Utilizing Protein Degradation Platforms to Enhance CAR-T Cell Therapy

Abstract

Background: Novel advances in cancer immunotherapy include “autonomous”, gene-modified cellular immunotherapies, that leverage genetic modifications to enhance expansion, dysfunction resistance, and effector function. However, there are concerns regarding the toxicity, accessibility, and cost, especially as many of the genes that limit T cell potency remain challenging to target. Approach: Synthetic biology provides refined ways to address the limitations of immunotheraphy; in our case, CAR-T cell biology. We are developing novel technologies that allow for conditional, multi-specific control of proteins that limit cellular immunotherapy function, without targeting the genetic loci itself. Targeted degradation of endogenous proteins is an alternative approach to target suppressive pathways in cellular immunotherapies. Some protein targets being assessed for degradation include SMAD, which mediates T-cell suppression by TGF-B, as well as Shp1 & Shp2 domains common among many T-cell inhibitory receptors. Results: We successfully developed a protein degradation platform targeting SMAD, which was shown to enhance CAR T cell proliferation and cytotoxicity, with and without the presence of TGF-B. While we also engineered a multi-inhibitory receptor platform targeting the Shp1 & Shp2 domains of multiple inhibitory receptors, we have not seen decrease in inhibitory receptor abundance using the platform. Conclusion: Targeted protein degradation platforms provide additional technologies to allow for space and time-limited genetic perturbation. Eventually, degrader synthetic biology will be able to alleviate risks of toxicity in cellular immunotherapy, and help safely deploy cell therapies in a routine, outpatient setting.