title: Regional CAR-T cell infusions for peritoneal carcinomatosis are superior to systemic delivery.
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.
authors.affiliation: Department of Surgery, Roger Williams Medical Center, Providence, RI, USA.|Department of Surgery, Boston University School of Medicine, Boston, MA, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Katz
authors.affiliation: Department of Surgery, Roger Williams Medical Center, Providence, RI, USA.
authors.forename: G R
authors.initials: GR
authors.lastname: Point
authors.affiliation: Department of Surgery, Roger Williams Medical Center, Providence, RI, USA.
authors.forename: M
authors.initials: M
authors.lastname: Cunetta
authors.affiliation: Department of Surgery, Roger Williams Medical Center, Providence, RI, USA.
authors.forename: M
authors.initials: M
authors.lastname: Thorn
authors.affiliation: Department of Surgery, Roger Williams Medical Center, Providence, RI, USA.
authors.forename: P
authors.initials: P
authors.lastname: Guha
authors.affiliation: Department of Surgery, Roger Williams Medical Center, Providence, RI, USA.|Department of Surgery, Boston University School of Medicine, Boston, MA, USA.
authors.forename: N J
authors.initials: NJ
authors.lastname: Espat
authors.affiliation: Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: C
authors.initials: C
authors.lastname: Boutros
authors.affiliation: Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: N
authors.initials: N
authors.lastname: Hanna
authors.affiliation: Department of Medicine, Tufts Medical Center, Boston, MA, USA.
authors.forename: R P
authors.initials: RP
authors.lastname: Junghans
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015415:Biomarkers; D064987:Cell- and Tissue-Based Therapy / Q000379:methods; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D006801:Humans; D056747:Immunomodulation; D016130:Immunophenotyping; D016219:Immunotherapy, Adoptive / Q000379:methods*; D051379:Mice; D010534:Peritoneal Neoplasms / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D016896:Treatment Outcome; D047368:Tumor Burden
chemical_list: D000951:Antigens, Neoplasm; D015415:Biomarkers; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins