folder

CD28 co-stimulus achieves superior CAR T cell effector function against solid tumors than 4-1BB co-stimulus

Authors

  • A. Textor
  • L. Grunewald
  • K. Anders
  • A. Klaus
  • S. Schwiebert
  • A. Winkler
  • M. Stecklum
  • J. Rolff
  • A.G. Henssen
  • U.E. Höpken
  • A. Eggert
  • J.H. Schulte
  • M.C. Jensen
  • T. Blankenstein
  • A. Künkele

Journal

  • Cancers

Citation

  • Cancers 13 (5): 1050

Abstract

  • Spacer or co-stimulatory components in chimeric antigen receptor (CAR) design influence CAR T cell effector function. Few preclinical mouse models optimally support CAR candidate pre-selection for clinical development. Here we use a model in which murine CAR T cells can be exploited with human tumor xenografts. This mouse-in-mouse approach avoids limitations caused by species-specific factors crucial for CAR T cell survival, trafficking and function. We compared trafficking, expansion and tumor control for T cells expressing different CAR construct designs targeting two antigens (L1CAM or HER2), structurally identical except for spacer (long or short) or co-stimulatory (4-1BB or CD28) domains to be evaluated. Using monoclonal, murine-derived L1CAM-specific CAR T cells in Rag-/- mice harboring established xenografted tumors from a human neuroblastoma cell line revealed a clear superiority in CAR T cell trafficking using CD28 co-stimulation. L1CAM-targeting short spacer-CD28/ζ CAR T cells expanded the most at the tumor site and induced initial tumor regression. Treating patient-derived neuroblastoma xenografts with human L1CAM-targeting CAR T cells confirmed the superiority of CD28 co-stimulus. CD28 superiority was also demonstrated with HER2-specific CAR T cells (targeting ovarian carcinoma xenografts). Our findings encourage incorporating CD28 signaling into CAR design for adoptive T cell treatment of solid tumors.


DOI

doi:10.3390/cancers13051050