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Monday, October 26, 2015

BriaCell Therapeutics Advances Breast Cancer Vaccine

BriaCell Therapeutics (OTC:BCTXF / TSX:BCT.V) is an emerging immunotherapy company with a whole cell vaccine for the potential treatment of metastatic breast cancer. The company is led by a team of PhD's and oncologists. I've met with management at the company and believe there is meaningful upside potential in BriaCell based on the existing Phase 1 data generated to date, along with independent clinical work available in the literature. BriaCell's market capitalization is only $20 million, and thus must be considered a high risk investment. However, I think there is real potential here and the valuation certainly suggests a "ground floor" entry should the company's technology ultimately prove to be successful.

The purpose of this introductory article is to familiarize investors with the BriaCell story and to alert my readers that I plan to continue to follow and work with the company in the foreseeable future. A Phase 1/2 open label study is expected to begin shortly that has the potential to provide meaningful valuation inflection upon successful results in 2016.

Whole Cell Vaccines - A Brief History

The concept of cancer immunotherapy is perhaps the hottest area of biotechnology research right now. Citigroup estimates the global market for cancer immunotherapies in 2020 will eclipse $35 billion, and big biopharma companies are making a strong push into all stages of development. Major players include AstraZeneca, Pfizer, Bristol-Myers, Celgene, Juno Therapeutics, Kite Pharma, ZioPharm, Incyte, Amgen, and Novartis.

The purpose of immunotherapy is to harness the body's own immune system to more effectively target and destroy cancer cells. Cytokines, antibody therapeutics, and cancer vaccines have been commercialized over the past two decades with various levels of success. Today, some of the most exciting technologies include new classes of drugs such as checkpoint inhibitors, chimeric antigen receptor (CAR) technologies, and next generation vaccines (source: Loncar Investments).

A cancer vaccine is a vaccine that either treats existing cancer or prevents development of a new cancer. Vaccines that treat existing cancer are known as therapeutic cancer vaccines. The first therapeutic cancer vaccine approved in the U.S. was Dendreon's Provenge® in April 2010. For a various number of reasons, Provenge® was a commercial failure, but dozens of biopharma companies, large and small, are continuing to developing therapeutic cancer vaccines today.

Autologous tumor cells are an obvious source of tumor-associated antigens (TAA) for vaccination purposes, since, by definition, all relevant candidate TAA should be contained within them (de Gruijl TD., et al., 2008) and their use precludes the need for antigen preselection. However, the use of autologous tumor cells has been met with little success throughout the years. An analysis of cancer vaccine trials involving 440 patients conducted by the National Cancer Institute in 2004 found an overall objective response rate of only 2.6% (Rosenberg SA. et al., 2004).

This could be because autologous tumor cell vaccines may do little to stimulate an immune response that has already failed against antigens expressed by the tumor. Another possible reason is that while certain whole cancer cells provide surface antigens that are targets for a desired immune response, they also contain a high abundance of housekeeping proteins, carbohydrates, nucleic acids, lipids, and other intracellular contents that are ubiquitous in all mammalian cells. These ubiquitous molecules are not the intended targets of this therapeutic approach, and thus, the immune response generated is not sufficient to eliminate the cancer cells present (Lokhov PG., et al, 2010). An autologous approach also has certain logistical issues, including manufacturing lead time, obtaining sufficient quantities of autologous tumor cells, and cost.

To overcome the logistical problems of autologous tumor cells, research has turned to allogeneic approaches. The use of allogeneic tumor cells as a generalized vaccine is supported by two observations. First, the patient’s own dendritic cells (DC), not the vaccine cells themselves, activate tumor immunity (Huang et al., 1994). Second, many tumor antigens are shared with a given histologic tumor type (van der Bruggen et al., 2002), and some are universal tumor antigens thought to be expressed by all tumors (Nadler and Schultze, 2002).

Early Proof-of-Concept with GM-CSF Whole Cell Vaccines

Research conducted by Dranoff et al, 1993 found that granulocyte-macrophage colony-stimulating factor (GM-CSF) is an effective immune modulator that induces long-lasting specific anti-tumor response. The concept has a rather simple mechanism of action. Local GM-CSF secretion, through whole tumor cells genetically-modified to secrete GM-CSF in a paracrine fashion, simultaneously delivers a variety of tumor-associated antigens (TAAs) that causes the influx and activation of bone marrow-derived dendritic cells that process and present TAAs delivered by the tumor vaccine cells.

The dendritic cells then prime tumor-specific CD4+ and CD8+ T cells to mediate direct tumor lysis (Huang et al., 1996). Because the tumor-specific T cells are primed by antigens in the context of major histocompatibility complex alleles present in host bone marrow-derived cells, there is no need to match the haplotypes of the vaccine and the patient (Huang et al., 1994) - i.e. this can be done with an allogeneic "off the shelf" strategy.

A paper by Gupta & Emens, 2010 describes the early success of allogeneic GM-CSF-secreting vaccines. For example, a Phase 1 study tested GM-CSF-secreting pancreatic cancer cell vaccines in 14 patients and found that disease-free survival of over 10 years was demonstrated in three out of 14 vaccinated patients (Jaffee et al., 2001). A follow up Phase 2 study tested higher doses of the vaccine in 60 patients and demonstrated an overall survival rate of vaccinated patients was 26 months, compared to a historical rate of 21 months with similarly treated non-vaccinated patients (Laheru et al., 2007). Another separate Phase 1 study in 19 patients with metastatic hormone-naive prostate cancer demonstrated a median time to disease progression of 9.7 months (Urba et al., 2008). A large Phase 2 trial in the same population enrolled 55 patients, 34 who had evaluable disease, and 21 who had only a biochemical relapse (rising PSA only). This trial documented a median survival of 26.2 months in patients with evaluable disease.

But Not All Results Have Been Positive

In July 2004, Cell Genesys initiated a Phase 3 clinical trial called VITAL-1. The trial was designed to compare GVAX cancer immunotherapy plus docetaxel to docetaxel chemotherapy plus prednisone in early stage hormone refractory prostate cancer patients with metastatic disease. VITAL-1 completed enrollment at 626 patients in 2007 and sailed smoothly through the first Data Safety Monitoring Board (DSMB) review in 2008. In June 2005, Cell Genesys initiated a second Phase 3 clinical trial called VITAL-2, this time focusing on patients with later-stage disease. The primary endpoint of both trials was an improvement in overall survival.

August 2008, the company announced it was terminating VITAL-2 due to an imbalance of safety seen by an independent review of the DSMB. The DSMB based its recommendation on observing 114 deaths, of which 67 occurred in the GVAX plus docetaxel combination treatment arm versus 47 deaths occurred in the control arm. Several weeks later, the company terminated the VITAL-1 study based on a futility analysis that predicted a less than 30% chance of meeting the primary endpoint (Higano et al., 2009). The company eventually reported the imbalance in deaths seen in the VITAL-2 study lessened to 85 versus 75 deaths (Small et al., 2009), all of which were the result of disease progression and death from prostate cancer.

The failure of VITAL-1 and VITAL-2 was a surprise considering Cell Genesys conducted two separate Phase 2 trials in 114 patients total. The first trial (n=34) demonstrated an overall median survival for the treated patients of 26.2 months, which compared favorably with the literature based on historic trials with docetaxel. The second Phase 2 trial (n=80) also demonstrated positive results, with no median overall survival reached 12 months into the study.

The narrowing of the imbalances in VITAL-2 upon the second analysis in October 2008 led some to conclude that immunotherapy responses occur more slowly and later than responses to conventional cytotoxic chemotherapy (Hales et al., 2010). Others hypothesized that it is important to begin treatment with a cancer vaccines earlier in the natural history of cancer, before it becomes metastatic (Jaffee et al., 2001; Laheru et al., 2007). Researchers were encouraged by the safety profile of the vaccine, and the fact that the VITAL study confirmed the importance of conventional therapy on the vaccine-induced immune response (Emens, 2010).

An Introduction To BriaCell

BriaCell Therapeutics is an immuno-oncology company with an early-stage, patent protected, therapeutic cancer vaccine called BriaVax™. BriaVax™ was developed by Dr. Charles Wiseman at St. Vincent Medical Center, Los Angeles, CA. Dr. Wiseman is the Founder and Chief Medical Officer of BriaCell Therapeutics, and BriaCell now owns unencumbered rights to the technology. BriaCell came public in November 2014 through a reverse takeover.

BriaVax™ is a proprietary whole tumor cell vaccine isolated from a chest wall lesion of a 39-year-old women with metastatic breast cancer. The irradiated cells, SV-BR-1, are ER/PR negative, and overexpress HER-2/neu, a clinically validated target of effective monoclonal antibody therapeutics. HER-2/neu protein is a non-mutated tumor antigen that is overexpressed in a variety of human malignancies, including breast and ovarian cancer. For example, work by Disis ML, et al., 2002 shows that immunizing patients with subdominant peptide epitopes derived from HER-2/neu stimulates T cell immunity to HER-2/neu. Work done by People GE, et al., 2005 showed that a HER-2/neu (E75) vaccine was safe and effective in eliciting a peptide-specific immune response in vivo, and that HER-2/neu immunity seems to reduce the recurrence rate in patients with node-positive breast cancer.

BriaVax™ has been genetically engineered to release sargramostim (granulocyte macrophage - colony-stimulating factor [GM-CSF]) for up-regulation of professional antigen-presenting cells. Work gone by Dranoff G., 2002 confirmed earlier findings that GM-CSF is the most potent immunostimulatory secreted molecule for inducing tumor immunity. GM-CSF is believed to provide an antitumor effect that prolongs survival and disease-free survival in subjects with stage III and IV melanoma (Spitler LE., et al., 2000) and metastatic non-small cell lung cancer (Salgia R., et al., 2003). Also part of the treatment regimen is the addition of low-dose cyclophosphamide 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.
Cyclophosphamide: There is considerable evidence in animal tumor systems that antitumor immunity is modulated by suppressor T-lymphocytes, and that the cytotoxic drug cyclophosphamide (CY) can abrogate that suppression. Work done by Berd D., et al., 1986 demonstrated that metastatic malignant melanoma patients pretreated with CY had significantly better antitumor response to an autologous melanoma cell vaccine than patients that just received the vaccine alone. In short, CY inhibits the generation and function of CD8+ regulatory T cells (Traverso I., et al., 2012). 
Interferon-alpha: The use of IFN-a as a powerful adjuvant for dendritic cells development has been well documented in the literature. Work done by Paquette RL., et al., 1998 demonstrated that peripheral blood mononuclear cells cultured with IFN-a and GM-CSF developed dose-dependent a dendritic morphology and expressed high levels of the class I and II human leukocyte antigens (HLA), B7 costimulatory molecules, adhesion proteins, and CD40. Marrack P., et al., 1999 showed that use of IFN-a prevented activated T cell death during infections, and Santini SM., et al., 2000 showed that the addition of IFN-a to freshly isolated GM-CSF monocyte-derived dendritic cells generated a potent immune response to various HIV-1 antigens. Similar results were observed with an influenza vaccine (Proietti E., et al., 2002).
Treatment with BriaVax™ is the result of decades of clinical investigation and research into therapeutic cancer vaccines and the use of an allogenic 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-a to "step on the gas" and evoke prolonged immune response.

Phase 1 Results

The first human clinical work with SV-BR-1 was conducted by Dr. Charles L. Wiseman in collaboration with St. Vincent Medical Center in California. The Phase 1 study initiated in May 1999 and enrolled 14 patients with late-stage, treatment-refractory breast cancer. It was a heterogenous patient population that included women with various combinations of ER, PR, and HER-2/neu positive and negative metastatic disease to the lungs, bone, liver, and nodes. Over the course of the trial, 54 tumor cell vaccines were administered with a median dose of 14 x 106. Results were published in the 2010 (Wiseman CL., et al., 2010).

The results show that while most patients showed progressive disease after the initial induction phase of three vaccines, five patients showed stabilization and continued to receive vaccine at monthly intervals. No patients developed significant clinical regression, although many patients reported improved sense of well-being as measured in various categories. The mean survival was 17.2 months (95% CI, 5.8-28.5 months) with a median overall survival of 9.5 months (1.2 to 85+ months). Nine of the 14 patients received peripheral blood lymphocytes in addition to the tumor cells. These patients demonstrated a mean overall survival of 21.1 months (95% CI 5.0-37.2 months) and a median overall survival of 14.3 months (1.2 to 85+ months). Five of the nine patients treated with SV-BR-1/PBL survived at least 12 months and three survived 24 months or more. One patient (#11) remained alive at 85 months since first inoculation at the time of publishing.

The authors reported that toxicity was mild and consisted principally of erythema and pruritus at injection sites. There were no Grade 4 adverse events. They also found that the greater the number of previous chemotherapy treatments, the shorter the survival following vaccine. Wiseman CL., et al, concluded that application of SV-BR-1 had acceptable safety and demonstrated a median overall survival at least as good as many recent Phase 1 studies at the time of publishing, as well as noticeable improvements in pain and increased vitality.

After reading the Wiseman paper, I combed PubMed to try to get a sense of the true median overall survival for late-stage, treatment-refractory breast cancer patients with metastasis to the lungs, liver, or nodes. A 2009 paper published by Tacca O., et al. conducted a retrospective analysis of 578 metastatic breast cancer patients and found that overall median survival for second-line chemotherapy decreased to 12.3 months versus 22.5 months for first-line treatment. The authors found that survival rates for third-line treatment and beyond were stable at around 8 months. A review article by Briest & Steams, 2007 found that treatment with docetaxel was superior to paclitaxel as a second-line treatment in patients advanced breast cancer, 15.4 versus 12.7 months, respectively. A separate paper by Cardoso F., et al., 2001 conducted a retrospective analysis on the outcomes of various Phase 3 chemotherapy programs for second and subsequent lines of chemotherapy, reporting an overall survival range between 9.4 and 15 months for women with advanced, metastatic disease. The chart below shows several more peer-reviewed publications, with the data showing a mean median overall survival of 12.6 months.

In the Wiseman Phase 1 study discussed above, the number of prior chemotherapy regimens ranged from one to five, with a median of three. The results showing a median overall survival of 9.5 months in all 14 patients and 14.3 months in the SV-BR-1/PBL population does indeed compare well with historical ranges for chemotherapies. It is important to note that in this first Phase 1 trial, the SV-BR-1 tumor cells were not genetically engineered to express GM-CSF. Instead, GM-CSF was injected systemically in conjunction with the cells. Scientists at BriaCell believe that locally expressed GM-CSF in situ offers superior immune response than exogenously injected GM-CSF, and published literature supports the hypothesis that GM-CSF secreted in a paracrine fashion in the tumor micro-environment is superior to systemic delivery. 

In this regard, BriaCell scientists conducted a second Phase 1 trial in four late stage, treatment-refractory breast cancer patients with an updated cell line, SV-BR-GM-1, genetically engineered to secrete GM-CSF. Similar to the first Phase 1 study, subjects were pre-treated with cyclophosphamide to down-regulate the activity of regulatory T cells and injected with interferon-alpha to induce differentiation of dendritic cells and prolong activated T cell response. The trial was originally designed to enroll 24 patients but cut short after only 4 patients had been enrolled due to a desire to expand the protocol into additional cancer types. A shortage of funds to make the necessary adjustments (BriaCell was not public at the time) also played a part in cutting-short the study.

Despite the truncated study, results from the four patients that did enroll demonstrated a median overall survival of an impressive 35 months (7, 34, 36, and 40 months for each patient). This is a substantial improvement from the 8 to 15 months that would be predicted based on previously published literature. One patient demonstrated > 90% regression during treatment, had subsequent relapse once the treatment period concluded, and then responded to retreatment with written informed consent from the U.S. FDA (Wiseman CL, et al., 2006). I plan to cover this very interesting case study in more detail in my next article on BriaCell. Nevertheless, the data I have discussed in this article compares incredible well to published data in patients with advanced breast cancer.

The Planned Phase 1/2 Study

On March 10, 2015, BriaCell submitted a protocol to the FDA, summarizing its plans to test up to 24 late-stage cancer patients in an open label Phase 1/2 clinical trial (NCT00095862). This trial is being run under the IND for the small four-patient Phase 1 trial noted above, but this time management did alter the protocol to be allowed to keep treating patients as long as possible (without having to file for compassionate use) and to expand beyond breast cancer. Although the majority of the patients in the trial will likely be breast cancer patients, the protocol change was made to allow for inclusions of selected patients with other late-stage metastatic disease, including prostate, ovarian, pancreatic, lung, and bladder cancers among others.

This is an interesting consideration for the company because it allows them to explore whether or not BriaVax™ has utility in other HER-2 positive non-breast tumors, potentially opening the door to development partnerships and larger commercial opportunities for the technology. The company is currently working with the U.S. to finalize the clearance to begin the Phase 1/2 trial and hopes to start enrolling patients before the end of the year. The proposed design can be seen below.

In June 2015, the company signed an agreement for the cGMP manufacture of BriaVax™ with the University of California, Davis. Under the terms of the agreement, UC Davis will provide a number of services to BriaCell beyond cGMP manufactured product, including quality control and release testing. BriaCell has also secured the Siteman Comprehensive Cancer Center of Washington University, St. Louis as a backup provider, if necessary. Assuming the trial initiates later this year, BriaCell anticipates interim data to become available during the second half of 2016.

Conclusion - What's The Potential For BriaVax?

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. Low-dose cyclophosphamide was associated with improved survival in a randomized breast cancer vaccine study (Holmberg LA, et al., 2001) and interferon-alpha used in combination with GM-CSF has been shown to trigger long-lasting T cell response (Bracci L, et al., 2008).

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 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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