Mata et al. demonstrate that delivering signal 2 to T cells using chemically inducible dimerization of alternative signaling endodomains (MyD88 fused to CD40) improves the activity of a co-delivered HER2-CAR by increasing antigen-driven cytokine production and proliferation capacity, extending persistence of cytotoxicity, and reducing PD-1 upregulation in vitro, culminating in improved tumor control in two solid tumor xenograft models.
Adoptive immunotherapy with T-cells expressing chimeric antigen receptors (CARs) has had limited success for solid tumors in early phase clinical studies. We reasoned that introducing into CAR T-cells an inducible co-stimulatory (iCO) molecule consisting of a chemical inducer of dimerization (CID)-binding domain and the MyD88 and CD40 signaling domains would improve and control CAR T-cell activation. In the presence of CID, T-cells expressing HER2-CARzeta and a MyD88/CD40-based iCO molecule (HER2zeta.iCO T-cells) had superior T-cell proliferation, cytokine production, and ability to sequentially kill targets in vitro relative to HER2zeta.iCO T-cells without CID and T-cells expressing HER2-CAR.CD28zeta. HER2zeta.iCO T-cells with CID also significantly improved survival in vivo in two xenograft models. Repeat injections of CID were able to further increase the antitumor activity of HER2zeta.iCO T-cells in vivo. Thus, expressing MyD88/CD40-based iCO molecules in CAR T-cells has the potential to improve the efficacy of CAR T-cell therapy approaches for solid tumors.