatment options, such as checkpoint inhibitors, looking for an additive or synergistic effect.


Speaking of the planned Phase I/II clinical study, the company recently announced they have selected a principle investigator (PI) for the trial. The PI will be Dr. Jarrod P. Holmes, a Board Certified Oncologist and a leading expert in breast cancer vaccines at Annadel Medical Group and St. Joseph Health-Sonoma County in Santa Rosa, CA. Dr. Holmes has served as a collaborating investigator in many vaccine research programs since 2006, specializing in breast cancer vaccines for the prevention of breast cancer recurrence. He has been published for his vaccine work (7) and was awarded Fellow of the American College of Physicians for his accomplishments in research and academics.

Dr. Holmes will work closely with Cancer Insight, LLC, the cancer-vaccine focused clinical research organization (CRO) selected by BriaCell to manage the clinical and regulatory aspects of the Phase I/II study.

 - Cash Secured To Move Forward - 

In August 2016, BriaCell announced the closing of a non-brokered private placement financing, pulling in gross proceeds of $1.7 million. The terms of the financing were quite favorable. The company sold shares at $0.20 per share (Canadian). Investors also received one warrant exercisable over the next three years. The warrants are exercisable at $0.30 per share (CAD) if exercised in the next 12 months or at $0.35 per share (CAD) if exercised during year two or three. BriaCell intends to use the proceeds to fund general corporate purposes, which include the planned Phase I/IIa program with BriaVax, as well as develop the companion diagnostic platform known as BriaDx™.

Conclusion

What I find most interesting about BriaVax is the potential for a potent targeted approach to immunotherapy. BriaVax is interesting because the administration of a genetically engineered whole tumor cell vaccine has the potential to present multiple tumor-specific antigens to the immune system, stimulating dendritic cells and inducing a humoral response. The biomarker and gene expression data presented at AACR in April 2016 significantly improves the likelihood of response based on the double matching of HLA alleles. BriaCell is working on a companion diagnostic, BriaDx, to prospectively identify patients most likely to respond to BriaVax and, potentially, as a way to monitor patients response during clinical studies.

BriaCell Therapeutics remains one of my favorite under-the-radar immuno-oncology names. Therapeutic cancer vaccines have a lamentable history, but the science has come a long way since the failures of Dendreon's Provenge®. BriaVax is an allogeneic whole cell vaccine, and thus not hampered by the immune masking or the logistical commercial nightmares of previous autologous approaches. Instead, BriaVax seems to offer the ideal immunotherapy - powerful enough to induce both a broad-scale innate and adaptive immune reaction, targeted to reduce systemic side-effects, and personalized based on genetic biomarkers to improve the odds of success. Plus, with a market capitalization (USD) of only $20 million, the upside looks tremendous if the Phase I/II trial succeeds.

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