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 CEA+ peritoneal tumors, when compared to 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.

Nanohybrids with Magnetic and Persistent Luminescence Properties for Cell Labeling, Tracking, In Vivo Real‐Time Imaging, and Magnetic Vectorization

“…Thus, we postulate that, by applying an appropriate magnetic field gradient, the approach developed in this study could be useful to assess cell targeting to specific locations inside the body for cell‐based therapies. This study also suggests the possibility to realize cell retention in the peritoneal cavity using our nanoparticles, which may be interesting for applications such as cancer cell therapies if similar results are further obtained with different kind of therapeutic cells.…”

Adoptive immunotherapy with CAR modified T cells in cancer current landscape and future perspectives

“…Other groups are exploring the possibility of local delivery, to enhance tumor killing and to reduce toxicity. Indeed, it has been shown that regional administration of anti-AFP or anti-CEA CAR T cells was equally effective or even superior to a systemic administration in xenograft models of peritoneal carcinomatosis (106,107), and the delivery of CAR T cells through percutaneous hepatic artery infusions has shown to be safe and clinically active in patients with CEA-expressing liver metastases (108). A different approach to favor the localization into the tumor site consists in the administration of CAR T cells overexpressing tumorspecific chemokine receptors enhancing their capacity of reaching the tumor tissues (109).…”

Regional immunotherapy for liver and peritoneal metastases

“…Pre‐clinical studies have demonstrated that intraperitoneal infusion of CAR T‐cells is worthy of further study for peritoneal carcinomatosis. In a murine model for peritoneal carcinomatosis, we evaluated intraperitoneal infusion of CAR T‐cells compared with systemic infusion for CEA+ peritoneal tumors . Not only did the intraperitoneal CAR T‐cells protect against tumor re‐challenge intraperitoneally, it also protected against tumor at subcutaneous sites.…”