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Mata, Melinda; Gerken, Claudia; Nguyen, Phuong; Krenciute, Giedre; Spencer, David M.; Gottschalk, Stephen

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

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  • Medientyp: E-Artikel
  • Titel: Inducible Activation of MyD88 and CD40 in CAR T Cells Results in Controllable and Potent Antitumor Activity in Preclinical Solid Tumor Models
  • Beteiligte: Mata, Melinda; Gerken, Claudia; Nguyen, Phuong; Krenciute, Giedre; Spencer, David M.; Gottschalk, Stephen
  • Erschienen: American Association for Cancer Research (AACR), 2017
  • Erschienen in: Cancer Discovery
  • Sprache: Englisch
  • DOI: 10.1158/2159-8290.cd-17-0263
  • ISSN: 2159-8274; 2159-8290
  • Schlagwörter: Oncology
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title> <jats:p>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.</jats:p> <jats:p>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.</jats:p> <jats:p>This article is highlighted in the In This Issue feature, p. 1201</jats:p>
  • Zugangsstatus: Freier Zugang