MyD88/CD40-based inducible co-stimulation to improve CAR T cell therapy

Background Adoptive immunotherapy with genetically modified T cells holds promise in improving outcomes for cancer patients. While a broad array of genetic modification strategies are being explored, few allow for the specific manipulation of adoptively transferred T cells in vivo. One successful example includes the introduction of an inducible ‘suicide gene’ to enable selective T-cell killing in the event of toxicities. Given the limited antitumor activity of adoptively transferred T cells for solid tumors in early clinical studies, we reasoned that introducing an inducible co-stimulatory molecule into T cells would allow for the selective activation of adoptively transferred T cells in vivo resulting in enhanced antitumor activity. Due to the role of MyD88 and CD40 signaling pathways to fine tune T-cell activation, and the recent success of using inducible (i) MyD88 and CD40 molecules to activate antigen-presenting cells, the goal of this project was to explore if T cells can be activated with iMyD88 and/or iCD40 molecules.