CAR T-Cell Therapy Shows ‘Limited Success’ in Solid Tumors, But ‘Incremental Changes’ Still Being Made

In recent years, there have been several CAR T-cell agents approved by the FDA to treat hematologic malignancies and even more are being developed in clinical trials. For the solid tumor field, however, no CAR T-cell agents have received regulatory approval.

Thus far, there have been no impressive results from the use of CAR T cells in solid tumors amongst ongoing phase 1 studies in brain, renal/hepatic, colorectal, ovarian, pancreatic, prostate, thoracic, and head and neck cancers.¹

In an interview with Targeted Oncology™, Steven M. Aldelda, MD, Wiliam M. Measey Professor of Medicine at the University of Pennsylvania Perelman School of Medicine, discussed the introduction of CAR T cells in solid tumor research and how it differs from what has been observed in hematologic malignancies.

TARGETED ONCOLOGY: Are any solid tumors seeing momentum with CAR T cells yet?

Albelda: The 1 that has had the most success with adoptive T-cell transfer has been melanoma. That's mostly been with the T cells that have been harvested from the tumors and expanded and then given back to the patients. This has been primarily done at the National Cancer Institute, but I know that [The University of Texas] MD Anderson is also doing this. There are also some companies that have been starting to try to develop that.

Mostly, the success in CAR Ts in solid tumors has been very limited. There was also some success in sarcomas. But in general, I don't know of any complete responses. There's an occasional partial response and some stable disease, but it's nothing like what's been seen with the blood tumors. That hasn't stopped people from trying. There's lots of trials in many types of cancers, lung cancer, and mesothelioma, which are the 2 that I'm most familiar with. But head and neck [cancer] has quite an active scene as well as brain tumors, glioblastomas, colon cancer, prostate cancer. There are a number of ongoing trials.

Can you discuss some of the ongoing clinical trials that are exploring CAR T-cell therapy in solid tumors?

The best reports [have] been from [investigators at] Memorial Sloan Kettering Cancer Center who were treating patients with mesothelioma with a CAR T that targets this protein called mesothelin, but they administered it locally. What they found was they didn't see very good responses to the CAR T cells by themselves. But then a couple of months later, they started the patients on PD-1 inhibitors, and then they saw a number of responses.

It’s a little bit difficult to know what role the CAR T cell displayed versus the effect of the PD-1 therapy itself, because there are only 2 therapies. But at least that's 1 trial that has positive results.

What are some of the challenges with potentially bringing CAR T-cell therapy to the solid tumor space?

I think all CAR T cells will suffer from this problem of tumor heterogeneity, where some tumor cells express the targeted antigen and some don't. That's not a real big problem with something like B-cell leukemias and lymphomas, because almost all the cells express the target, which is CD19. It's a much bigger problem with solid tumors, because there's so much more heterogeneity that there's hardly ever a tumor where 100% of the cells would express the target antigen. So that's going to be a big problem, which is either going to have to be addressed by targeting multiple antigens or having the CAR deliver cargoes that then kill the tumor cells in different ways, or potentially inducing an immune response in the patient that is much broader than what the CAR T cell is, that could target some other antigens.

A second problem [is] that the CAR T cells tend to lose their function after they're stimulated, chronically with the same antigen rather than hit-and-run type of things. That's true both in the blood tumors and in the solid tumors, and people are working on ways to get around that by altering the biology of the CAR T cell or potentially having the CAR T cells rest for a while by disconnecting them through various genetic or chemical mechanisms, potentially giving antibodies or ways to get around these checkpoint inhibitors that get induced. That's a problem on both sides.

What is unique in solid tumors is that the CAR T cells have to traffic from the blood into the tumors. And that turns out to be a very, very inefficient process. Much less than 1% of the injected cells end up in the tumors. So that's an area in the solid tumor world where we really have to work on to figure out ways in which we can make the cells or genetically alter the cells, so that instead of going to lymph nodes, bone marrow where they normally like to go, we can get them to move into the tumors. And that might require preparing the cells in a different way, and just having a completely different way of thinking about the cells than we do with the blood tumors.

So, there are many challenges, and my personal idea on this subject is that we will have to do multiple adaptation to the T cells. This can’t necessarily be something that we pull from a patient because we really can’t do a lot of genetic changes, so it will probably be an off-the-shelf product. My prediction is that we’ll be using these pluripotent stem cells that a number of investigators and companies are working on or natural killer cells. For natural killer cells, I think the science [shows] this is more advanced and there are some clinical trials for pluripotent T cells for which the biology is a little less known.

What is your key message about CAR T cell use in solid tumors now and in the future?

With the success in blood tumors, the field is really excited about trying to achieve the same success in solid tumors, but it may take a while. And if you think about how long it's taken for monoclonal antibody therapy to really become a mainstay or more traditional gene therapy, and that's the area I started in. Sometimes it could take 20 to 25 years of iterative progress, or sometimes a big breakthrough comes that changes everything. So, I think the field is really hoping towards that, and we're making incremental changes, and hopefully in the next 5 years, we'll be close to the stage that we're at with the blood tumors.

_REFERENCE:

_{Patel U, Abernathy J, Savani BN, et al. CAR T cell therapy in solid tumors: A review of current clinical trials. EJHaem Open Access. 2022;3(51): 24-31. doi: 10.1002/jha2.356}