Activation of CAR and non-CAR T cells within the tumor microenvironment following CAR T cell therapy
| Autor: | Scott J. Rodig, Zachary J. Roberts, William Y. Go, John J. Rossi, Caron A. Jacobson, Stuart A. Sievers, Adrian Bot, Mikel Lipschitz, Pei-Hsuan Chen, Jason L. Weirather, F. Stephen Hodi, Kyle Wright, Philippe Armand |
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| Rok vydání: | 2020 |
| Předmět: |
T-Lymphocytes
medicine.medical_treatment T cell Antigens CD19 Receptors Antigen T-Cell Immunotherapy Adoptive GZMB Immune system Tumor Microenvironment medicine Humans Biological Products Tumor microenvironment Receptors Chimeric Antigen business.industry General Medicine medicine.disease Chimeric antigen receptor Granzyme B Cytokine release syndrome Cytokine medicine.anatomical_structure Cancer research Lymphoma Large B-Cell Diffuse business human activities Biomarkers Research Article |
| Zdroj: | JCI Insight |
| ISSN: | 2379-3708 |
| Popis: | Mechanisms of chimeric antigen receptor (CAR) T cell–mediated antitumor immunity and toxicity remain poorly characterized because few studies examine the intact tumor microenvironment (TME) following CAR T cell infusion. Axicabtagene ciloleucel is an autologous anti-CD19 CAR T cell therapy approved for patients with large B cell lymphoma. We devised multiplex immunostaining and ISH assays to interrogate CAR T cells and other immune cell infiltrates in biopsies of diffuse large B cell lymphoma following axicabtagene ciloleucel infusion. We found that a majority of intratumoral CAR T cells expressed markers of T cell activation but, unexpectedly, constituted ≤5% of all T cells within the TME 5 days or more after therapy. Large numbers of T cells without CAR were also activated within the TME after axicabtagene ciloleucel infusion; these cells were positive for Ki-67, IFN-γ, granzyme B (GzmB), and/or PD-1 and were found at the highest levels in biopsies with CAR T cells. Additionally, non-CAR immune cells were the exclusive source of IL-6, a cytokine associated with cytokine release syndrome, and were found at their highest numbers in biopsies with CAR T cells. These data suggest that intratumoral CAR T cells are associated with non-CAR immune cell activation within the TME with both beneficial and pathological effects. |
| Databáze: | OpenAIRE |
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