Regional CAR-T cell infusions for peritoneal carcinomatosis are superior to systemic delivery
| Autor: | Gary Point, Steven C. Katz, Richard P. Junghans, N J Espat, Cherif Boutros, Nader Hanna, Marissa Cunetta, Prajna Guha, Mitchell Thorn |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
Cytotoxicity
Immunologic 0301 basic medicine Cancer Research Recombinant Fusion Proteins Genetic enhancement medicine.medical_treatment T cell Cell- and Tissue-Based Therapy Receptors Antigen T-Cell Immunotherapy Adoptive Article Immunophenotyping Immunomodulation Mice 03 medical and health sciences Peritoneal cavity 0302 clinical medicine Carcinoembryonic antigen Antigen Antigens Neoplasm T-Lymphocyte Subsets Animals Humans Medicine Molecular Biology Peritoneal Neoplasms biology business.industry Cancer Immunotherapy medicine.disease Chimeric antigen receptor Tumor Burden 3. Good health Disease Models Animal Treatment Outcome 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Immunology biology.protein Molecular Medicine business Biomarkers |
| Zdroj: | Cancer gene therapy |
| ISSN: | 1476-5500 0929-1903 |
| DOI: | 10.1038/cgt.2016.14 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink