Abstract
Chimeric antigen receptor (CAR) T cell therapy for solid tumors has shown limited efficacy in early-phase clinical studies. The majority of CARs encode CD28 and/or 41BB costimulatory endodomains, and we explored whether MyD88 and CD40 (MC) costimulatory endodomains in CARs could improve their antitumor activity. We generated CD28-, 41BB-, and MC-CAR T cells and demonstrated that MC-CAR T cells have greater proliferative capacity and antitumor activity in repeat stimulation assays and in tumor models in vivo. Transcriptomic analysis revealed that MC-CAR T cells expressed higher levels of MYB and FOXM1, key cell cycle regulators, and were activated at baseline. After stimulation, MC-CAR T cells remained in a less differentiated state than CD28- and 41BB-CAR T cells as judged by low levels of transcription factor TBET and B lymphocyte induced maturation protein 1 expression and lower cytolytic activity in comparison with CD28- and 41BB-CAR T cells. Thus, including MyD88 and CD40 signaling domains in CARs may improve current CAR T cell therapy approaches for solid tumors.
Highlights
Immunotherapy with T cells expressing chimeric antigen receptors (CAR T cells) had remarkable success for CD19+ hematological malignancies, leading to their FDA approval [1,2,3]
We show here that incorporating MyD88 and CD40 signaling domains into the endodomain of Chimeric antigen receptor (CAR) enhances the effector function of CAR T cells both in vitro and in vivo
MyD88 and CD40 (MC)-CAR T cells displayed higher levels of transcription factors associated with the maintenance of a stem-like phenotype in T cells and low expression of transcription factors that drive T cell differentiation
Summary
Immunotherapy with T cells expressing chimeric antigen receptors (CAR T cells) had remarkable success for CD19+ hematological malignancies, leading to their FDA approval [1,2,3]. The adoptive transfer of CAR T cells for solid tumors and brain tumors has had limited clinical success so far [4,5,6]. This lack of efficacy is most likely multifactorial, including heterogenous antigen expression, limited homing of infused T cells to tumor sites, and reduced CAR T cell function within the tumor microenvironment [7]. Mechanistic studies with iMC and cMC ζ-CAR T cells have been limited, showing decreased PD-1 expression after stimulation of iMC and cMC CAR T cells; activation of NF-κB, TNF, and antiapoptotic pathway signaling after iMC activation; and baseline cytokine expression of cMC CAR T cells [12,13,14]
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