Preclinical In Vivo Modeling of Cytokine Release Syndrome Induced by ErbB-Retargeted Human T Cells: Identifying a Window of Therapeutic Opportunity?

Sjoukje Van Der Stegen, David M Davies, Scott Wilkie, Julie Foster, Jane Sosabowski, Jerome Burnet, Lynsey Whilding, Roseanna Petrovic, Sadaf Ghaem-Maghami, Stephen Mather, Jean-Pierre Jeannon, Ana Parente Pereira, John Maher*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

104 Citations (Scopus)

Abstract

The ErbB network is dysregulated in many solid tumors. To exploit this, we have developed a chimeric Ag receptor (CAR) named T1E28z that targets several pathogenetically relevant ErbB dimers. T1E28z is coexpressed with a chimeric cytokine receptor named 4αβ (combination termed T4), enabling the selective expansion of engineered T cells using IL-4. Human T4+ T cells exhibit antitumor activity against several ErbB+ cancer types. However, ErbB receptors are also expressed in several healthy tissues, raising concerns about toxic potential. In this study, we have evaluated safety of T4 immunotherapy in vivo using a SCID beige mouse model. We show that the human T1E28z CAR efficiently recognizes mouse ErbB+ cells, rendering this species suitable to evaluate preclinical toxicity. Administration of T4+ T cells using the i.v. or intratumoral routes achieves partial tumor regression without clinical or histopathologic toxicity. In contrast, when delivered i.p., tumor reduction is accompanied by dose-dependent side effects. Toxicity mediated by T4+ T cells results from target recognition in both tumor and healthy tissues, leading to release of both human (IL-2/IFN-γ) and murine (IL-6) cytokines. In extreme cases, outcome is lethal. Both toxicity and IL-6 release can be ameliorated by prior macrophage depletion, consistent with clinical data that implicate IL-6 in this pathogenic event. These data demonstrate that CAR-induced cytokine release syndrome can be modeled in mice that express target Ag in an appropriate distribution. Furthermore, our findings argue that ErbB-retargeted T cells can achieve therapeutic benefit in the absence of unacceptable toxicity, providing that route of administration and dose are carefully optimized.
Original languageEnglish
Pages (from-to)4589-4598
Number of pages10
JournalJournal of Immunology
Volume191
Issue number9
DOIs
Publication statusPublished - 1 Nov 2013

Keywords

  • EPIDERMAL-GROWTH-FACTOR
  • CHIMERIC ANTIGEN RECEPTOR
  • EPITHELIAL OVARIAN-CANCER
  • NORMAL HUMAN ADULT
  • SCID BEIGE MICE
  • FACTOR-ALPHA
  • NEUREGULIN RECEPTOR
  • CARDIAC DEVELOPMENT
  • FETAL TISSUES
  • BREAST-CANCER

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