Therapeutic activity of retroviral replicating vector-mediated gene therapy in combination with anti-PD-1 antibody in a murine pancreatic cancer model

• Published in: Cancer gene therapy Vol. 31; no. 9; pp. 1390 - 1401
• Main Authors: Niwa, Hiroki, Nakamura, Toru, Kushiya, Hiroki, Kuraya, Tomotaka, Inoko, Kazuho, Inagaki, Akihito, Suzuki, Tomohiro, Sasaki, Katsunori, Tsuchikawa, Takahiro, Hiraoka, Kei, Shichinohe, Toshiaki, Hatanaka, Yutaka, Jolly, Douglas J, Kasahara, Noriyuki, Hirano, Satoshi
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.09.2024
• Subjects: 5-Fluorouracil; Animals; Antitumor activity; Apoptosis; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell death; Cell Line, Tumor; Clinical trials; Combination therapy; Combined Modality Therapy; Cytosine; Cytosine deaminase; Cytosine Deaminase - genetics; Cytosine Deaminase - metabolism; Cytotoxicity; Disease Models, Animal; Female; Flucytosine - pharmacology; Flucytosine - therapeutic use; Gene therapy; Genetic Therapy - methods; Genetic Vectors - administration & dosage; Genetic Vectors - genetics; Humans; Immune response; Lymphocytes T; Metastases; Mice; Pancreatic cancer; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - pathology; Pancreatic Neoplasms - therapy; PD-1 protein; Peritoneum; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Retroviridae - genetics; Tumors
• ISSN: 0929-1903; 1476-5500; 1476-5500
• DOI: 10.1038/s41417-024-00810-7

Toca 511, a tumor-selective retroviral replicating vector encoding the yeast cytosine deaminase (yCD) gene, exerts direct antitumor effects through intratumoral prodrug 5-fluorocytosine (5-FC) conversion to active drug 5-fluorouracil by yCD, and has demonstrated therapeutic efficacy in preclinical and clinical trials of various cancers. Toca 511/5-FC treatment may also induce antitumor immunity. Here, we first examined antitumor immune responses activated by Toca 511/5-FC treatment in an immunocompetent murine pancreatic cancer model. We then evaluated the therapeutic effects achieved in combination with anti-programmed cell death protein 1 antibody. In the bilateral subcutaneous tumor model, as compared with the control group, enhanced CD8 T-cell-mediated cytotoxicity and increased T-cell infiltration in Toca 511-untransduced contralateral tumors were observed. Furthermore, the expression levels of T-cell co-inhibitory receptors on CD8 T-cells increased during treatment. In the bilateral subcutaneous tumor model, combination therapy showed significantly stronger tumor growth inhibition than that achieved with either monotherapy. In an orthotopic tumor and peritoneal dissemination model, the combination therapy resulted in complete regression in both transduced orthotopic tumors and untransduced peritoneal dissemination. Thus, Toca 511/5-FC treatment induced a systemic antitumor immune response, and the combination therapy could be a promising clinical strategy for treating metastatic pancreatic cancer.