Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape

J Clin Invest. 2016 Aug 1;126(8):3036-52. doi: 10.1172/JCI83416. Epub 2016 Jul 18.

Abstract

In preclinical models of glioblastoma, antigen escape variants can lead to tumor recurrence after treatment with CAR T cells that are redirected to single tumor antigens. Given the heterogeneous expression of antigens on glioblastomas, we hypothesized that a bispecific CAR molecule would mitigate antigen escape and improve the antitumor activity of T cells. Here, we created a CAR that joins a HER2-binding scFv and an IL13Rα2-binding IL-13 mutein to make a tandem CAR exodomain (TanCAR) and a CD28.ζ endodomain. We determined that patient TanCAR T cells showed distinct binding to HER2 or IL13Rα2 and had the capability to lyse autologous glioblastoma. TanCAR T cells exhibited activation dynamics that were comparable to those of single CAR T cells upon encounter of HER2 or IL13Rα2. We observed that TanCARs engaged HER2 and IL13Rα2 simultaneously by inducing HER2-IL13Rα2 heterodimers, which promoted superadditive T cell activation when both antigens were encountered concurrently. TanCAR T cell activity was more sustained but not more exhaustible than that of T cells that coexpressed a HER2 CAR and an IL13Rα2 CAR, T cells with a unispecific CAR, or a pooled product. In a murine glioblastoma model, TanCAR T cells mitigated antigen escape, displayed enhanced antitumor efficacy, and improved animal survival. Thus, TanCAR T cells show therapeutic potential to improve glioblastoma control by coengaging HER2 and IL13Rα2 in an augmented, bivalent immune synapse that enhances T cell functionality and reduces antigen escape.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, Neoplasm / metabolism
  • Antineoplastic Agents / chemistry
  • Brain Neoplasms / metabolism*
  • Cell Line, Tumor
  • Glioblastoma / metabolism*
  • Humans
  • Immunotherapy, Adoptive
  • Interleukin-13 / metabolism
  • Interleukin-13 Receptor alpha2 Subunit / metabolism*
  • Lymphocyte Activation
  • Mice
  • Mice, SCID
  • Neoplasm Recurrence, Local
  • Neoplasm Transplantation
  • Protein Binding
  • Protein Multimerization
  • Receptor, ErbB-2 / metabolism*
  • Receptors, Antigen, T-Cell / metabolism
  • T-Lymphocytes / metabolism*
  • Transgenes
  • Tumor Escape*

Substances

  • Antigens, Neoplasm
  • Antineoplastic Agents
  • Interleukin-13
  • Interleukin-13 Receptor alpha2 Subunit
  • Receptors, Antigen, T-Cell
  • Erbb2 protein, mouse
  • Receptor, ErbB-2