Synthetic Chimeric Antigen Receptors: Hijacking Nitrenium Ions for Targeting, Therapy and Safety of Next Generation T Cell Therapy

Introduction

Chimeric antigen receptor (CAR) T cell therapy is a promising approach for cancer treatment with remarkable clinical outcomes. CAR T therapy involves the isolation of patients' T cells that are genetically modified with an engineered antigen receptor to attack cancer cells.

Challenges in CAR T Cell Therapy

Despite the great promise, the rapid activation and proliferation of CAR T cells can lead to serious side effects. In addition, CAR T therapy is challenged by:

1. Limited effectiveness
2. Difficulties in infiltrating solid tumors
3. Targeting of healthy cells
4. Cell exhaustion
5. An expensive, lengthy, and personalized manufacturing process

Over the past years, researchers have explored many strategies to improve and control CAR T cell function and to develop more universal CAR T cell platforms. Yet, an off-the-shelf approach that allows full control of CAR T effector function, that is flexible in use and can be obtained at low manufacturing costs, is currently not available.

Proposed Solution

To address the above challenges, I will develop a highly innovative, universal synthetic CAR (SynCAR) T cell platform where the antigen receptor is easily adaptable by using synthetic, functionalized targeting ligands to control T cell effector function in space and time.

Methodology

At the basis of this proposal lies the use of highly reactive and activatable aryl nitrenium ions for protein modification, drug delivery, and as a novel class of therapeutics. I will:

1. Tune nitrenium ion reactivity for bioconjugation and drug activation
2. Use enzyme-activatable nitrenium ion precursors for synthetically modified antigen receptors
3. Develop novel nitrenium ion-based prodrug strategies to improve CAR T efficiency
4. Use innovative bioorthogonal chemistry to control CAR T activity in time and space

Goals

In this work, I will develop beyond the state-of-the-art chemical biology methods and molecular targeting tools to control, potentiate, and tune T cell activity with the ultimate goal to broaden the CAR T targeting landscape to solid tumors and beyond.