GoTCR: Inducible MyD88/CD40 (iMC) enhances proliferation and survival of tumor-specific TCR-modified T cells and improves anti-tumor efficacy in vivo
Tsvetelina Pentcheva-Hoang1, Tania Rodriguez1, David Torres1, Ana Korngold1, Jeannette Crisostomo1, Mirjam HM Heemskerk2, JH Frederik Falkenburg2, Annemarie Moseley1, Kevin M Slawin1, David M Spencer1 and Aaron E Foster1
1Bellicum Pharmaceuticals, Inc., Houston, TX 77030
2Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands
Use of engineered T cells expressing antigen-specific T cell receptors (TCRs) provides a promising cancer immunotherapy treatment; however, durable responses have been limited by poor T cell persistence and expansion in vivo. Additionally, MHC class I downregulation on tumor cells further reduces therapeutic efficacy. Therefore, we co-expressed in human T cells a proprietary, small molecule dimerizer (rimiducid)-dependent T cell activation “switch”, called inducible MyD88/CD40 (iMC), along with tumor antigen-specific TCRs to better regulate T cell activation and expansion.
Activated human T cells expressing either PRAME- or Bob1-specific TCRs in the presence or absence of iMC displayed antigen-specific IFN-g production and cytotoxicity. However, both TCR ligation and rimiducid-dependent iMC-based costimulation were required for IL-2 production. Coculture assays against multiple tumor lines showed that target elimination was optimized with concurrent rimiducid-driven iMC activation in both “GoTCR” constructs, which was accompanied by maximal IL-2 secretion and T cell proliferation. Further, iMC activation produced TCR-independent IFN-g, which significantly increased MHC class I expression on tumor cells. In vivo, “GoPRAME” TCR-modified T cells prevented U266 myeloma growth, unlike any other T cell groups. Importantly, weekly rimiducid injection dramatically expanded GoPRAME TCR-expressing T cell numbers by ~1000-fold on day 81 post-injection, compared to T cells expressing only PRAME TCR (p < 0.001).
Thus, iMC-enhanced TCRs are prototypes of novel GoTCR engineered T cell therapies that may increase efficacy, safety and durability of adoptive T cell therapies.