Inducible activation of MyD88 and CD40 in CAR T-cells results in controllable and potent antitumor activity in preclinical solid tumor models [Research Articles]

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-CAR and a MyD88/CD40-based iCO molecule (HER2.iCO T-cells) had superior T-cell proliferation, cytokine production, and ability to sequentially kill targets in vitro relative to HER2.iCO T-cells without CID and T-cells expressing HER2-CAR.CD28. HER2.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 HER2.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.

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