Preclinical In Vivo Modeling of Cytokine Release Syndrome Induced by ErbB-Retargeted Human T Cells: Identifying a Window of Therapeutic Opportunity?
| Autor: | Jane K. Sosabowski, Sadaf Ghaem-Maghami, Lynsey M. Whilding, Jean-Pierre Jeannon, Jerome Burnet, Sjoukje J. C. van der Stegen, Stephen J. Mather, Roseanna Maria Petrovic, Ana C. Parente-Pereira, David M. Davies, Julie Foster, John Maher, Scott Wilkie |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Recombinant Fusion Proteins
T-Lymphocytes medicine.medical_treatment Immunology Mice SCID Pharmacology Biology Immunotherapy Adoptive Cell Line Interferon-gamma Mice ErbB Receptors ErbB In vivo Neoplasms medicine Animals Humans Immunology and Allergy Interleukin 4 Interleukin-6 Macrophages Oncogene Proteins v-erbB Immunotherapy medicine.disease Chimeric antigen receptor Cytokine release syndrome Interleukin-2 Interleukin-4 Cytokine receptor Signal Transduction |
| Zdroj: | The Journal of Immunology. 191:4589-4598 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.1301523 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|