Investigators Are Making Headway Bringing CAR T-Cell Therapy to Solid Tumors

Renier Brentjens, MD, PhD

Target antigen heterogeneity, an immunosuppressive microenvironment, and fibrotic structure are crucial differences between hematologic malignancies and solid tumors that must be overcome if CAR T-cell therapies are to someday join the solid tumor landscape, according to Renier Brentjens, MD, PhD.

“There [are] a lot of problems that are not easy to overcome. Do I think that CAR T cells will have a role in solid tumors in the next 5 to 10 years? I absolutely do. The concept isn’t flawed, we’re just not there with the technology,” Brentjens said in an interview with OncLive®. “I have a slide when I give talks about CAR T cells where I have a picture of a Ford Model T and then next to it a picture of a Ford Mustang. The caption reads, we have a Model T Ford, what we need is a Mustang. The concept of an automobile is appropriate, we just need to make it a better automobile.”

In the interview, Brentjens highlighted ways researchers are looking to overcome these challenges in the development of CAR T-cell therapies for this population of patients. Brentjens is chair of the Department of Medicine, the Katherine Anne Gioia Endowed Chair in Cancer Medicine, deputy director, and a professor of oncology at Roswell Park Comprehensive Cancer Center in Buffalo, New York. He is also a professor of medicine at the Jacobs School of Medicine and Biomedical Sciences at the State University of New York at Buffalo.

OncLive: How can what’s been learned with CAR T-cell therapies in hematologic malignancies be applied to the solid tumor space?

Brentjens: Approximately 20 to 25 years ago, I started working on this idea that you could reeducate an immune cell to recognize proteins on the surface of cancer cells. I’m a leukemia doctor [and] one of the first diseases that we looked at was acute lymphoblastic leukemia [ALL] and we targeted the CD19 protein, which is expressed on the surface of many different types of cancer. We were very fortunate that we picked a blood cancer because 99.99% of the [ALL] tumor cells express that protein. If the protein isn’t being expressed, then the engineered immune cell can’t kill it.

In early clinical trials, we saw that some patients [experienced] relapse with disease that no longer had that CD19 protein on the surface. But fortunately for blood cancers, that doesn’t happen that often. [There is not a lot of] target antigen heterogeneity [where] some of the tumor cells may express it [and] some of them don’t. [Also], blood cancers are in tissues like the lymph nodes and the bone marrow where the immune cells can have ready access to bind, target, and kill the tumor cells.

When we talk about cancers in general, they’re very distinct. When you move from blood cancers to solid tumor cancers—colon, breast, prostate, etc.—the structure of the tumor is a lot different. The first thing is that there is a massive amount of target antigen heterogeneity. If you go after a particular protein, let’s say carcinoembryonic antigen [CEA] in colon cancer, some of the cancer cells will express the CEA target, and others won’t. Using the approach and the paradigm that we developed for blood cancers for solid tumor cancers is not likely to work.

What strategies are being explored to make CAR T-cell therapy a treatment option for patients with solid tumors?

One of the ways that people have tried to get around [target antigen heterogeneity] is to put 2 different receptors on the [engineered] immune cell, on the T cell—these are dual targeted CAR T cells—and that tries to minimize the risk of antigen escape. That only gets you so far because if 1 target is heterogeneously expressed, then another target is also going to be heterogeneously expressed, and it becomes a numbers game where you lose out.

A far more significant limitation than this is that solid tumors tend to have a very immunosuppressive microenvironment. The solid tumors tend to scaffold themselves with immune cells that suppress the immune system, and then, if that wasn’t bad enough, they also encase themselves with fibroblasts, so it makes it very difficult for the CAR T cells to reach the tumor.

There are 3 basic issues that are different between liquid and solid tumors, and that is target antigen heterogeneity, an immunosuppressive microenvironment, and a fibrotic structure that makes it difficult for the CAR T cells to get into the tumor. Although the first CAR T-cell therapy was approved for pediatric ALL back in 2017, there haven’t been any FDA-approved CAR T-cell therapies for solid tumors because if you apply that paradigm that we did for blood cancers to solid tumors, it’s going to fail for those 3 reasons.

There are some minor exceptions to that rule, and there is a great deal of enthusiasm now to extend this technology to solid tumors, but I would argue that there’s still a lot of research that needs to be done to tackle those 3 obstacles that we see in the context of solid tumors. There is a logarithmic increase in the number of clinical trials using this technology for solid tumors but we’re not seeing the success rate that we saw initially with the blood cancers yet with solid tumors. We have to come up with ways to overcome those obstacles and come up with new designs; CAR T cells that are stronger, more potent, longer lived; [and strategies] to change that microenvironment in such a way that the CAR T cells can eradicate the tumor cells.

Are there any promising strategies that are being investigated now to address those 3 problems?

There are a variety of [strategies]. People are working on combining more conventional chemotherapy drugs with immune-based therapies. There are approaches where the CAR T-cell secretes a bispecific T-cell engager that could help engage endogenous immune effectors. There is research looking at going after the stroma, targeting that tumor microenvironment itself and the fibroblasts around it. There is a lot of nibbling at the edges of these problems, but we’re not yet at a point where we can confidently say we can address all 3 of them.

What needs to happen at some point, and we came up with this [in my laboratory], is [the examination of] armored CAR T cells. Armored CARs are CAR T cells that can recognize a target on the tumor, but are additionally engineered to, for example, secrete proinflammatory cytokines. What happens then is that the CAR T cell gets into the tumor, it secretes this proinflammatory cytokine which overcomes a lot of that immune suppression and engages the patient’s own immune system to recognize the cancer [similar to the] way that immune checkpoint inhibitors can overcome that immune suppression. It’s going to be a combination of technologies and a combination of immune-based therapies [that will push the field forward]. Another example is combining CAR T cells with immune checkpoint inhibition to overcome these limitations.