What is SV-BR-1-GM Whole Cell Therapeutic Vaccine and how can it help patients with metastatic breast cancer? I want to introduce you to BriaCell and to our therapeutic approach. I'm gonna start by sharing my screen and show you, the way our therapy works. We've developed a cellular approach to cancer immunotherapy, that's also a targeted approach. The way that it works is that we've isolated a breast cancer cell line. Which we call Bria-IMT, and this breast cancer cell line has multiple functions. It's been stably transected with the CSF2 (Colony Stimulating Factor 2), which encodes GM-CSF. And so we believe that it works by several different mechanisms. One is that, it produces a number of breast cancer (metastatic breast cancer) related antigens. These are taken up by dendritic cells, processed and then associated with HLA molecules, and then that complex is presented on the surface to CD4 and CD8 positive T cells.
And these then go on to recognize that same, antigen HLA complex on the surface of the patient's breast cancer and attack it, and the GM-CSF is known to boost this dendritic cell response. But what appears to be relatively unique to our approach is that the cell line also expresses both class 1 and class 2 HLA molecules, which is a bit unusual and we've shown in a publication that it's able to function as an antigen presenting cells. In other words, the antigen presenting cells can directly stimulate CD4 and CD8 positive T-cells to further boost the response. So we've come to refer to this as the indirect mechanism through dendritic cell processing and presentation of breast cancer related antigens produced by the Bria-IMT and a direct mechanism whereby there's a direct stimulation through the HLA molecules of the Bria-IMT cell line. Now, we have taken this into the clinic in 3 clinical studies over time. The first one was started by our scientific founder, Dr. Charles Wiseman. Dr. Charles Wiseman initially developed the Bria-IMT cell line and used it in a couple of studies. First without, before it was transfected with GM-CSF and got good safety and some encouraging survival data (sheets).
And then in the study in four patients with the GM-CSF trans -stably produced by the cell line. And in that study there was a remarkable responder, a lady who had a metastatic breast cancer that is spread to the lungs and to the soft tissues and into the breast.
And she had a remarkable a partial response, but almost a complete response to the therapy. And it turns out that she matched the Bria-IMT cell line at two different HLA types, and of course, based on our mechanism of action, this makes sense because it means that Bria IMT are stimulating the T-cells to re recognize the antigen HLA complex that is also present on the patient's tumor. So those same T-cells can be stimulated by the Bria-IMT and then go on to attack the tumor (burden). And so this is very encouraging early data. We then went on to perform a 23 patient study with the same regimen, and by the way, let me just describe in a little bit of detail how we do this. So the Bria-IMT cells are grown under GMP conditions.
They're then harvested and irradiated, so their replication incompetent. They can't grow anymore, but they are still viable (cell viability) or about 90% viable, and they're frozen down in viable freezing media, and they're available to ship overnight to the clinical site. Where they can then be thought out and injected into the patient. It's been combined in the initial studies with a little bit of low dose cyclophosphamide 2 days before to reduce immune suppression (immune response). And then we follow up with some local, again, very low dose alpha interferon to help boost that response. So this has been initial study we had cycles every 2 weeks for the first month, and then once a month after that.
And after Dr. Wiseman's initial very encouraging results, we did an additional 23 patients. And we also noted that there was a marked proclivity for patients with HLA matching to have enhanced clinical benefit. So overall, we dozed a total of 27 patients with this monotherapy regimen. So in our combined experience with the, what we call the monotherapy regimen we dozed a total of 27 patients and again, if they had especially two or more HLA allele matches with the Bria-IMT, they were much more likely to have disease control than clinical benefit, especially in patients who were able to mount an immune response. Some of these patients were so sick that they couldn't mount an immune response against the Bria-IMT. The inoculations that we give are into the skin intradermal in the upper back and in the thighs, and some patients just don't develop any response to that. But during the study they do come back a couple of days later to check their delayed type hypersensitivity response.
And in those who did have a DTH response, if there was HLA matching the disease control rate was actually very good. So we went on from, and we decided to combine with PD-L1 inhibitors or PD-1 inhibitors rather. And the reason for this is twofold. One is that it just makes sense. because the PD-1 inhibitor would take the foot off the brakes of the immune system while we're putting the foot on the gas and that should be synergistic (immune response). But also because in our initial study we evaluated circulating cancer cells and cancer associated cells, and these in over 90% of the patients express PD-L1. And in some cases we saw the PD-L1 expression go up over time during the study. So we thought it would be good to combine with a PD-1 inhibitor and see if we could enhance our response. And that's brings us to our current presentation at the San Antonio Breast Cancer (SABCS) meeting. So at this in our study, we started with 11 patients who were treated in combination with Pembrolizumab and these patients were very heavily pretreated as might be expected. I think it was a median of 5 prior failed therapy attempts, four of them did roll over from our monotherapy study. And some of them could not mount an immune response, but in spite of this, we still saw some very encouraging results with one patient achieving a partial response and several others doing well on having, tumor reductions on the study.
We then developed a collaboration with Inside Corporation and started to use their PD-1 inhibitor, Retifanlimab. So Retifanlimab is very similar to Pembrolizumab in these studies. By the way, we're doing our cycles every 3 weeks, so it just makes it much simpler to just do it every 3 weeks throughout. And also, that was the pembrolizumab regimen when we started our clinical trial it was interrupted by COVID, but we're back on track now in recruiting patients, and we've treated a total of 22 patients overall. So that brings us to our combined experience with pembrolizumab and Retifanlimab. And you can see that this is our poster from the San Antonio Breast Cancer meeting.
These patients, again the monotherapy experience is shown in the upper in the first table here, table 1 in the upper row. And then in the bottom is the combination, experience again, 22 patients altogether. Median age of 62, BMI 27, average of on the median 6.5 prior regimens that they've failed with a range of 2 to 13 and approximately 3 years since the initial diagnosis of that range from 0.2 years up to 15 years, and I've already talked about our experience in the monotherapy, but in the PD-1 combination, we had all told 2 partial (response) responders, and I believe 5 altogether stable disease patients. Out of these 22, and again, you can see that in the patients who matched at least at one HLA type, we had a higher clinical benefit rate.
Now, in terms of the data here in this lower left, there's a total of 14 patients because the clinical trial is ongoing, so we don't have data on all 22 patients. We have data on 11 treated in combination with pembrolizumab. One actually transitioned from pembrolizumab to Retifanlimab. And then we have a data on total of four patients in this particular table here. But you can see that in the patients in this graph, in the lower left. The bar graph with the up and down bars that of the patients who got to their first imaging endpoint and were able to get imaging, 3 out of 5 in the Pembrolizumab combination had reductions in tumor. Another one had stable disease, and in for the Retifanlimab, again, it was 3 out of 5 with reductions in the size of their tumors.
Read and Share the Article Here: https://oncologytube.com/v/41510
Another thing we wanted to look. Was the time on clinical trial as you can probably deduce, it's very hard to compare things like progression-free survival in this type of patient population with any data because the treatments for breast cancer are evolving so rapidly that it's hard to get a good control group to compare to. So what we decided to do was to compare each patient to themselves to their last therapy. So we looked at the time on their last therapy, and then we looked at the time on our clinical trial and we basically subtracted the one from the other. And you can see in this bar graph on the lower right here, figure 3, that approximately half of the patients and actually a little bit more than half.
We present exploratory post-hoc data for patients with metastatic breast cancer (MBC) treated with the SV-BR-1-GM regimen (SV) alone (NCT03066947) and in combination (CO) with immune checkpoint inhibitors (ICIs) (NCT03328026).
SV comprises cyclophosphamide 300 mg/m2 i.v. 48-72 hours prior to SV-BR-1-GM (20 x 106 cells) intradermally, followed by interferon-alpha-2b on days 2 and 4 at the SV-BR-1-GM inoculation sites. In NCT03066947, SV was administered every 2 weeks for 3 cycles and thereafter monthly, but in NCT033226, SV was administered every 3 weeks in combination with PD-1 inhibitors. The treatment was continued until progression of the disease or severe toxicity.
There were two grade 4 adverse events that were not treatment-related: worsening pleural effusion and changed mental status. Patients with matched HLA and the delayed-type hypersensitivity skin test, peripheral blood circulating tumor cells, and cancer-associated macrophages exhibited a significant improvement in PFS.
Multiple subtypes of BC shown clinical advantages, notably in individuals with HR+ illness undergoing combination therapy. Currently, a Phase II clinical investigation is evaluating the efficacy of SV-BR-1-GM in combination with ICIs.
Produces antigens (proteins made by breast cancer cells). GM-CSF is a protein that, when secreted, augments the immunological response. Antigens are "presented" to CD4+ and CD8+ T-cells, which are known to destroy tumors. Additionally boosts cancer-fighting T-cells directly, thereby enhancing the response.
Had either a similar or a longer time on our study compared to their last therapy, and several of these patients with the arrows are still ongoing. So we think this is very encouraging in terms of progression-free survival and we believe we may be having a survival benefit here in these patients. Another thing to note is the imaging results shown here. You can see some patients had very remarkable responses. One lady with a retro orbital tumor or an, or actually an orbital tumor was causing proptosis, and this completely resolved on the study. She had improvements elsewhere. Another lady with liver metastases had a marked reduction in the size of her liver mets, and you can see a lymph node with metastatic disease completely disappearing on our therapy.
In addition, the safety profile seems very good. We really have very few grade 2 or higher adverse events. The most common adverse events are injection site reactions, which is to be expected and very few serious adverse events, no dose limiting toxicities on our study. In addition, we've seen patients who have had improvements in their quality of life in this figure number 5, you can see patients quality of life from the SF-36 instrument compared to the screening time. So if you, we compared them first, everything compared to screening when they got to cycle one before they'd had actually any therapy. You can see that a number of these patients that are already worsened, which is the orange color, and if you had gotten a little bit better, which is the blue.
But in the patients with disease control, even though several of them had worsened between screening and cycle 1 many of them improved by the time cycle 2, and cycle 3, and cycle 4 rolled around. And in the patients who did not have, disease control, although many of them worsened. There were still others who improved in terms of quality of life. And this is also true in terms of pain. If you look at figure 6, you can see that these individual dots represent individual patients at each visit at each cycle. The blue dots of the patients who had clinical benefit and the orange dots are the ones who did not.
You can see quite a number of them had improvements in their pain score. Anything in the positive direction is improvement in pain going upward in this graph. You can see that there's also a potential benefit in terms of pain relief with our therapy. There was also a difference in who developed delayed type hypersensitivity either erythema or induration the patients with clinical benefit or were had the higher measurements of erythema and induration for delayed type hypersensitivity and tumor markers also were improved in several patients, including CEA, CA-27, 29, and CA-15-3, and the patients where those were looked at, especially again in those who had clinical benefit. And you can see some of these had pretty good marked reductions, noting that this is a logarithmic scale. So at the end of the day, we think that we have very encouraging data here. In terms of standard response rates. We also did detect a group that had very good overall response rate of 25%.
These are patients who had hormones receptor positive cancer and who also had grade 1 or grade 2 histologically, I should mention that Bria-IMT was originally derived from a grade 2 moderately differentiated breast cancer tumor. And at it's also genetically matches very closely with other grade 1 or grade 2 derive breast cancer cell lines. So we've been looking at this subset of grade 1, and 2 patients, and we see a very high clinical benefit rate in that subgroup. So again, very encouraging data is being presented in this poster.
So in closing, in terms of this poster with the majority of our clinical data, I just wanted to quote Dr. Saranya Chumsri from the Mayo Clinic in Florida. She is the first author on the poster and also did a recording, an audio recording summarizing the results. And I just want to quote one of her conclusions.
"First, this is a heavily pretreated group of end stage metastatic breast cancer patients. For many of these patients, other therapies don't exist or cannot be tolerated. Bria-IMT does not have any theoretical cross resistance or overlapping toxicity with other metastatic breast cancer treatments, which is why it is so encouraging to see responses across all NBC subtypes and a very manageable adverse event experience." Saranya Chumsri, MD from the Mayo Clinic
William V. Williams, MD, FRCP - About The Author, Credentials, and Affiliations
Dr. Williams is an accomplished biopharmaceutical executive with more than 35 years of business and academic experience, including extensive clinical management in international pharmaceutical companies. Dr. Williams has served as President and CEO of BriaCell since October 2016. Previously, Dr. Williams served as Incyte Corporation's vice president of exploratory development from 2005 to 2016. He assisted the clinical introduction of approximately 20 drugs, including ruxolitinib (Jakafi) and baricitinib (Olumiant). As GlaxoSmithKline's vice president of clinical pharmacology and experimental medicine, Dr. Williams examined several compounds in clinical studies pertaining to various therapeutic fields. A variety of oncology medications, including Bexxar (lymphoma), Hycamtin (ovarian cancer), and Navelbine (non-small cell lung cancer), as well as ibandronate (Boniva) for osteoporosis, received new or supplemental drug authorizations with his assistance.
As Head of Rheumatology Research at the University of Pennsylvania, he oversaw a substantial research program in receptor biology, cooperated with David B. Weiner, PhD to produce DNA vaccines, and was able to introduce innovative DNA vaccines for the treatment of cutaneous T cell lymphoma into the clinic. Dr. Williams obtained a Bachelor of Science in Chemistry and Biotechnology from MIT and a Doctor of Medicine from Tufts School of Medicine.
In the molecular immunology laboratory of Mark I. Greene, MD, PhD, FRCP, at the University of Pennsylvania, he established unique methodologies for the design of bioactive peptides and collaborated on the study of the (cell) activation of the p185/Human epidermal growth factor receptor 2 (HER2) receptor. HER-2 is a protein known to stimulate the development of cancer cells. Dr. Williams is the author of over 130 peer-reviewed papers, over 15 patents, and multiple Investigational New Drug Applications (INDs) and New Drug Applications (NDAs).