Efficacy and safety of Her2-targeted chimeric antigen receptor (CAR) T cells using MyD88/CD40 costimulation and iCaspase-9 suicide switch.

Abstract

3050Background: Efficacy of chimeric antigen receptor T cells (CAR-T) is dependent on their in vivo survival and expansion following adoptive transfer. Here, we show that constitutive expression of the MyD88/CD40 (MC) fusion protein dramatically enhances CAR-T proliferation resulting in improved antitumor efficacy against Her2+ solid tumors. Importantly, CAR-T cell levels and cytokine-related toxicity can be controlled by graduated administration of rimiducid to activate the inducible iCaspase-9 (iC9) suicide gene without detriment to tumor control. Methods: T cells were modified with a tricistronic retrovirus encoding iC9, a Her2-specific CAR (Her2.ζ) and constitutively active MC (iC9-Her2.ζ-MC), or control vectors (iC9-Her2.ζ and iC9-Her2.CD28.ζ) and compared for cytotoxicity, cytokine production and proliferation in coculture assays against Her2+ breast (SK-BR-3), ovarian (A2780, SKOV-3), gastric (N87, Kato III, SNU-1) and pancreatic (HPAC) cancer cell lines. CAR-T efficacy was assessed in NSG mice eng...