"Enhancing the safety and efficacy of engineered T cells using protease-based technologies"

Abstract

Chimeric antigen receptors (CARs) are synthetic modular proteins that allow for directing immune cell reactivity towards a molecular target of interest, such as a cancer-associated antigen. CAR-T cells have demonstrated remarkable clinical activity in patients with refractory hematologic malignancies, leading to six FDA-approved products to date. There is much hope that next-generation platforms leveraging synthetic biology and genetic engineering will expand this class of therapeutics to solid tumors, where toxicity risks and limited efficacy are major barriers to progress. However, current platforms for enhancing CAR potency are at risk for increased toxicity, while those that are designed for safety exhibit diminished potency. In the first part of my talk, I will present on SNIP, an extensively optimized CAR ON switch that dually enhances safety and efficacy of T cells and is regulated by an FDA-approved small molecule. SNIP CARs outperformed conventional CARs in numerous solid tumor models. Through phenotypic and functional studies, we show that the enhanced activity of SNIP CARs is due to diminished T cell exhaustion and greater generation of memory T cells.

In order to meet the multiple obstacles facing CAR-T cells in solid tumors, next-generation smart therapies need to be multi-specific, resistant to exhaustion, and maintain their fitness in a hostile tumor microenvironment. Engineering NextGen therapies with these enhanced capabilities will require the introduction of additional genetic modules that often do not fit within the payload capacity of a single vector. In the second part of my talk, I will introduce STASH Select, a simple platform technology for enriching cells that have been engineered with multiple vectors using a single-step selection that results in high purity/yield and is compatible with current cell manufacturing workflows and closed loop systems.