Samuel Katz, MD, PhD
Yale University (New Haven, CT)
Refining CAR T immunotherapy for solid tumors by multifactor reprogramming.
Harnessing a patient’s own immune system to attack blood cancers has recently enjoyed remarkable success. In one strategy, a patient’s T cells are harvested, reprogrammed to recognize the cancer as foreign, and then returned to the body. The reprogrammed T cells produce a novel artificial protein, a chimeric antigen receptor commonly called a CAR, which brings together the ability of two other proteins: one that recognizes the tumor cells and another which can stimulate the T cell to attack.
These so-called CAR-T cells are highly effective and specific anti-tumor agents that kill tumor cells and further stimulate other parts of the immune system. In several recent clinical trials, approximately 70% of terminally ill patients, refractory to standard treatments, were cured by CAR-T therapy. However, most protocols reprogram the T cells to express the CAR by permanently altering their DNA using retroviruses.
We have developed an alternate system, using RNA, which transiently reprograms the T cells to attack the cancer. This approach has many benefits including increased safety, speed, control and the ability to deliver multiple beneficial proteins at the same time. The flexibility to accurately adjust therapeutic conditions and introduce different proteins into T cells at different times according to the needs of the patient makes this a useful tool for individualized medicine. Moreover, RNA reprogramming is essentially transient. After conclusion of the therapeutic treatment all of the RNAs and the proteins they make are degraded and the T cells return to their normal state, which minimizes any possible side effects of the treatment. Our technology has wide applicability for many different tumors and a high potential for further development.
Despite the success of CAR-T cells in blood cancers, duplicating these achievements in solid cancers like breast cancer, melanoma and sarcoma remains a “holy grail” for the field. Two key barriers to success are (1) most CAR-T cells that recognize solid cancers also recognize normal tissues, and (2) solid tumors have the ability to prevent the activation of T cells. The ability of our RNA approach to make multiple helpful proteins in the patient’s T cells in one-shot has the potential to overcome both of these obstacles. In addition to the CAR, our RNA approach provides proteins that limit the T cell’s ability to attack normal tissues, and other proteins that will help the T cell survive and be active while it avoids the suppressive signals being sent to it from the solid tumor. Collectively, this approach will induce the CAR-T cells to become more sensitive, specific and effective killers of solid tumors.
This Alliance for Cancer Gene Therapy Research Fellow is funded in part by Swim Across America.
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Samuel Katz, MD, PhD
Associate Professor of Pathology
Yale School of Medicine
310 Cedar Street, PO Box 208023
New Haven, CT, 06520-8023