Running in the Marathon for Improving CAR Ts in Solid Tumors


Marcela Maus, MD, PhD, Associate Professor of Medicine at Harvard Medical School discussed innovative new research in the field and in her own lab.

Marcela Maus, MD, PhD

Marcela Maus, MD, PhD

While chimeric antigen receptor (CAR) T-cell therapy has seen success in treating hematological malignancies, hurdles remain to the use of CAR T-cell therapy for the treatment of solid tumors. Many researchers and companies are actively working to combat these challenges. Among these is a program out of Massachusetts General Hospital developing a novel, dual-specific, tandem CAR T (TanCART) targeting EGFRvIII and IL-13Rα2 for the potential treatment of glioblastoma. A trial evaluating TanCART cells has enrolled and treated 3 patients as of November 2023.

Another innovative program comes from A2 Biotherapeutics, which has used its logic-gated T-cell therapy platform (Tmod) to develop the A2B530 CAR T-cell therapy that allows for the selective elimination of CEA-expressing cancer cells that have permanently lost the HLA-A*02 gene. A2B530 is being evaluated in the phase 1 EVEREST-1 clinical trial (NCT05736731), which is currently dosing patients.

CGTLive spoke with Marcela Maus, MD, PhD, Associate Professor of Medicine, Harvard Medical School, and director, cellular immunotherapy, Cancer Center, Massachusetts General Hospital, to learn more about these promising new research strategies and others. She touched on A2’s and Mass Gen’s program as well as other exciting modes of research.

DISCLOSURE: Maus serves as a member of A2 Bio’s scientific advisory board.

CGTLive: What new modes of research are you and your team working on to improve CAR-T therapy for solid tumors?

Marcela Maus, MD, PhD: We've been looking at CAR T-cells that carry a payload that secretes a T-cell engager antibody molecule, we call it a TEAM. We think that's exciting, because it’s a modular approach to different kinds of tumors and with different kinds of problems that you might be trying to overcome. For example, in brain tumors, we want to be able to target a very good antigen that's expressed in most glioblastoma, wild type EGFR, but it's really hard to target it with antibodies, bispecifics, or even small molecule drugs, because it doesn't really get past the blood brain barrier very well. But with CAR T-cells, they can go anywhere, and they do get past the blood brain barrier, they actively traffic. So, we've been trying to use the T-cells to deliver another drug, essentially, to that tumor microenvironment, into the brain tumor. So, we've been working on this CAR that secretes a T-cell engager to wild type EGFR, and we've just treated the first 3 patients and presented data at the Society of Neuro Oncology meeting [in November].

What other research are you keeping an eye on in the field?

I think that there's a lot of interesting approaches. I like the dual targeted or next gen approaches, but those are also a little bit earlier in development and time...It's not like the Olympics where there's a single winner. It's like those marathons with lots of different people running towards different races and there's all sorts of different divisions and winners in the whole thing. Ultimately, of course, we all want the patients to be winners, and get something out of this.

Are there any specific programs you have your eye on? What are your thoughts on A2 Bio’s Tmod therapies?

I've done consulting work for various companies and I'm not here to advertise one over any others... I think the A2 Bio concept is really interesting. And this really leveraging like loss of heterozygosity to use as not gating and expand the reach of what you can target, I think it's a really cool concept. The data, of course, are still ongoing. So,I'm obviously paying attention to that, but I'm kind of paying attention to it from the inside more than from the outside. And there's also, you know, people exploring Gamma Delta cells or exploring subsets of cells that might have advantages in terms of trafficking or natural anti-tumor activity that can be leveraged to overall enhance activity in solid tumors.

This transcript has been edited for clarity.

A2 Bio announces first patient dosed in phase 1 clinical trial of A2B530, a novel cell therapy for the treatment of colorectal, pancreatic, and non-small cell lung cancers. News release. A2 Biotherapeutics, Inc. May 30, 2023. Accessed June 1, 2023.
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