The Pediatric Cancer Research Foundation is proud to support Dr. Surojit Sarkar of Seattle Children’s Hospital with a Basic Science Research Grant for advancements in CAR T cell therapy. The focus of his work is best described in his own words.
Clinical trials conducted by our Ben Towne Center for Childhood Cancer Research (BTCCCR) at the Seattle Children’s Hospital have reported 94% remission rates in patients with relapsed or refractory leukemia using T cells engineered to recognize and “kill” tumor cells based on specific cell surface proteins. Referred to as chimeric antigen receptor (CAR) T cell therapy, this strategy is also being tested against solid tumors (such as brain tumors and neuroblastoma) in ongoing FDA-approved clinical trials at the Seattle Children’s Hospital. However, solid tumors pose formidable challenges to CAR T cell therapy – of note is the loss of T cell function inside solid tumors. It is believed that with repetitive attacks against tumors, T cells slowly enter a state of “exhaustion” or dysfunction wherein they shutdown their anti-tumor functions. This state of inaction is reinforced through negative signals from tumor cells, which further suppress their metabolic capacity for mounting an anti-tumor attack.
We propose a novel “Trojan Horse” strategy for “melting” solid tumors from within using CAR T cells controlled with bioengineered ON-OFF switches. The idea is to first allow CAR T cells to infiltrate solid tumors without undergoing functional exhaustion – this will be achieved by administering CAR T cells in an “OFF state” wherein they do not express CAR, and are hence incapable of recognizing or reacting to tumors. Next, we will activate CAR expression simultaneously in all therapeutic T cells, thus leading to a synchronous anti-tumor attack. The anti-tumor agents released by active CAR T cells are also expected to attract and activate more of the patient’s own anti-tumor immune cells, thus leading to immune synergy. We further propose that the rapid and efficacious tumor clearance resulting from this synchronous and synergistic anti-tumor activity will lead to long-term persistence of functionally potent CAR T cells, which may be called upon again in case of future tumor relapse.
In this proposal we will conduct preclinical testing of all aspects of the “Trojan Horse” strategy – therapeutic efficacy, long-term functional potency and durability of therapeutic T cells, toxicity and immune synergy. With the convenient on-site location of GMP-grade T cell production core at BTCCCR, we envisage seamless and rapid translation into clinical trials in high-risk pediatric patients in collaboration with oncologists at the Seattle Children’s in the future.