Research provides clues to improving CAR-T for solid tumors
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Recent molecular science research may provide important insights as to why chimeric antigen receptor T-cell therapies for solid tumors have failed to achieve results that match those observed in blood cancers.
Researchers from Thomas Jefferson University developed CAR T cells that target high-molecular-weight melanoma-associated antigen and compared them with designed to target a specific peptide-MHC ligand in melanoma cell lines.
Testing conducted in an in vitro model system showed that even though the modified cells contained a similar number of receptors, TCR T cells required “significantly lower” levels of their target molecule on cells before triggering the release of cytolytic granules that kill cancer cells, according to Yuri K. Sykulev, MD, PhD, professor of microbiology and immunology at Thomas Jefferson University and researcher at the Sidney Kimmel Cancer Center —Jefferson Health.
“CAR T cells required much higher levels of the target antigen to be expressed by melanoma cells, and further study may show this applies to other solid tumors,” Sykulev told Healio.
At first glance, the results seem to suggest TCR T cells are a more worthwhile endeavor for treating solid tumors and melanoma. However, as Sykulev noted, focusing on refinements that improve CAR T-cell sensitivity to target antigens has the potential to positively influence outcomes for a larger number of patients.
Healio: Can you explain your group’s rationale for conducting this study?
Sykulev: Our aim was to explore the differences between CAR-T and TCR T cells. Unlike successfully targeted lymphoblastoid cells that are in circulation, reaching solid tumors within the body provides a difficult challenge. I have been working with T cells for more than 3 decades and my initial assumption was that the way these two modified cell types trigger activation is different. Our group also assumed from experience that TCR T cells would be more effective than CAR T cells.
I am a basic scientist, so I like to understand how things work. My colleague — Takami Sato, MD, PhD — is professor of medical oncology and director of the metastatic uveal melanoma program at Sidney Kimmel Cancer Center — Jefferson Health. His dream is to find an effective treatment for uveal melanoma, which, unfortunately, is difficult to treat and 100% fatal when it metastasizes. He had a collection of melanoma cell lines that I did not originally appreciate for their value but, once I started working with them, I realized they were a treasure because no one else had tumor cells like these that expressed various levels of target proteins.
Healio: What do you consider the key takeaway from your study?
Sykulev: When we compared cells transduced with a CAR with those that had a TCR, the results were clear: CAR T cells were much less sensitive in the detection and killing of tumor cells. CAR T cells required a higher level of target antigen molecules on the surface of tumor cells compared with the level of target molecules required for TCR-modified T cells to mount an attack and kill tumor cells.
Our results suggest that, for CAR T to be more effective, future efforts should focus on tumors that express a relatively high level of a target antigen. We think this research will help provide a basis for the understanding and improvement of CAR T-cell sensitivity that can be leveraged to successfully treat solid tumors.
Healio: Will CAR T cells need to target multiple antigens to successfully treat solid tumors?
Sykulev: There already are researchers in the field who are evaluating multi-antigen CAR-T products — both in solid tumors and blood cancers — and the strategy makes sense. But until we see the results of in-human testing with these therapies, it's hard to say what type of impact this strategy will have for CAR-T in solid tumors.
My guess is that it will take a lot of hard work and research beyond multiantigen targeting to make this modality successful for solid tumors, and a lot of that hard work is already underway.
Healio: Why pursue CAR-T for solid tumors when research like yours shows that TCR T cells are more potent at lower molecular expression levels?
Sykulev: We have seen TCR T cells be successfully used in trials by the NIH but, until now, we really didn't have a comparison between CAR-T and TCR T cells in terms of their sensitivity. CAR-T has an advantage in that it is genetically modified to identify a protein in the cancer cell regardless of the patient's haplotype. For example, the TCR T cells we used in our study would have required a person who was HLA-A*02-positive or else therapy would be useless for them. TCR T cells may be more effective, but they are limited in that one specific construct cannot be given to all patients.
Healio: How limiting are the differences between the two therapies?
Sykulev: HLA-A*02 is one of the most regularly expressed alleles, especially among white individuals. It is expressed by approximately 70% to 80% of the global population. In fact, five or six alleles would account for more than 98% of the population. Developing TCR T cells for these can be done and is being explored by other research groups. It's all part of this newly emerging field of T-cell therapeutics.
TCR T cells are an interesting and seemingly effective approach to treating some types of cancer, but they are expensive to produce, just like CAR T cells. From a commercial perspective, given that the cost to produce both therapies is similar, finding ways to maximize the efficacy of CAR-T may be more beneficial because it can be applied to a larger group of patients.
For more information:
Yuri K. Sykulev, MD, PhD, can be reached at Bluemle Life Sciences Building, 233 S. 10th St., Room 706, Philadelphia, PA 19107; email: yuri.sykulev@jefferson.edu.
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