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Regional CAR-T cell infusions for peritoneal carcinomatosis are superior to systemic delivery

Cancer Gene Therapy volume 23, pages 142–148 (2016)Cite this article

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Abstract

Metastatic spread of colorectal cancer (CRC) to the peritoneal cavity is common and difficult to treat, with many patients dying from malignant bowel obstruction. Chimeric antigen receptor T cell (CAR-T) immunotherapy has shown great promise, and we previously reported murine and phase I clinical studies on regional intrahepatic CAR-T infusion for CRC liver metastases. We are now studying intraperitoneal (IP) delivery of CAR-Ts for peritoneal carcinomatosis. Regional IP infusion of CAR-T resulted in superior protection against carcinoembryonic antigen (CEA+) peritoneal tumors, when compared with systemically infused CAR-Ts. IP CAR-Ts also provided prolonged protection against IP tumor re-challenges and demonstrated an increase in effector memory phenotype over time. IP CAR-Ts provided protection against tumor growth at distant subcutaneous (SC) sites in association with increases in serum IFNγ levels. Given the challenges posed by immunoinhibitory pathways in solid tumors, we combined IP CAR-T treatment with suppressor cell targeting. High frequencies of myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) were found within the IP tumors, with MDSC expressing high levels of immunosuppressive PD-L1. Combinatorial IP CAR-T treatment with depleting antibodies against MDSC and Treg further improved efficacy against peritoneal metastases. Our data support further development of combinatorial IP CAR-T immunotherapy for peritoneal malignancies.

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Acknowledgements

This project was made possible by a grant from the National Organization for Rare Disorders (NORD). Additional support for this work was provided by the National Institutes of Health (1K08CA160662-01A1). We would like to thank Immunomedics, Inc. for generously providing the Wi2 anti-idiotype antibody to detect CAR expression. We would like to thank Dr John Morgan and Roger Williams Medical Center Core Facility for providing us with the necessary equipment to carry out flow cytometry and in vivo bioluminescence experiments.

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Authors and Affiliations

  1. Department of Surgery, Roger Williams Medical Center, Providence, RI, USA

    S C Katz, G R Point, M Cunetta, M Thorn, P Guha & N J Espat

  2. Department of Surgery, Boston University School of Medicine, Boston, MA, USA

    S C Katz & N J Espat

  3. Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA

    C Boutros & N Hanna

  4. Department of Medicine, Tufts Medical Center, Boston, MA, USA

    R P Junghans

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  1. S C Katz
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  2. G R Point
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Correspondence to S C Katz.

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Katz, S., Point, G., Cunetta, M. et al. Regional CAR-T cell infusions for peritoneal carcinomatosis are superior to systemic delivery. Cancer Gene Ther 23, 142–148 (2016). https://doi.org/10.1038/cgt.2016.14

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