BriaCell Therapeutics (TSXV:BCT; OTCQB:BCTXF) has reported impressive early safety and efficacy data with its lead immunotherapies for the treatment of advanced breast cancer.
“Right now, there is no immunotherapy that works by itself against advanced breast cancer, an unmet medical need that was responsible for more than 40,000 deaths in the U.S. in each of 2017 and 2018,” Dr. Bill Williams, president and CEO, says in an interview with BioTuesdays.
Immunotherapy is a type of cancer treatment that marshals the ability of the body’s immune cells to destroy cancerous tumors, with the advantage of fewer side effects than chemotherapy.
BriaCell’s lead drug candidate, Bria-IMT, completed a Phase 1/2a clinical study in December, with “outstanding safety and efficacy data,” Dr. Williams contends.
Bria-IMT is now in a Phase 1/2a combination study with Merck’s (NYSE:MRK) checkpoint inhibitor, KEYTRUDA, and has shown “excellent safety and evidence of additive or synergistic activity,” he adds.
Dr. Williams says the company recently signed a clinical trial collaboration and supply agreement with Incyte (NASDAQ:INCY), which “will give us additional combination immunotherapies to try with Bria-IMT.”
BriaCell also is developing Bria-OTS, an off-the-shelf personalized immunotherapy, with patients matched to one or two of 15 HLA (human leukocyte antigen) alleles based on a quick diagnostic test performed on human saliva. HLA typing, for example, is used to match donor and recipient to ensure the success of the organ transplantation.
Personalized therapy without the need for personalized manufacturing
“We have seen several remarkable responses in late-stage breast cancer patients who match Bria-IMT at certain HLA alleles,” Dr. Williams says, adding that this “supports development of Bria-OTS and a related diagnostic test, BriaDX.”
Bria-IMT traces its roots to a breast cancer cell line called, SV-BR-1, developed by Dr. Charles Wiseman, a co-founder and inventor of most of the company’s intellectual property.
He conducted the first proof-of-concept study with SV-BR-1 between 1999 and 2003. The study, with 14 late-stage, treatment-refractory breast cancer patients, demonstrated a median overall survival of 12.1 months, about twice what he was expecting, and no severe drug-related adverse events.
According to Dr. Williams, SV-BR-1 was then genetically engineered to secrete granulocyte/macrophage-colony stimulating factor (GM-CSF), a monomeric glycoprotein which activates the immune system, effectively creating Bria-IMT.
Dr. Wiseman conducted a second proof-of-concept study with one ovarian cancer and three breast cancer patients between 2004 and 2006, using a combination of Bria-IMT; cyclophosphamide, a chemotherapy; and interferon alpha.
The study generated a median overall survival of 35 months, which was very impressive without serious side effects. Dr. Williams says one robust responder had a more than 90% tumor regression during treatment. When treatment halted, according to the FDA protocol, the patient relapsed, but then responded when treatment resumed.
“This patient was the only one matching a key HLA allele with Bria-IMT and she experienced tumor regression and complete remission at some metastatic sites,” Dr. Williams points out.
Dr. Williams, who joined BriaCell in late 2016, says Dr. Wiseman’s research funding ended after the second proof-of-concept study and little progress was made until the company was recapitalized during a reverse takeover earlier in the decade.
In 2017, the company reinitiated treatment with the Bria-IMT regimen in an FDA-approved clinical trial with 23 advanced breast cancer patients. “We confirmed Bria-IMT’s mechanism of action and achieved proof of concept,” Dr. Williams contends. “Tumor regression was seen in patients who matched Bria-IMT at HLA loci, confirming our main hypothesis.”
In the study, 21% of patients with one or more HLA matches had tumor shrinkage and 37% of patients had a biological response, which includes tumor shrinkage or lower circulating cancer-associated cells. In a subset of patients, with two or more HLA matches, 40% of patients had tumor shrinkage and 60% had a biological response.
“One patient in the study had previously failed seven rounds of chemotherapy and had 20 lung metastases. She also had two HLA matches and after she was treated with a Bria-IMT regimen, her lung tumors either disappeared or shrunk to tiny scars,” Dr. Williams notes.
In addition, Dr. Williams says BriaCell observed high levels of PD-L1 molecules on circulating cancer cells and cancer-associated cells in more than 90% of the patients. PD-L1 molecules block immune cells from attacking cancer cells. Checkpoint inhibitors, such as KEYTRUDA, are designed to neutralize PD-L1 induced immune suppression in cancer patients.
“That’s why we believe there is a strong rationale of combining Bria-IMT, which increases an immune system response, with checkpoint inhibitors, which are designed to decrease suppression of the immune system,” Dr. Williams suggests.
BriaCell is now in a Phase 1/2a study combining Bria-IMT and Merck’s checkpoint inhibitor, KEYTRUDA, in hopes of inducing a more potent anti-cancer response in advanced breast cancer patients.
At the 2019 American Association for Cancer Research annual meeting in April, BriaCell reported initial findings from the first six heavily pretreated “salvage” patients enrolled in the Bria-IMT and KEYTRUDA combination study. Early evidence suggests “rapid additive or synergistic anti-tumor activity, including examples of tumor reduction at multiple sites and disease stabilization,” he notes. The combination also was safe and well tolerated.
“While in earlier monotherapy studies, HLA matching between patients and Bria-IMT appeared to be important for the development of anti-cancer activity, we have seen some evidence suggesting that Bria-IMT in combination with KEYTRUDA may work for patients regardless of HLA matching,” Dr. Williams offers.
The company expects to have additional study data to report at the San Antonio Breast Cancer Symposium in December.
BriaCell also is advancing its combination thesis with additional compounds for advanced breast cancer under a clinical trial collaboration with Incyte. The companies hope to begin a Phase 1/2a study in the second half of 2019 with approximately 60 patients, and report safety and efficacy data by the end of 2020.
Incyte plans to provide compounds from its development portfolio, including INCMGA0012, an anti-PD-1 monoclonal antibody similar to KEYTRUDA, and Incyte’s lead cancer immunotherapy candidate, epacadostat, an IDO1 inhibitor, to be used in combination with Bria-IMT.
Hypothetical Mechanism of Targeted Immune Activation by Bria-IMT™ & Bria-OTS™ in Advanced Breast Cancer
Dr. Williams says the company also is developing Bria-OTS cell lines to express both GM-CSF and interferon-alpha along with patient-specific matching HLA types. “Cell lines will be pre-manufactured, expressing HLA alleles and matching more than 99% of the overall advanced breast cancer population.”
Using BriaDX’s companion diagnostic, he says the off-the-shelf alleles will be matched and selected for each patient prior to treatment. As a result, each patient would have a personalized mix and match of off-the-shelf alleles. “This has the potential to be personalized therapy without the need for personalized manufacturing.”
Dr. Williams explains that the mechanism of action of Bria-IMT/Bria-OTS involves the production of breast cancer antigens. Bria-IMT/Bria-OTS further boosts the immune response by secreting the GM-CSF protein. “Breast cancer antigens are taken up by dendritic cells and presented to CD4+ and CD8+ T-cells implicated in tumor destruction,” he suggests.
Bria-IMT/Bria-OTS also directly stimulates cancer-fighting CD4+ and CD8+ T-cells, further boosting the immune response, he adds. This unique mechanism sets Bria-IMT/Bria-OTS™ apart from similar immunotherapies. “Bria-IMT/Bria-OTS efficacy is enhanced when there is HLA matching of Bria-IMT/Bria-OTS with the patient. So, if the HLA type of a patient matches at least partially the HLA type of our cell line, we believe it is much more likely that the patient will experience a strong anti-tumor response.”
The company hopes to receive FDA authorization to begin dosing patients with Bria-OTS at the end of 2019, and expects to report initial safety and efficacy data by the end of 2020. “These results should allow us to segue into a combination study with Bria-OTS and a checkpoint inhibitor, as informed by our results with Bria-IMT combination therapy, at the end of 2020.”
“We anticipate that 2020 may be our value inflection point as we prepare for a registration study of Bria-IMT in combination with a checkpoint inhibitor,” Dr. Williams suggests.
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