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.
Author Info: (1) Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine. (2) Center for Cell and Gene Therapy, Texas Children's Hosp
Author Info: (1) Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine. (2) Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine. (3) Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine. (4) Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine. (5) Bellicum Pharmaceuticals. (6) Department of Bone Marrow Transplant and Cellular Therapy, St. Jude Children's Research Hospital stephen.gottschalk@stjude.org.
