CAR T cell treatment, which has already been approved for some blood cancers, such as certain types of leukemia and lymphoma, is still not completely effective, even in some people who initially respond well to the therapy. One limitation is that the T cells seem to lose their potency after a while, a phenomenon called T cell exhaustion that has hampered many types of cancer immunotherapy.
In a talk, as part of AACR 2021, on April 14, physician-scientist Michel Sadelain, director of the center for cell engineering at MSK, spoke about the intense efforts underway to understand what leads to this loss of T cell function.
MSK, which pioneered chimeric antigen receptor (CAR) T cell therapy, is developing three approaches to address this limitation.
One tactic involves using gene editing technology, CRISPR CAS-9, to deliver the gene for the CAR protein to a very specific location in the genome of the T cell. This precise approach creates CAR T cells with more stamina, in other words they can kill tumor cells for longer. Another strategy is to modify the T cells’ epigenetic features, that relate to changes in gene activity that do not involve changes in their DNA sequence.
A third approach involves using a novel CAR design to enhance the power of the T cells so they are effective at a lower dose. It implements a new molecule called 1XX that is designed to improve CAR T cell effectiveness and prolongs their anticancer potency. This technology was created at MSK and currently has an open phase I clinical trial for people with B cell leukemia and lymphoma, led by hematologic oncologist Jae Park. Another trial, led by medical oncologist, Roisin E. O’Cearbhaill, is testing 1XX-modified CARs in people with pleural mesothelioma, a cancer that develops in the thin tissue lining the lungs.
A second major limitation of CAR T therapy is that the T cells often cannot eliminate cancer cells that have very low levels of the cancer antigen that they have been engineered to target and destroy — a problem known as ‘antigen escape.’ MSK researchers have developed a technology that incorporates a molecule called a HIT receptor into T cells. The T cells armed with HIT can detect much lower antigen levels. MSK just got funding to start a trial testing HIT within the next year or so.
Dr Sadelain commented: “The present evolution of CAR T cell manufacturing is informed by meticulous analyses of how T cells are wired and what receptors make them work. It’s not just an academic discussion of mechanisms — it aims to push the limits of our immune system and will impact many clinical trials. Ultimately, it will make this revolutionary form of immunotherapy even more effective for patients.”