Abstract 3580: Enhancing adoptive cell therapies through exogenous regulation

Abstract

Abstract Adoptive cell therapy with chimeric antigen receptor (CAR) modified T cells has demonstrated remarkable clinical efficacy in the treatment of certain B cell malignancies and more recently in multiple myeloma. However, in solid tumors, CAR-T therapy has been far less successful, likely due to the lack of robust CAR-T cell expansion, the immunosuppressive microenvironment, and clonal heterogeneity within these tumors. The trafficking of CAR-T cells to tumor sites provides an opportunity for selective delivery of cargo that can enhance CAR-T cell activity at the site of the tumor. Interleukin-12 (IL12) and membrane tethered interleukin-15 (mbIL15) have previously been shown to enhance CAR-T activity, yet the unregulated expression of either compromises safety and/or efficacy. The Obsidian Therapeutics platform equips engineered immune cells with new functionalities whose activity can be regulated via the administration of FDA-approved small-molecule drugs, putting dosing control back in the hands of the treating physician. We utilize small, fully human protein sequences called destabilizing domains (DDs) that confer reversible destabilization to a fused target protein. In the absence of ligand the fusion protein is degraded, whereas the presence of small molecule ligand restores expression and functionality. Furthermore, stabilization is titratable with small molecule ligand dose, providing finely tuned control over target protein expression and function. We have applied our technology to create DD-IL12 and DD-mbIL15 “cassettes” that provide exogenous regulation of cytokine activity when transduced into CAR-Ts for enhanced cellular function. We describe here the successful implementation of the DD technology in engineered primary human T cells and show small-molecule ligand controlled regulation of DD-IL12 and DD-mbIL15 protein expression in vivo in mouse models. These data demonstrate the feasibility of exogenous control over protein expression in primary human T cells for the development of next-generation CAR-T cell products with enhanced efficacy and more favorable safety profiles. Citation Format: Celeste Richardson, Kutlu Elpek, Michelle Ols, Tariq Kassum, Steve Shamah. Enhancing adoptive cell therapies through exogenous regulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3580.