Translatable efficacy & safety testing of mAb, bispecific, & CAR T therapies

Monoclonal antibodies (mAb), bispecific antibodies, and chimeric antigen receptor T-cell (CAR T) therapies signify a transformative era in precision medicine, promising to revolutionize treatment across various conditions. In this on-demand webinar, Dr. Brian Soper, Senior Scientific Engagement Manager at The Jackson Laboratory, delves into preclinical data, showcasing how immune humanized platforms revolutionize lead optimization and safety data sets in the context of investigational new drug (IND) applications.

Dr. Soper highlights the significant role of monoclonal antibody-based human immune modulation in enhancing therapeutic outcomes. He also explores donor-specific differences in bispecific antibody-mediated tumor efficacy and cytokine release, shedding light on personalized treatment approaches. Additionally, he discusses the advancements in CAR T cell-mediated tumor efficacy and safety, presenting compelling data that showcases the potential of this groundbreaking technology.

Key learning objectives

• Explore the role of monoclonal antibody-based human immune modulation in enhancing therapeutic outcomes
• Discover the donor-specific differences in bispecific antibody-mediated tumor efficacy and cytokine release, shedding light on personalized treatment approaches
• Learn about the advancements in CAR T cell-mediated tumor efficacy and safety

Read on for highlights from the Q&A discussion at the end of the live webinar or register to watch the full webinar on demand >>

Q: In addition to licensing CD3 T cells in the tumor microenvironment, do CD3-bispecific antibodies drive recruitment and further infiltration of activated T cells into the tumor in mice?

BS: There is Johanna Sam with a group from Roche in Europe who have done a lot of work with T cell bispecifics (TCBs). They have used these on solid tumors and harvested the tumors to look at different T cell populations, both CD4s and CD8. They've studied the histochemistry and looked at pre and post and against different control molecules and have found a higher infiltration of both CD4 and CD8 T cells into the tumor.

Q: Will mice co-engrafted with human hematopoietic cells from a healthy donor and cells from a tumor cell line, both of the same human leukocyte antigens (HLA) haplotype, reject the tumor cells? And is it necessary to engraft CD34+ cells to test CAR T cell therapies?

BS: When we take CD34-engrafted mice and we put tumors on board those mice, they are largely accepted. About 80% of the tumors that go on board in a completely non-HLA-matched situation are accepted. There's a number of publications out there where people have tried to do matching and the overall conclusion of the scientific community at this point is that HLA matching or mismatching doesn't seem to have a large impact on whether these tumors will grow and proliferate. There are instances where in a non-HLA-matched situation, the tumors are rejected, but it's not completely understood. There's a lot of complex things going on in this situation.

Classical immunologists had always predicted that if it's not HLA matched, it's going to be rejected. This is a pro-inflammatory environment, class one and class two get downregulated on the tumor and there's also an upregulation of a number of different molecules, like checkpoint inhibitor pathways and other things that are preventing the progression of any T cells that infiltrate into the tumor. So, it's a very complex situation. For the second part of the question, is it necessary to engraft those cells for CAR T-cell therapies? The answer is it's not necessary. There are a number of papers in the literature where people just take a regular NOD scid gamma (NSG) mice, put tumors on board, inject the mice with an adopted T cell type of scenario, introduce the CAR T cells, and those CAR T cells respond against the tumor. The question becomes whether you want to see additional things like the consequences of that activity in terms of cytokine release.

Additional human hematopoietic stem cells are required to measure the consequences of the activity of those cells in the following cytokine release. When the CAR T start responding to those tumors, you'll get what's called a tumor lysis syndrome. The CARs become activated, and they'll have an initial cytokine release. What the question becomes then is, is that a cascading response that leads to something called cytokine release syndrome? In order to measure that in vivo, yes, you need to have those additional human hematopoietic cells there that can respond to that initial cytokine release and to give you a measure of whether you're going to have a cascading response or not.

If you're looking for an efficacious response, the answer is no. If you're looking for efficacy in the combination of safety and cytokine release, then, yes, you will want to have those additional human hematopoietic cells there, whether it's after CD34 engraftment, or in the platform JAX has developed where you have co-engraftment of human peripheral blood mononuclear cells.

Q: Are there differences in TIL across the different strains of mice discussed?

BS: The tumor microenvironment itself appears to be the primary controlling factor for what type and what degree of immune cell infiltrates you have into the tumor. The tumor itself seems to be expressing cell adhesion molecules, and there are other chemoattractants that are helping to explain why one particular tumor type is heavily infiltrated with T cells and another tumor type is heavily infiltrated with myeloid cells. Some tumors are consistently myeloid heavy, and other tumors are more T-cell infiltrated, and then other tumor types are what we call cold tumors, which have hardly any immune cell infiltrates. The overall thought is it's the tumor cells themselves and what they're expressing that seem to control that. Instances where people are using different host platforms, such as the NSG-IL15, if, for example, they would like to recruit natural killer cells in their mechanism of action to attack the tumor, then they would choose that type of platform to try to enhance the ability of those natural killer cells to respond against the tumor in certain ways.

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