A rational mouse model to detect on-target, off-tumor CAR T cell toxicity

JCI Insight. 2020 Jul 23;5(14):e136012. doi: 10.1172/jci.insight.136012.

Abstract

Off-tumor targeting of human antigens is difficult to predict in preclinical animal studies and can lead to serious adverse effects in patients. To address this, we developed a mouse model with stable and tunable human Her2 (hHer2) expression on normal hepatic tissue and compared toxicity between affinity-tuned Her2 chimeric antigen receptor T cells (CARTs). In mice with hHer2-high livers, both the high-affinity (HA) and low-affinity (LA) CARTs caused lethal liver damage due to immunotoxicity. In mice with hHer2-low livers, LA-CARTs exhibited less liver damage and lower systemic levels of IFN-γ than HA-CARTs. We then compared affinity-tuned CARTs for their ability to control a hHer2-positive tumor xenograft in our model. Surprisingly, the LA-CARTs outperformed the HA-CARTs with superior antitumor efficacy in vivo. We hypothesized that this was due, in part, to T cell trafficking differences between LA and HA-CARTs and found that the LA-CARTs migrated out of the liver and infiltrated the tumor sooner than the HA-CARTs. These findings highlight the importance of T cell targeting in reducing toxicity of normal tissue and also in preventing off-tumor sequestration of CARTs, which reduces their therapeutic potency. Our model may be useful to evaluate various CARTs that have conditional expression of more than 1 single-chain variable fragment (scFv).

Keywords: Cancer immunotherapy; Immunology; Therapeutics.

Publication types

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

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Disease Models, Animal
  • Gene Expression Regulation / drug effects
  • Humans
  • Immunotherapy, Adoptive / methods
  • Interferon-gamma / genetics*
  • Liver / drug effects*
  • Liver / pathology
  • Mice
  • Receptor, ErbB-2 / genetics*
  • Receptors, Antigen, T-Cell / genetics*
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Chimeric Antigen / genetics*
  • Receptors, Chimeric Antigen / immunology
  • Single-Chain Antibodies / immunology
  • Single-Chain Antibodies / pharmacology
  • T-Lymphocytes / immunology
  • Xenograft Model Antitumor Assays

Substances

  • IFNG protein, mouse
  • Receptors, Antigen, T-Cell
  • Receptors, Chimeric Antigen
  • Single-Chain Antibodies
  • Interferon-gamma
  • ERBB2 protein, human
  • Receptor, ErbB-2