EXECUTIVE INTERVIEW – BriaCell Therapeutics: Recognizing the Power of Targeted Immunotherapies
Dedicated to enhancing the lives of cancer patients who are facing limited therapeutic options, BriaCell Therapeutics Corp’s mission has been to develop novel immunotherapies, as the most cutting-edge technology to fight cancer. Immunotherapies have become the forefront of the cancer treatments because they use the body’s immune system to destroy the cancer cells, offering higher levels of safety and efficacy than chemotherapy, with less likeliness of recurrence. Drug Development & Delivery recently interviewed Dr. William “Bill” Williams, MD, President and CEO, to discuss the value of targeted immunotherapies in the biopharmaceutical industry.
Q: What are the current limitations in the immunotherapy space, and why do you believe an “off-the-shelf” approach is ideal?
A: Immunotherapy takes advantage of the patient’s own immune system in fighting cancer. Immune responses all start with an antigen (which is something, usually a protein, recognized by the immune system) encountering an antigen-presenting cell. These antigen-presenting cells take up the antigen and process it. This processing usually involves breaking the antigen up into small pieces (peptides for a protein antigen). These peptide antigens are then bound to molecules called HLA molecules. Structurally, this is like a hot dog (peptide antigen) fitting into a hot dog bun (the HLA molecule). This complex of peptide antigen bound to HLA molecule is then displayed on the surface of the antigen-presenting cell. There it can be recognized by the antigen receptor on a T cell, also known as the T cell receptor. T cells are white blood cells that coordinate the immune response. Our bodies have billions of T cells with different T cell receptors. When a T cell has a T cell receptor that binds to a peptide antigen –HLA complex, that T cell is stimulated. In the case of a cancer antigen, that T cell would be stimulated to attack the cancer. There are different types of T cells. The major subtypes are CD4+ “Helper” T cells and CD8+ “Killer” T cells. The CD4+ T cells recognize peptide antigens bound to Class II HLA molecules, while the killer T cells recognize peptide antigens bound to Class I HLA molecules.
If T cells recognize a cancer antigen, they should be stimulated to attack the cancer. However, cancers have several strategies to avoid immune attack. One strategy is to shut down the T cells by making a molecule called CTLA4. CTLA4 works to deactivate both helper and killer T cells. This is a so-called immune checkpoint, as during normal immune responses (eg, when fighting an infection), CTLA4 is expressed late in the immune response to cool off the immune system after its work is done fighting off the infection. Cancer cells will sometimes express CTLA4, or stimulate its expression on other cells, to stop the immune system from attacking the cancer. Yervoy (ipilimumab) works by binding to CTLA4 and preventing it from shutting down the immune response. Another mechanism is for the cancer to express another checkpoint, called PD-L1 or PD-L2. These molecules can be expressed on the cancer cell and can bind to a molecule on CD8+ killer T cells called PD-1. This will shut off the killer T cells. This immune checkpoint has been the subject of great interest with several drugs currently available that bind either to PD-1, such as Keytruda (pembrolizumab) and Opdivo (nivolumab) or to PD-L1, such as Tecentriq (atezolizumab), Bavencio (avelumab), and Imfinzi (durvalumab). These current immunotherapies are known as checkpoint inhibitors. Because they work by releasing suppression of the immune system, they are prone to side effects. Immune checkpoints are typically used to prevent development of autoimmune diseases, where the immune system attacks normal tissues of the body. Because the current checkpoint inhibitors, as well as others in development, do not distinguish cancer-specific immune responses from any other immune response, they can lead to the development of autoimmune diseases. Thus, use of these agents can cause inflammation of the intestines (enterocolitis), liver (hepatitis), skin (dermatitis), nerves (neuropathy), and glandular system (endocrinopathy). This is because checkpoint inhibitors work by taking the “foot off the brakes” of the entire immune system.
Ideally, the immune response should be directed toward the tumor and not the rest of the body. Such a targeted immune response has been attempted using so-called “therapeutic cancer vaccines.” However, these have generally not been successful. One exception is a personalized medicine called Provenge (sipuleucel-t). Provenge works by taking antigen-presenting cells from a patient, stimulating them, and charging them with prostate-specific antigen (PSA). These are then given back to the patient where they induce an immune response specific for prostate cancer. Provenge prolongs survival in prostate cancer patients but suffers from the drawback that each dose of the treatment has to be manufactured for each patient. This is time consuming, very costly, and difficult to generalize. Ideally, it would be best to generate a targeted, personalized immune response against the cancer with an agent that is more readily available, or off-the-shelf. This would combine the success of the personalized approach with the ease of administration with an off-the-shelf drug. Such an agent, which puts the “foot on the gas” of the immune response, but in a targeted way only against the cancer, should also readily be combined with checkpoint inhibitors, which have a complementary mechanism of action.
Q: How does your signature immunotherapy drug work?
A: Our immunotherapy works by inducing an immune response specific for breast cancer and personalized to the patient. Bria-IMTTM was developed by Dr. Charles Wiseman at Saint Vincent’s Medical Center in California. Dr. Wiseman was treating a patient with metastatic breast cancer, and he obtained a piece of her cancer. He took this into the laboratory and developed a cell line called SV-BR-1. He then would take some of the SV-BR-1 cells and irradiate them, so they would not grow and used these to immunize patients with breast cancer against their tumors. He devised a regimen to boost the immune response. This included some low-dose cyclophosphamide to reduce immune suppression and local injections with granulocyte-macrophage colony stimulating factor (GM-CSF) to boost the response. He treated 14 patients with this regimen and had better clinical outcomes than expected. Dr. Wiseman then decided to engineer the cell line to directly express GM-CSF. He dubbed this SV-BR-1-GM, aka, Bria-IMT. He treated an additional 4 patients with irradiated Bria-IMT in conjunction with low dose cyclophosphamide to reduce immune suppression and followed-up with local interferon alpha to help boost the response. They all did well in general, but one patient in particular stood out. She had metastatic breast cancer that had initially responded to chemotherapy but then she relapsed. The cancer had metastasized to the lungs, soft tissues, and bones. After 5 treatments over 3 months, the cancer had shrunk, and then after a total of 7 treatments over 5 months, the lung and soft tissue metastases had disappeared, the breast tumors had gotten much better, and the bone metastases also improved. At that time, the study only allowed 5 months of treatment, so the treatment stopped. She relapsed several months later, and this included spread of the breast cancer to the brain (brain metastases). She was treated again and responded a second time, including disappearance of the brain metastases. Further analysis showed that she matched with Bria-IMT for HLA type. HLA molecules were mentioned earlier. These are the molecules that bind antigenic peptides and present them to T cells. HLA molecules are known to be “polymorphic.” That means that they are different in different patients but shared by some patients. This is an inherited trait similar to eye color. Eye color can be different in different people, but it is also shared by some people. HLA molecules are like that: they are different in different people, but it is also shared by some people. When people get tissue transplants (like kidney transplants), they are matched for HLA type. So immunologically it makes sense that the patient with the best response matched Bria-IMT at HLA because the same HLA type that is recognized by cancer-fighting T cells on Bria-IMT would also be present on the patient’s own cancer. The antigen-HLA complex recognized by T cells on Bria-IMT would stimulate cancer-specific T cells. These would then recognize the same antigen-HLA complex on the patient’s own cancer and attack it. This explains why the patient with the HLA match with Bria-IMT had the best clinical response.
BriaCell is using this information to innovate. We are modifying the HLA-type of the SV-BR-1 cell line, so we will be able to match more patients. Currently, the HLA types expressed on Bria-IMT match at one HLA allele to ~50% of the population, and match at two alleles for ~20%. (An allele is a version of a gene. For example, each person has two copies of each gene, one from their mother and one from their father. For eye color, they might have inherited a gene for blue eye color from their mother (the blue eye color allele) and the brown eye color allele from their father. We have determined that with eight different Class I HLA types (or alleles) and seven different Class II HLA alleles, we can single match >99% of the breast cancer population and double match ~90% of the population. BriaCell is developing SV-BR-1 cell lines that will express GM-CSF (as Bria-IMT does) along with interferon-alpha to stimulate the immune response. We will engineer these cells to express 15 different HLA alleles. These cell lines will be pre-manufactured, irradiated, and frozen in a state that will allow them to be shipped directly to clinics where they can be thawed and used to inject patients directly. This will allow us to match the cell line to the patient, providing personalized immunotherapy that is off-the-shelf (Bria-OTSTM).
Q: What has earlier proof-of-concept studies shown and current Phase I/IIa data shown?
A: I mentioned some of the early clinical studies earlier. Briefly, Dr. Wiseman treated four patients with the Bria-IMT regimen and had one remarkable responder who matched Bria-IMT at some HLA types. More recently, we treated an additional six patients in 2017. These patients all had very advanced breast cancer. The treatment was safe and well tolerated, and we had an additional remarkable responder. This patient had breast cancer that had spread to the liver and to the lungs. She had 20 different breast cancer metastases in the lungs. She also had failed seven prior rounds of treatment with eight different agents. In spite of this, all 20 of her lung metastases shrank and most completely disappeared with Bria-IMT treatment. She also matched Bria-IMT at two different HLA-types. This is very important confirmation of our HLA-matching hypothesis. This study is ongoing, and more patients are being treated. So far, treatment has been safe and well tolerated. We expect additional data to be available later this year on at least 12 patients.
Q: Why does BriaCell believe combination therapy is key?
A: Combination therapy has shown great promise for immunotherapy for some diseases. This includes combinations of two checkpoint inhibitors, both working by essentially “taking the foot off the brakes” of the immune response. But the side effects of autoimmune disease may also worsen for the combinations. Bria-IMT and Bria-OTS are designed to put the “foot on the gas” of the immune response in a targeted way, just targeting the cancer. So, when combined with checkpoint inhibitors that take the foot off the brakes, this should produce a very potent immune response against the patient’s cancer without worsening the autoimmune side effects.
Q: Your team is exploring HLA-typing? What can that offer patients?
A: HLA typing offers the chance to have patients treated with Bria-OTS, which will be personalized and tailored to induce to most potent immune response against the cancer. But the cell lines used will be pre-manufactured and stored in the frozen state, which offers the convenience of an off-the-shelf therapy. Contrast this with the recently developed CAR-T therapy. This therapy requires that patients have white blood cells removed and then manipulated in tissue culture, and then infused back into the patient. This process takes approximately a month, is very expensive, and has to be repeated for each treatment. The same is true for Provenge (mentioned earlier). Or approach circumvents these logistical and cost problems by using cell lines that grow easily in tissue culture at low cost and are premanufactured. The HLA typing personalizes the process, so you still get an immune response tailored to the patient.
Q: What is the timeline for your breast cancer drug?
A: Bria-IMT is in Phase IIa testing now and could progress on to a registration study as early as 2020. This would mean filing a licensing application with the FDA in 2022 and marketing approval as early as 2023. These are aggressive timelines but are feasible given the large unmet need in advanced breast cancer and the progress we have made in manufacturing. The Bria-OTS cell lines are being developed with the goal of initiating GMP manufacturing later this year and introducing them into the clinic in 2019. We anticipate ~2 years for Phase I/IIa testing to establish the safety of the new cell lines and preliminary efficacy. We would then negotiate with the FDA the design of a pivotal registration study, which would likely take ~1 year to recruit, 1 year to run, and 6 months to compile the data for filing with the FDA. Assuming accelerated review, Bria-OTS could be approved 6 months later (~2025).
Q: What will your team be doing with checkpoint inhibitors? Protein kinase C Delta?
A: Our team is in conversation with multiple large- and medium-size pharmaceutical companies to perform additional combination studies with other checkpoint inhibitors. This includes approved drugs (Keytruda, Opdivo, Yervoy, Tecentriq, Bavencio, and Imfinzi) as well as other drugs in earlier stages of development. We hope to run additional combination therapy studies, so we can best evaluate the combinations that will have maximal benefit for the patients.
The protein kinase C delta (PKCδ) program is separate from Bria-IMT and Bria-OTS. This program is based on the observation that ~30% of all cancers have mutations in a gene called RAS, and mutated RAS can drive these cancer cells to grow and proliferate. Many pharmaceutical companies have tried to make a RAS inhibitor, but to date, none have been successful. However, cells that are transformed by RAS mutations appear to become “addicted” to PKCδ signaling. This appears to be because PKCδ acts on RAS to prevent it from being broken down and degraded. When PKCδ is inhibited in a RAS transformed cancer cell, the RAS is degraded, and the cells stop growing and die. BriaCell has licensed PKCδ inhibitors that are small molecule drugs. These are potent and selective inhibitors. They have shown activity against a number of RAS-transformed cancers in pre-clinical studies, including pancreatic, colorectal, lung, and breast cancer as well as melanoma. We are perfecting the drug-like properties of our molecules and hope to introduce them into the clinic within the next 2 years.
Q: How do you stack up to other immunotherapy companies?
A: BriaCell is markedly undervalued compared with other immunotherapy companies at a similar stage of development. BriaCell is in Phase IIa clinical testing, with cutting-edge technology, developing an off-the-shelf approach to personalized immunotherapy. But our valuation is far below other companies at a similar stage of development, and even below the value of many immunotherapy companies that have not yet entered the clinic. BriaCell has an experienced management team, is involved in over 10 drug approvals, and is establishing proof-of-concept for a large number of drugs. This experience will ensure that Bria-IMT, Bria-OTS, and PKCδ inhibitors will be properly developed to reach the finish line. This should benefit a large number of cancer patients as these promising drugs become available.
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