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Monday, November 9, 2015

Case Study Shows Potential For Breast Cancer Vaccine

Last month I wrote an article introducing investors to BriaCell Therapeutics (OTC:BCTXF / TSX:BCT.V). I encourage investors to view that article >> HERE << because it provides very good background on cancer immunotherapy and the company's whole cell cancer vaccine, BriaVax™, for the treatment of late-stage breast cancer. BriaCell is currently preparing to enroll the first patient in an open-label Phase 1/2 study with BriaVax™ before the end of the year. The company just received U.S. FDA approval of its revised Investigational New Drug (IND) application last week, although investors should keep in mind that BriaVax™ has already been tested in 18 patients to date, delivering impressive results in these Phase 1 studies.

The purpose of my article today is to follow up on the story for investors by specifically looking at a case study from one of those 18 advanced metastatic breast cancer patients treated with BriaVax™ in June 2005.

Quick Background On BriaVax™

BriaVax™ is a proprietary 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 in HER-2/neu. 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.

Case Report - Undeniably Impressive Results

Patient #10312:
In September 2003, a 58-year old postmenopausal woman presented to St. Vincent's Medical Center with infiltrating ductal carcinoma of the right breast (3 cm x 2.5 cm mass at 6 o’clock in the right breast [T2N3M1]) with right axillary adenopathy. The cancer was modified Bloom-Richardson grade II/III, with bony metastases identified in the manubrium. Histochemistry studies reported estrogen positive / progesterone weak; HER-2/neu histochemistry weak, fluorescent in situ hybridization (FISH) negative. The patient had a history of carcinoma in situ in 1998. Additional clinical problems at presentation included impending superior vena cava syndrome, pulmonary densities, a history of mitral valve prolapse, lumbar degenerative osteoarthritis, allergic rhinitis controlled with fexofenadine, and possible old granulomatous disease.

History: The subject was treated with doxorubicin and cyclophosphamide and showed prompt and complete remission after treatment. Subsequently, the patient was placed on letrozole; regional irradiation (5800 cGy) was directed to the manubrium and node-bearing areas (but not to the breast). In April 2005, there were multiple new and recurrent lesions in the right breast on mammography and increased activity in the sternal metastasis by isotope bone scan. By June 2005, a pulmonary lesion measuring 2.3 cm had clearly progressed.

Treatment: The patient then began treatment on an Institutional Review Board (IRB) and U.S. FDA-approved Phase 1/2 clinical trial (NCT00095862) under principal investigator, Dr. Charles L. Wiseman, MD, FACP. The patient was treated with intradermal injections of BriaVax™ (20,000 viable irradiated vaccine cells in four aliquots were applied to the back and thighs, and repeated every two weeks for three weeks, then monthly for three months). Approximately 2-3 days before inoculation, the patient received low-dose cyclophosphamide (300 mg/m2) intravenously. The patient received interferon-alpha to provide a “danger signal” 2-4 days after vaccine injection. Study investigators reported the treatment to be well tolerated, although the patient had a self-limited, untreated recurrence of benign positional vertigo.

Results: Study results were published by Charles L. Wiseman, MD and Alex Kharazi, MD in The Breast Journal in September 2006 (4). Repeat scanning after three inoculations showed substantial regression of virtually all identified tumor sites. CT scans showed only some residual, but non-measurable density in the lung, corresponding to a change in PET standardized uptake values (SUVs) from 10.2 to 5.3. The lesion was improved on MRI, which also showed regression of all the lesions in the breast.

After an additional three inoculations, the pulmonary lesion was undetectable on CT and PET. The MRI studies of the breast lesions showed a sequential decrease in aggregate volume from, initially 15.1 ml to 2.46 ml after three inoculations and to 1.6 ml after six inoculations (see below). The right axillary lesions were undetectable on PET and CT. Left axillary lesions, indeterminate as to inflammatory or neoplastic origin, regressed only slightly in volume, although showing reduced enhancement on MRI and PET. Isotope bone scans before and after treatment showed activity in the sternum, marginally less, without evidence of new lesions. No new lesions were identified, nor were any previously suspicious sites found to enlarge. Active disease was not confirmable on any imaging.

Follow-Up: Approximately three months (106 days) after the last inoculation (six total), PET, CT, and MRI studies identified multiple areas of recurrence in the right breast. Also noted were several brain metastases, lesions in the lung and mediastinum, and probable involvement in the liver.

Compassionate Use: The original protocol allowed for a total of six cycles of the BriaVax™ regimen. Study investigators petitioned and received approval from the FDA to reinitiate treatment in the subject under a compassionate use. Evaluation following three more inoculations demonstrated marked measurable regression of multiple brain and breast lesions, and improvement in the liver and chest. PET scan activity confirmed interval improvement of the size and intensity of previously seen multiple foci. No new lesions were identified, and no areas showed enlargement or growth by any imaging method.


Patient #10312, a 58-year old postmenopausal woman, presented with multiple sites of progressive metastatic breast cancer identified by CT, MRI, and PET scans. The patient demonstrated clear evidence of disease progression two months after cessation of letrozole. Following the administration of the whole-cell vaccine, BriaVax™ and adjuvant IFN-alpha, the patient demonstrated substantial regression with consistent findings in all three imaging methods. Multiple areas in the breast regressed in size and number, and the ipsilateral axillary node became undetectable. The MRI findings show tumor regression, changes in peak enhancement, and reduced vascularity post inoculation. 

This case is more remarkable because recurrence with metastases occurred following cessation of vaccine therapy, but reinitiation of vaccine inoculations led again to tumor regression, including regression of brain metastases. Importantly, the safety of the vaccine was confirmed, and the patient completed a total of ten cycles of therapy. Survival was 40 months post initial treatment, over three-times the 12.6 months that I calculated for the median overall survival for a patient with late-stage, treatment-refractory metastatic breast cancer by looking at various meta-analysis publications on PubMed (5, 6, 7).

It is important to note that this case study represents only one patient, and outliers will clearly exist in any data set; but, the results of patient #10312 cannot be denied. Only four patients were enrolled in the Phase 1/2 clinical that treated patient #10312. The survival rates for the patients were 7, 34, 36, and 40 months, yielding a median overall survival of 35 months. This is a superior median overall survival to every clinical trial or publication on patients with advanced metastatic disease we found PubMed (8).


BriaCell Therapeutics has a very interesting whole tumor cell cancer vaccine under development. It is admittedly very early-stage and has only been tested in 18 patients to date; however, the technology itself has been around for decades and company scientists have spent the last several years enhancing the platform by genetically engineering the cells to secrete GM-CSF, as well as improving the regimen by incorporating concomitant use of things like cyclophosphamide and interferon-alpha.

The company's initial focus is on late-stage metastatic HER-2-positive breast cancer, an estimated market in the U.S. of around 8,000 patients per year. The likely median overall survival for this population ranges only around 12-13 months (referenced above), creating a significant market opportunity for any company that can improve upon the existing treatment paradigm. I see this as easily a multi-hundred million dollar opportunity. Plus, the company has already received U.S. FDA approval to expand the current Phase 1/2 program into other HER-2-positive tumors, including ovarian, pancreatic, lung, bladder, and gastric cancer. This takes the target population in the U.S. from 8,000 to potentially 50,000 patients that might benefit from BriaVax™, easily putting the peak sales for the vaccine in excess of a billion dollars.

Obviously, this will all need to be validated in the current Phase 1/2 trial, but existing data generated to date looks encouraging, and with a market capitalization of only $20 million BriaCell Therapeutics certainly offers investors tremendous upside opportunity.


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