Tumor-targeted nonablative radiation promotes solid tumor CAR T-cell therapy efficacy Journal Article
| Authors: | Quach, H. T.; Skovgard, M. S.; Villena-Vargas, J.; Bellis, R. Y.; Chintala, N. K.; Amador-Molina, A.; Bai, Y.; Banerjee, S.; Saini, J.; Xiong, Y.; Vista, W. R.; Byun, A. J.; De Biasi, A.; Zeltsman, M.; Mayor, M.; Morello, A.; Mittal, V.; Gomez, D. R.; Rimner, A.; Jones, D. R.; Adusumilli, P. S. |
| Article Title: | Tumor-targeted nonablative radiation promotes solid tumor CAR T-cell therapy efficacy |
| Abstract: | Infiltration of tumor by T cells is a prerequisite for successful immunotherapy of solid tumors. In this study, we investigate the influence of tumor-targeted radiation on chimeric antigen receptor (CAR) T-cell therapy tumor infiltration, accumulation, and efficacy in clinically relevant models of pleural mesothelioma and non-small cell lung cancers. We use a nonablative dose of tumor-targeted radiation prior to systemic administration of mesothelin-targeted CAR T cells to assess infiltration, proliferation, antitumor efficacy, and functional persistence of CAR T cells at primary and distant sites of tumor. A tumor-targeted, nonablative dose of radiation promotes early and high infiltration, proliferation, and functional persistence of CAR T cells. Tumor-targeted radiation promotes tumor-chemokine expression and chemokine- receptor expression in infiltrating T cells and results in a subpopulation of higher-intensity CAR-expressing T cells with high coexpression of chemokine receptors that further infiltrate distant sites of disease, enhancing CAR T-cell antitumor efficacy. Enhanced CAR T-cell efficacy is evident in models of both high-mesothelinexpressing mesothelioma and mixed-mesothelin-expressing lung cancer-two thoracic cancers for which radiotherapy is part of the standard of care. Our results strongly suggest that the use of tumortargeted radiation prior to systemic administration of CAR T cells may substantially improve CAR T-cell therapy efficacy for solid tumors. Building on our observations, we describe a translational strategy of "sandwich"cell therapy for solid tumors that combines sequential metastatic site-targeted radiation and CAR T cells-a regional solution to overcome barriers to systemic delivery of CAR T cells. © 2023 American Association for Cancer Research. |
| Keywords: | cell line, tumor; chemokine; receptors, antigen, t-cell; tumor cell line; malignant mesothelioma; mesothelioma; adoptive immunotherapy; immunotherapy, adoptive; lymphocyte antigen receptor; chemokines; chemokine receptor; receptors, chemokine; mesothelin; procedures; gpi-linked proteins; glycosylphosphatidylinositol anchored protein; humans; human; mesothelioma, malignant |
| Journal Title: | Cancer Immunology Research |
| Volume: | 11 |
| Issue: | 10 |
| ISSN: | 2326-6066 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2023-10-01 |
| Start Page: | 1314 |
| End Page: | 1331 |
| Language: | English |
| DOI: | 10.1158/2326-6066.Cir-22-0840 |
| PUBMED: | 37540803 |
| PROVIDER: | scopus |
| PMCID: | PMC10592183 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Corresponding author is MSK author: Prasad S. Adusumilli -- Source: Scopus |
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