February 21, 2023

Improving CAR-T Cell Safety and Efficacy Through Computational Protein Design

5th Call, TPdF

Short Summary

CAR-T cell therapy is a new type of cancer therapy. It is based on equipping T cells with engineered receptors that enable the cells to recognize and kill cancer cells. Unfortunately, CAR-T cell therapy is still risky and to date has only been effective against a few types of cancer. Here, we use computational protein design to develop sensors that respond to small-molecule drugs. We insert these sensors into a modified CAR receptor to drug-dependently turn the CAR-T cells on or off. In this way, we aim to reduce side effects as the drugs allow precise dosing of CAR-T cell activity. This could also enable the treatment of other types of cancer where previous approaches have failed due to the high risk of severe side effects.

Goals

We aim to make CAR-T cell therapy safer and more effective. We will improve CAR receptors in such a way that they can be turned on or off with approved, orally bioavailable medicines. To do this, we will rationally design protein pairs that react to the respective small molecule and insert them into established receptors. We focus on medicines suitable for clinical use and base the newly developed sensors on natural human proteins with a minimum of mutations to reduce the likelihood of immune responses to them. By optimizing the affinities of the protein pairs and placing them into the receptor on the extracellular side, we strive to increase the speed at which the receptors can be turned on or off.

Significance

Controlling cell therapies by classical small molecule medicines, could decrease the side effects of this form of therapy. This would also simplify dosing and risk-benefit assessments of CAR-T cell therapies. Many new potential applications for CAR-T cells have never been tried or have failed in clinical trials because of large risks to patients. With new CAR receptors that can be turned off in an emergency or turned on more slowly, it may be possible to also bring these currently too risky therapies closer to clinical use.

Background

Better use of the immune system in cancer therapy is an important goal of current research. One possibility is to equip T cells with a modified receptor (Chimeric Antigen Receptor; CAR) with which the cells can specifically recognize and kill cancer cells. However, this only works for a few forms of cancer and often results in severe side effects. Controlling CAR-T cells with small molecules is therefore heavily investigated but has so far mostly required receptor domains or drugs that are unsuitable for clinical use.

Publications

Rational Design of Chemically Controlled Antibodies and Protein Therapeutics, Anthony Marchand, Lucia Bonati, Sailan Shui, Leo Scheller, Pablo Gainza, Stéphane Rosset, Sandrine Georgeon, Li Tang, and Bruno E. Correia, ACS Chemical Biology 2023 18 (6), 1259-1265, DOI: 10.1021/acschembio.3c00012