SV-BR-1-GM: Turning Cells into Antigen-presenting Cells Dr. Williams SABCS 2022
How does SV-BR-1-GM help turn cells into antigen-presenting cells? Now our next presentation was looking at our pipeline development, capitalizing on the observations we’ve. With the Bria-IMT therapy we’ve decided to take our cell line and some other cancer cell lines and to modify them so that they express different HLA types. I mentioned in our monotherapy and in our combination therapy experience with Bria-IMT, that there appears to be a clinical benefit associated with having an HLA match.
With the Bria-IMT cell line. So by adding or substituting different HLA molecules for the native ones in Bria-IMT or just adding them to Bria-IMT, we’ve actually found a methodology where we can single match over 99% of the population by focusing on the less polymorphic HLA types. And so that uses both a class 1 HLA molecule and a class 2 HLA molecule. And I mentioned also already, if you look at our poster here, the mechanism of action. If you look at the table in the middle of the poster, you can see the specific HLA types and their frequency that allows us to match so many different patients focusing on HLA and HLA-DR beta 3, 4, or 5.
These are the least polymorphic, class 1 and class 2 HLA loci respectively. So we’ve genetically modified ourselves to express these different HLA types so that again, we’ll be able to match more and more patients and enhance our clinical benefit for them. Now, the other thing that we’ve done is that we’ve started to further modify these cells.
Just the HLA type shuffling that we did is what we call our first generation BRIA-OTS, which stands for off the shelf, because what we’re trying to develop here is a personalized immunotherapy that’s off the shelf. It gets around a lot of the complex manufacturing issues they have with things like CAR-T therapy.
But on the other hand, we wanna keep it personalized by matching the HLA type, of the cell lines we’re developing to the patient and our first generation via OTS is we’re hoping we’ll be in the clinic early next year, but we’ve decided to also further enhance the potency of these important immunotherapy cell lines by further genetically modifying.
So in addition to GM-CSF, we also are adding other cytokines to be expressed by the cells, including interferon IL12 and IL7, and we’re adding co-stimulatory molecules that act to initiate immune responses like CD86, CD80 and 4-1BB ligand.. And this combination of molecules should actually make it possible for our cells to stimulate naive T cells.
Now, this is a very important advance, I believe, because naive T cells cannot be activated by most of them. There are cancer vaccine strategies out there right now, and it should be a major advance to be able to get them engaged in the immune response to the cancer. So we’ve modified our Bria-IMT cells to express not only the different HLA types but also these cytokines and co-stimulatory molecules. Now, I should mention just one thing because it looks like there are a lot of HLA types that we would be putting into one cell line, but we’re not doing it that way. The way we’re doing it is we’re using four different cell lines, with each cell line expressing two HLA types and two HLA-DR beta 3, 4four, or 5 types, because of course each cell can express two of each alleles, in the normal course of things. So we’ve now developed four different cell lines, and we’re now looking at these for their ability to express the HLA molecules, which they do quite well, and also for their ability to activate naive T-cells. So the assay that we decided to use is actually a very old assay called the mixed lymphocyte reaction.
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7 key takeaways from the SV-BR-1-GM Clinical Trial
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An 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).
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SV comprises cyclophosphamide 300 mg/m2 i.v. 48-72 hours prior to SV-BR-1-GM (20 x 106 cells) intradermally, then 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.
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V-BR-1-GM is a GM-CSF-expressing breast cancer cell line exhibiting antigen presentation cell (APC) characteristics due to the production of many immunomodulatory molecules, such as MHC-I (HLA-A, B, and C) and MHC-II (HLA-DRB3 & -DRA). Initial findings from patients treated with irradiated SV-BR-1-GM cells, low dose cyclophosphamide, and local IFN indicate that patients who match SV-BR-1-GM at least at one HLA allele are more likely to have clinical benefit.
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There were 2 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.
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Multiple subtypes of BC shown clinical advantages, notably in individuals with HR+ illness undergoing combination therapy. Currently, a Phase 2 clinical investigation is evaluating the efficacy of SV-BR-1-GM in combination with ICIs.
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Using flow cytometry and DNA sequencing, the lack of HLA-A and HLA-DRB3 expression was confirmed.
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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, therefore enhancing the response.
Mixed lymphocyte reactions happen when you take the lymphocytes of one patient and mix them with the lymphocytes of another patient. And in that case, the dendritic cells will actually initially initiate a primary response against the allo-HLA molecules on that dendritic cell, and a fair proportion of T-cells in the population are able to recognize allo-HLA molecules. So we did this very simple allo-HLA response in this mixed lymphocyte type of setting where we took resting lymphocytes from patient donors—not patients in our studies necessarily, but just normal resting lymphocytes—and we mixed them with either SV-BR-1, which is our apparent cell line that we derive Bria-IMT from, or SV-BR-1, expressing the different co-stimulatory molecules and cytokines.
And then we look at gamut interferon production by the responding lymphocytes in the upper panel here on the right, where you can see just the expression levels of our different co-stimulatory molecules and cytokines. And in the lower right you can see the gam interferon production in figure 6 here by the resting lymphocytes.
And you can see that as we increase the number of these what we call antigen presenting tumor cells or PTCs, increases in the production of gamma interferon, as we have been engineering these, we now have these cell lines that can activate naive T-cells. And we’re very interested in getting these pushed forward and into the clinic because we believe they will be very important and very potent in stimulating a immune response.
Against the patient’s cancer and a very potent way to vaccinate patients to actually immunize patients against their own cancers. And of course, we would be eventually looking at this in combination with checkpoint inhibitors to again, take the foot off the brakes of the immune response. But we think this will really put the foot on the gas in a very potent and strong way, and we look forward to introducing these into the clinic in the future.
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 Therapeutics Corporation 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).