Next generation armored CAR-T cells with a drug inducible cytokine circuit

Abstract

Immunotherapies which direct the bodys own immune system against tumors are a safer and more efficacious alternative to other types of cancer treatments. Chimeric Antigen Receptor or CAR T cell therapy has emerged at the forefront of contemporary cancer immunotherapy research and is highly specific for a wide range of cancer types, resulting in improved patient outcomes. Early generations of CAR T cells were ineffective and failed to proliferate due to lack of costimulatory signals and immunosuppression within the tumor microenvironment (TME), but later generations of armored CAR T cells added costimulatory receptor domains and constitutive expression of stimulatory immunocytokines to ameliorate this. However, increased aggressiveness in T cells comes with issues such as off-site toxicity, fails to address relapse due to immune evasion, and combined with the prohibitive cost of engineering CAR T cells limit the efficacy of the treatment. Next generation CAR T-cells address these problems with the engineering of synthetic biological circuits that provide selective control over immune function in response to inducers. In this research proposal, we design a next generation armored CAR T cell with a small molecule inducible cytokine circuit, combining different synthetic biology approaches from previous research on CAR T cells to enhance the safety of the therapy by providing a reversible, safe, and rapid method of modulating CAR T cell stimulation.