Inducible Activation of MyD88 and CD40 in CAR T Cells Results in Controllable and Potent Antitumor Activity in Preclinical Solid Tumor Models

Cancer Discov. 2017 Nov;7(11):1306-1319. doi: 10.1158/2159-8290.CD-17-0263. Epub 2017 Aug 11.

Abstract

Adoptive immunotherapy with T cells expressing chimeric antigen receptors (CAR) has had limited success for solid tumors in early-phase clinical studies. We reasoned that introducing into CAR T cells an inducible costimulatory (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-CARζ and a MyD88/CD40-based iCO molecule (HER2ζ.iCO T cells) had superior T-cell proliferation, cytokine production, and ability to sequentially kill targets in vitro relative to HER2ζ.iCO T cells without CID and T cells expressing HER2-CAR.CD28ζ. HER2ζ.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 HER2ζ.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.Significance: Inducible activation of MyD88 and CD40 in CAR T cells with a small-molecule drug not only enhances their effector function, resulting in potent antitumor activity in preclinical solid tumors, but also enables their remote control post infusion. Cancer Discov; 7(11); 1306-19. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 1201.

MeSH terms

  • Animals
  • CD40 Antigens / genetics*
  • CD40 Antigens / immunology
  • CD40 Antigens / therapeutic use
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Gene Expression Regulation, Neoplastic / immunology
  • Humans
  • Immunotherapy, Adoptive / methods*
  • Mice
  • Myeloid Differentiation Factor 88 / genetics*
  • Myeloid Differentiation Factor 88 / immunology
  • Myeloid Differentiation Factor 88 / therapeutic use
  • Neoplasms / genetics
  • Neoplasms / immunology
  • Neoplasms / therapy*
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / immunology
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / therapeutic use*
  • T-Lymphocytes / immunology
  • Tumor Necrosis Factor Receptor Superfamily, Member 7 / genetics
  • Tumor Necrosis Factor Receptor Superfamily, Member 7 / immunology
  • Xenograft Model Antitumor Assays

Substances

  • CD40 Antigens
  • MYD88 protein, human
  • Myeloid Differentiation Factor 88
  • Receptors, Antigen, T-Cell
  • Tumor Necrosis Factor Receptor Superfamily, Member 7
  • ERBB2 protein, human
  • Receptor, ErbB-2