Researchers Explore More Safe and Effective CAR T-Cell Therapy for Cancer Treatment

In an interview with Pharmacy Times at the 2022 Sixth International Cancer immunotherapy Conference (CICON) 2022– brought by The Cancer Research Institute (CRI), the European Network for Cancer Immunotherapy (ENCI), and the American Association for Cancer Research (AACR) — Yvonne Chen, PhD, Associate Professor at the University of California, Los Angeles, discusses the significance of next-generation CAR-T cell therapies and new innovations in the field.

Q: How do you see the next generation of CAR-T cell cancer immunotherapy ?

Yvonne Chen, PhD: I mean CAR-T cell therapy has now shown quite impressive efficacy for B-cell malignancies, leukemia lymphoma, as well as multiple myeloma- which is a plasma cell malignancy. And I think in that space, the next step is to make sure that we have durable responses, as well as minimizing toxicity to the extent possible. I think most of the field is now primarily focusing on developing CAR-T cell therapy for solid tumors, which account for 90% of cancer diagnoses and cancer deaths in the US every year.

I think the next generation of CAR-T cells really has to figure out how do we make CAR-T cells work for these solid malignancies.And there are a number of challenges that we know about. There are probably additional ones that we don't know about yet. And that includes, for example, accessibility. How do CAR-T cells find the solid tumors? It includes how the T cells can penetrate the solid tumor once they do find the tumor. And also how the T cells can remain functional in the tumor microenvironment, which tends to be very immunosuppressive, such that immune cells (including T cells), oftentimes become dysfunctional in that location. And so these are just a number of different challenges that we and many others have been working on overcoming.
Q: How might engineering CAR-T cells enhance specificity, reduce toxicity, and improve the ability to overcome tumor-associated immunosuppression?

Yvonne Chen, PhD: There are several different topics here. So let me try to break it down one by one, focusing on efficacy first.

Efficacy has different components. As I had mentioned, there's the issue of how whether you can recognize a tumor in the first place find it. And secondly, overcoming immunosuppression so that the T cells or other kinds of effector cells remain functional. In that regard, you know, there's been a lot of activity in, for example, using CRISPR screens to identify genes that you can knock in or knock out that would either enhance the effector function of the T cells or enhance the stemness of the T cells, or both, so that they not only are functional but remain functional for a long time.

We have taken the strategy of doing rational protein design, for example, engineering T cells to overcome TGF beta, transforming growth factor receptor beta or to transform growth factor beta, which is one of the main immunosuppressive cytokines that is secreted by a lot of different solid tumors. And the way we do that is we engineered a CAR that can respond to soluble TGF beta.

Unlike conventional CARs, which generally respond to surface bound antigens, we figured out how to engineer CARs that can respond to soluble antigens. And specifically respond to TGF beta, such that not only do the T cells not become dysfunctional in the presence of TGF beta, they actually convert TGF beta into a stimulant for the T cells. So in effect, we turn the tumors defense mechanism on its head and use that tumor signature to activate our T cells. And so that's another strategy in which we try to overcome this immunosuppression problem.

You mentioned toxicity, which certainly has been an issue as well, for solid tumors. In fact, emerging evidence seems to suggest that the kind of toxicity profile we see in solid tumors may be different from the toxicities that we've grown to anticipate for B cell malignancies.

For example, macrophage activation syndrome has been observed and it can be quite severe to the point of potentially triggering fatality. And I think the data are still coming out, so we don't have a complete picture yet in terms of, first of all, what kind of toxicities? What triggers them? And how one can potentially mitigate them, right? Of course, there's active research going on the clinicians in you know, as in the frontlines, are doing everything they can when these toxicities arise, but I think there's a lot more to be learned in that regard.