Selective “Off-Switch” Control of Chimeric Agonist Receptors (CARs) Activity for Safer Cell-based Immunotherapies

Project by Pamela Lewis

About This Project

Our technology seamlessly creates a split Chimeric Antigen Receptors (CARs) including an extracellular antigen recognition, a transmembrane, and an intracellular signaling domain for a pharmacologically conditional “off-switch” via a small-molecule drug. The addition of this receptor allows for modulation of T cell activity in the body. Upon introduction, the small-molecule compound would bind and activate the negative regulatory domain on the CAR-T or TCR, resulting in inhibition of T-cell activation. This “off-switch” domain allows for addition of an unprecedented safety switch that can be immediately activated upon the first signs of unwanted side-effects. This is different from the “on-switch”, which had been previously developed by the Wendell Group, in that this technology represses T-cell activity upon activation, rather than activating.

Project's Context

It is well established that the potentials of CAR-Ts and TCRs to cure cancer are unprecedented, however there is still great concern in the field for such side effects as cytokine release syndrome and destruction of healthy tissue. Our invention proposes to add an “off-switch” to both types of immunotherapies, CAR-Ts and TCRs, that allows for efficient and effective modulation of T-cell activity once introduced in to the patient.

Project's Relevance

An “off-switch” for CAR-Ts and TCRs that allows for better in vivo activity modulation, for rapidly turning off t-cell activity resulting in increased safety.

The advantages of this technology includes:

- Addition of an “off-switch” to modulate in vivo activity, thus creating a safety switch in case of unwanted side effects
- Activation of the “off-switch” does not result in destruction of the T-cell, but instead tunes its activity
- Ability to readily add this technology to existing CAR-T and TCR platforms
- Use of a small molecule allows for inactivation of TCRs that can recognize MHC-associated intracellular antigens

Project's Goals

To develop this “off-switch”, or “safety switch”, technology alongside their current CAR-T and TCR platforms to increase safety and reduce adverse side effects.