Synthetic Mechano-Transduction For Improved Cell Therapies In Immuno-Oncology

ABSTRACT
The utilization of genetically engineered T-cells containing Chimeric Antigen Receptors (CARs) has
demonstrated remarkable efficacy in treating hematologic malignancies. Despite this success, CAR-T cell
therapies have encountered challenges in specificity and off-target toxicity when confronting solid tumors. To
address these challenges, we propose an innovative approach that harnesses mechanical forces, which is
overlooked in current therapeutic strategies. Mechanical forces are pivotal in immune signaling because they
impact the activation of key receptors, such as the T cell receptor, chimeric antigen receptor (CAR), and co-
receptor PD1. We recently developed force sensitive coiled-coils that can be genetically encoded and inserted
into any protein of interest. These coiled-coils change conformation under force and expose reactive residues
that can be harnessed for force detection or enzyme recruitment. This project aims to build on our experience
to engineer a mechano-transduction platform that will be implemented to enhance CAR T-cell therapies. In aim
1, we will use our force sensors to measure the forces along key immune receptors. In aim 2, we will engineer
force transduction modules by combining our force sensors to releasable transcription activators able to induce
the expression of any protein of choice, and insert these tools into CARs to enhance CAR T-cell specificity and
safety. The successful realization of this project will demonstrate the feasibility and utility of new capabilities to
improve the efficacy of CAR-T therapies, extend their application and speed up their development, with high
potential impact in cancer immuno-therapies. It will also lay the foundations for new immuno-therapies using
different receptors and modes of action.

Grant Number: 1R21CA294038-01A1
NIH Institute/Center: NIH
Principal Investigator: Julien Berro