Decoupling acute toxicities and antitumor efficacy in adoptive cell therapy

Project Summary Adoptive cell therapy (ACT) with chimeric antigen receptor (CAR) T cells has demonstrated impressive response rates in B cell malignancies, but ACT has not mediated sustained responses in solid tumors. CD19 CAR T cell therapy has reached up to 80% response rate in the clinic; however, the main side effects are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), which occur in 37–83% and about 25-35% of patients, respectively. Furthermore, one of the major obstacles in ACT is the heterogeneity of targeted antigens and relapse due to antigen escape. Recently, we screened a cohort of 16 FDA-approved anti-inflammatory drugs and identified clofazimine (CLF) as the top candidate for its desired bifunctional effect for anti-CRS/ICANS and anti-antigen escape roles. Aim 1 will determine the role of CLF in reducing macrophage-derived ROS to curtail CRS/ICANS. Aim 2 will determine the role of CLF in driving dsRNA/dsDNA signals in macrophages for the eradication of tumors. We expect this study to demonstrate the ability of CLF in potentiating the anti-antigen escape capacity in ACT, curbing intractable CRS, and may also fill a desperate clinical need to improve the dismal patient survival with ICANS. This strategy of repurposing the clinically approved CLF may hold great promise to overcome a critical obstacle in realizing the full potential of ACT with CAR-T cells. This translationally relevant work could then lay the foundation for future clinical trials.