Chimera Research Group: What sets Briacell apart from other immuno-oncology approaches?
Dr. William V. Williams, President and CEO of Briacell: Briacell is developing a novel cancer immunotherapy based on a cancer cell line called SV-BR-1-GM a.k.a. Bria-IMT™. It was originally taken from a breast cancer patient, and further genetically altered to express GM-CSF, a stimulator of the immune system. The treatment, termed a targeted immunotherapy, is given as a live, irradiated, whole-cell preparation.
Bria-IMT™ is thought to work against breast cancer in the same way as Provenge does against prostate cancer by stimulating the immune system. But whereas Provenge is an autologous drug requiring complex manufacturing, we believe we can deliver a similarly personalized treatment with the ease of an allogeneic production.
Checkpoint inhibitors have become one of the greatest achievements so far in oncology, even leading to a Nobel Prize for pioneers in the field. Despite this success there are limitations; this class of compounds work best in “hot” tumors and less so in “cold”. Targeted cancer immunotherapies may not be affected by such environments; indeed, some research suggests they may actually turn “cold” tumors “hot”. This makes these treatments almost ideal therapies to combine with the checkpoint inhibitors to increase the immune responses.
Chimera Research Group: What makes Bria-IMT different from Bria-OTS?
Dr. William V. Williams, President and CEO of Briacell: There are two variants of the targeted immunotherapy. The first, Bria-IMT is currently in clinical trials. It is the original design using native cells which express GM-CSF. Bria-OTS is the next generation product now in development.
Briacell has seen signs of activity with Bria-IMT, notably in the preliminary PI/IIa study of 3 breast cancer and 1 ovarian cancer patients. Breast cancer Patient A002, termed a super responder, was a patient with advanced breast cancer whose tumor had an HLA allele matching one in Bria-IMT cells. She had near complete regression of multiple breast lesions and complete remission of a lung metastasis. Bria-OTS aims to improve the likelihood of success by delivering matches to 2 alleles, covering 90% of the population.
In a recent study, Bria-IMT was found to express high levels of Tumor-Associated-Antigens and demonstrated the potential to act as Antigen Presenting Cells, potentially activating previously primed CD4+ T-cells. These are all suggestive of mechanisms by which the cells can activate the immune system. We believe this combined with HLA matching will make for a more potent response.
Chimera Research Group: In the most recent Bria-IMT trial in breast cancer, how do you define tumor shrinkage? What would the disease control rate using RECIST 1.1 criteria?
Dr. William V. Williams, President and CEO of Briacell: We have been monitoring the tumors with CT scans and measuring the tumor size. While we do have one RECIST responder in our database (the original HLA match patient), there are none in the breast cancer trial although several have shown tumor shrinkage. These responses would be considered stable disease if using RECIST criteria.
The patients in the breast cancer trial were quite sick. The patients had received a median of 4.5 previous therapies most of which were chemotherapies leading to weakened immune systems. In fact, one patient had 20 lung metastases and 8 previous lines of therapy and despite those hurdles we still observed disappearance or shrinkage of all 20 tumors, which would be coded as a stable disease with the RECIST criteria. Breast cancer is already a difficult to treat tumor with immuno-oncology agents let alone the very late stage patient population in this trial.
Despite the high hurdles, however, we do see tumor shrinkage and see it in the patients we would have expected with the HLA matching hypothesis. While there is work to be done to increase those responses, the results of the trial go a long way in validating the proposed mechanism of action.
Chimera Research Group: What information is most important to take from the breast cancer data?
Dr. William V. Williams, President and CEO of Briacell: We think there are a couple of important points. First, the responses confirm what we already believed about the HLA matching hypothesis. The patients that we would have expected to have had the stronger responses had the stronger responses. Given that these patients had a median of 4.5 previous treatments and breast cancer is generally a tough indication for immuno-oncology, one would not expect RECIST responses but we certainly wanted to see an activated immune system that was impacting the tumor cells. This is what we observed and we see this as a vital confirmation of the HLA matching hypothesis and that we are on the right development path.
The trial also provided information about how Bria-IMT works and how to target patients. Part of the development process for drugs is not only to get information about its safety and efficacy but also to understand what type of patients are responding. This helps guide future trials and allows for an enrichment of these trials with patients most likely to see real benefits. The confirmation of the HLA matching hypothesis has given us the information needed to better design our future trials and increase our ability to succeed and demonstrate the ability of Bria-IMT to help patients.
Chimera Research Group: How important is it that you found PD-L1 expression on the circulating tumor cells?
Dr. William V. Williams, President and CEO of Briacell: This is an interesting but not entirely unexpected finding from the trial. Breast tumors already have PD-L1 expressed as did the patients in this trial but we also saw some upregulation of the expression after treatment with Bria-IMT. As has become abundantly clear over the past couple years, the expression of PD-L1 acts as a strong suppresser of immune responses direct against tumor cells. This is certainly the case here as well but this provides us a strong rationale to move forward to the combination trial.
If treatment with Bria-IMT is activating the immune system and the tumors respond by upregulating PD-L1, then the rational strategy on our part would be to combine it with a checkpoint inhibitor. This would limit the ability of the tumor micro-environment to dampen the immune response triggered by Bria-IMT and thus increase its efficacy.
Our goal is to have the first safety data from the combination trial in late 2018 with the early efficacy data to follow in early 2019.
Chimera Research Group: When would you expect data from a Bria-OTS trial?
Dr. William V. Williams, President and CEO of Briacell: The Bria-OTS trial has already started dosing in 2019 with the early safety data arriving late 2019. This would allow us to have the first efficacy look in early 2020.
Chimera Research Group: What do you believe would be the most important catalysts that will occur in the next 12 to 18 months?
Dr. William V. Williams, President and CEO of Briacell: We have touched on many of the important upcoming catalysts. Certainly the start of the combination trial of Bria-IMT with the safety data at the end of the year and efficacy in early 2019 is critical. Hand in hand with those first cuts of the data would be potential data presentations at AACR and/or ASCO. We certainly plan on submitting the data for scientific conferences and while we do not yet know where the presentations would occur, we fully expect to be presenting the early combination data at scientific conferences in 2019.
Looking a little further out in 2019 would see the start of the Bria-OTS trial, which would be our second clinical stage asset. A late 2019 start to the trial would lead to an early safety look at the beginning of 2020 and efficacy later in the year.
Finally, we are actively working on partnering our assets. While this process takes time and has no guarantees, the goal would be to bring on a partner that would provide not only additional capital but also the developmental experience to accelerate the process and potentially additional combination therapies to evaluate. The exact form and timing of any partnership is difficult to know but this is something our team is actively and aggressively working to complete and could certainly happen in the next 6 to 18 months.
Disclose: Briacell is a client of CRG