By John Vandermosten, CFA
NASDAQ:BCTX
BriaCell Therapeutics Corp. (NASDAQ:BCTX) is a clinical stage oncology company incorporated and first listed on the public markets in 2014 pursuing breast cancer treatment. It is using cell-based targeted immunotherapies to stimulate a cancer fighting immune response to destroy tumor cells. The company’s lead candidate, Bria-IMT™, is being advanced in combination with other therapies including checkpoint inhibitors to combat breast cancer. In addition to Bria-IMT™, the company offers a portfolio of other preclinical assets addressing prostate, non-small cell lung, melanoma and other cancers. In clinical work to date, BriaCell has shown a strong correlation between the efficacy of Bria-IMT™ and patients that have a close human leukocyte antigen (HLA) match with the therapeutic cells. Read on for further details about immunotherapy, the company’s achievements in the clinic, and what to expect from this innovator down the road.
Immunotherapy
Over the last several decades, immunotherapy has emerged from obscurity into the mainstream of cancer and other disease treatment. Some of the earliest records of immunotherapy date back to ancient Greek and Egyptian times where tumor regression was recognized in patients that had contracted an infection.1 In the late 19th century, physician William Bradley Coley pioneered work in the discipline by injecting streptococcus into cancer patients which dissolved tumors, although with inconsistent results. In 1896, physician George Dock observed that a woman who recovered from the flu experienced remission from her cancer. While the field was largely dormant for the next several decades, it began to reemerge in the 1980s with research related to hepatitis B. However, it was in cancer where immunotherapy or immuno-oncology (IO) would reach its broadest audience. Immunologists Tasuku Honjo of Japan and James Allison of the United States made dramatic strides in immune cell research during the 1990s. Their work led to the development of checkpoint inhibitors and receipt of the Nobel Prize in 2018. This class of drug has transformed the field of IO and is widely included as part of combination therapies with other innovative immunotherapies.
New Frontiers in Immunotherapy
While checkpoint inhibitors and other immunotherapies have improved the survival and side effect profile of cancer treatment and provided a complement and even an alternative to surgery, radiation and chemotherapy, there is still a long way to go. This unmet need has encouraged new candidates to emerge that seek to more precisely stimulate the immune system and work in conjunction with other immunotherapies to eradicate cancer. One of the emerging areas for cancer treatment is in therapeutic vaccines, a subclass of targeted immunotherapies. In contrast to a prophylactic vaccine which is administered before a disease is contracted, a therapeutic vaccine is given afterwards as treatment. One of the first therapeutic vaccines was Dendreon’s Provenge for prostate cancer which was approved in 2010. While only a few in this class have been given the regulatory nod, there are almost ten Phase III and dozens of Phase II assets in development.2
Bria-IMT™
BriaCell’s lead candidate, Bria-IMT™, is a targeted immunotherapy derived from a human breast cancer cell line. The source of the cell line was a grade II, estrogen receptor (ER) and progesterone receptor (PR) negative tumor overexpressing the HER2/neu protein. The product is genetically engineered to activate the immune system to destroy breast cancer tumors by producing cancer antigens and granulocyte macrophage-colony stimulating factor (GM-CSF), which acts as a cytokine and boosts the presentation of antigens to T cells. While the mechanism of action has not yet been fully characterized, Bria-IMT is thought to leverage the patient’s antigen presentation system via the stimulation of dendritic cells which in turn stimulate T cells to attack the cancer.
GM-CSF is a hematopoietic growth factor and immune modulator, produced by a variety of cell types. It stimulates stem cells to produce granulocytes and activates dendritic cells, all activities of the innate immune system. Activated dendritic cells trigger CD4+ and CD8+ T cells to recognize tumor cells and eliminate them. Cancer-specific antigens are presented to T cells, which are then activated to seek out and destroy the cancer via direct or indirect means. The indirect approach functions by inducing a humoral immune response while the direct mechanism involves the T cells directly attacking the malignancy. Bria-IMT™’s efficacy is enhanced by combining it with other immune system activators, low doses of cyclophosphamide, and interferon-α which are expected to improve the success of the therapy.
Bria-IMT™ has proven particularly effective in patients whose human leukocyte antigens (HLA) closely match that of the source for the therapy. HLA markers are proteins and are used by the immune system to determine whether a cell is self or non-self. They also are the molecules in the immune system that initiate immune responses. Antigens, which are proteins recognized by the immune system, bind to HLA molecules and this complex of antigen-HLA is recognized by T cells and activates them. Individuals have many HLA markers which are inherited from our parents. Brothers and sisters are frequently a close match for one of their siblings. Some HLA types are more common than others supporting an allogeneic approach that could address a high proportion of the breast cancer population. BriaCell is developing an off-the-shelf candidate, designated Bria-OTS™, which is based on multiple cell lines that have been genetically engineered to HLA-match over 99% of all third-line breast cancer patients.
Encouraging results from BriaCell’s 23-patient monotherapy study showed improved progression free survival (PFS) in the group matching at two or more HLA classes. The superior performance in this group is attributed to improved communication between the patient’s immune system and the HLA-matching cell line where the antigen-HLA complex presented by Bria-IMT™ can directly stimulate the cancer-fighting T cells. In patients whose HLA profile does not match that of Bria-IMT™, the immune system may not recognize it as a legitimate source of disease-associated antigens.
Bria-IMT™ is administered intradermally in multiple sites on the thighs and upper back. The treatment regimen includes cyclophosphamide to reduce immunosuppression and interferon-α to direct the immune response towards a Th1 response. The candidate is also being investigated in combination with the IDO inhibitor epacadostat and PD-1 inhibitor retifanlimab.
Full Pipeline
In addition to Bria-IMT™, BriaCell is developing other oncology programs using variations of the lead candidate. Bria-OTS™, an off the shelf approach, is the subject of an upcoming investigational new drug (IND) application which, if cleared, will allow for the start of studies to support a second breast cancer indication. Bria-OTS™ will match with patient HLA types to produce a potent and selective immune response against the target cancer and address over 99% of the patient population. The pipeline offers other programs harnessing the same technology targeting prostate, non-small cell lung (NSCLC), melanoma and other cancers which are expected to be the subject of INDs submitted over the next two years.
Bria-IMT™ Clinical Trials
Phase I Study
BriaCell has initiated several early stage studies to investigate Bria-IMT™. A small 4-patient Phase I study was conducted at St. Vincent Medical center in Los Angeles from 2004 to 2006. It showed efficacy in advanced disease with one patient experiencing widespread regression at multiple sites of metastatic breast cancer.
Phase I/IIa (Completed)
This success prompted further work in a Phase I/II study of Bria-IMT™ for breast cancer patients who were refractory to standard therapies. In this trial, 23 individuals with advanced metastatic breast cancer were dosed over the 2017 – 2018 period. It was designed to administer a pre-treatment of a low dose of the chemotherapeutic agent cyclophosphamide (to reduce immune suppression) then Bria-IMT™ followed by interferon-α at the inoculation sites to boost the response. Treatment was given every two weeks for the first month, then monthly afterward. Tumor regression was noted in three patients and a clinical benefit of 71% (5/7) was achieved for patients with grade I and II disease.
Phase I/IIa Combination (Ongoing)
A separate and ongoing Phase I/IIa study is investigating Bria-IMT™ along with an anti-PD-1 antibody6 and IDO17 inhibitor epacadostat8 in a combination approach in breast cancer patients that have failed two or more prior lines of therapy. The regimen includes a pre-dose of the chemotherapy cyclophosphamide and post-dose antiviral interferon-α2b. 12 patients have been evaluated so far and three of four patients with grade I/II tumors attained disease control.
Briacell provided an update of the trial progress in Spring 2021 at the American Association for Cancer Research (AACR) Annual Meeting. A poster was presented with several important highlights related to Bria-IMT™’s consolidated performance in the multiple Phase I and II trials that have been completed or remain active.
Consolidated Trial Findings
➢ Bria-IMT™ induced an effective immune response and disease control in heavily pre-treated patients;
➢ Patients with grade I and II tumors were more likely to respond to therapy;
➢ A stronger immune response evidenced by delayed type hypersensitivity (DTH) correlated with disease control and longer progression free survival;
➢ In the Bria-IMT™ monotherapy group, there was a correlation between HLA matching and disease control;
➢ No patients with elevated circulating tumor cells achieved disease control.
While trial enrollment has slowed due to the pandemic, additional patient enrollment and updated analyses are expected to be provided at AACR and American Society of Clinical Oncology (ASCO) in the spring of 2022.
Summary
BriaCell has conducted several early-stage trials investigating Bria-IMT™ in heavily pretreated breast cancer patients. Initial data has shown improvements in progression free survival for this difficult to treat group, especially for those with an immune reaction (DTH), grade I/II tumors and a strong HLA match with the cancer cell line. The active Phase I/IIa combination study is of an adaptive design and will continue to enroll patients until there is sufficient data to schedule an end of Phase II meeting with the FDA. Based on what we have seen so far, we anticipate that the pivotal trial design will target patients that are a close HLA match to the breast cancer cell line presenting lower grade tumors. There is also hope for patients that are not a close HLA match for Bria-IMT™ as the company is developing multiple cell lines that express other HLA phenotypes and should be able to address up to 99% of the target population.
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1. Dobosz, P., Dzieciatkowski, T. The Intriguing History of Cancer Immunotherapy. Front Immunol. 2019; 10: 2965.
Published online 2019 Dec 17. doi: 10.3389/fimmu.2019.02
2. Source: Evaluate Pharma, Ltd. Accessed October 2021.
3. Source: BriaCell Website Accessed November 2021. MOA - BriaCell
4. BriaCell AACR 2020 Poster Presentation. Predictors of response to a modified whole tumor cell immunotherapy in patients with advanced breast cancer from two phase I/IIa trials.
5. Source: BriaCell Website accessed November 2021.
6. The trial has used Incyte/Macrogenics’ retifanlimab and Merck’s Keytruda in the role of PD-1 inhibitor.
7. IDO: indoleamine 2,3-dioxygenase
8. Epacadostat targets and binds to IDO1, an enzyme responsible for the oxidation of tryptophan into kynurenine. By inhibiting IDO1 and decreasing kynurenine in tumor cells, epacadostat increases and restores the proliferation and activation of various immune cells, including dendritic cells (DCs), NK cells, and T-lymphocytes, as well as interferon (IFN) production, and a reduction in tumor-associated regulatory T cells (Tregs). (Source: NIH Drug Dictionary)
9. BriaCell Investor Presentation Fall 2021