Toca 511 gene transfer and treatment with the prodrug, 5-fluorocytosine, promotes durable antitumor immunity in a mouse glioma model

• Published in: Neuro-oncology (Charlottesville, Va.) Vol. 19; no. 7; pp. 930 - 939
• Main Authors: Mitchell, Leah A, Lopez Espinoza, Fernando, Mendoza, Daniel, Kato, Yuki, Inagaki, Akihito, Hiraoka, Kei, Kasahara, Noriyuki, Gruber, Harry E, Jolly, Douglas J, Robbins, Joan M
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.07.2017
• Subjects: Animals; Antineoplastic Agents - therapeutic use; Basic and Translational Investigations; Brain Neoplasms - drug therapy; Brain Neoplasms - immunology; Cell Line, Tumor; Cytosine Deaminase; Disease Models, Animal; Flucytosine - therapeutic use; Genetic Therapy; Genetic Vectors; Glioma - drug therapy; Glioma - immunology; Immunity; Mice; Monocytes - drug effects; Myeloid Cells - drug effects; Prodrugs - therapeutic use; Retroviridae; T-Lymphocytes - drug effects; 5-fluorouracil; retroviral gene transfer; cytosine deaminase; myeloid-derived suppressor cell; immunotherapy
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/nox037

Toca 511 (vocimagene amiretrorepvec) is a retroviral replicating vector encoding an optimized yeast cytosine deaminase (CD). Tumor-selective expression of CD converts the prodrug, 5-fluorocytosine (5-FC), into the active chemotherapeutic, 5-fluorouracil (5-FU). This therapeutic approach is being tested in a randomized phase II/III trial in recurrent glioblastoma and anaplastic astrocytoma (NCT0241416). The aim of this study was to identify the immune cell subsets contributing to antitumor immune responses following treatment with 5-FC in Toca 511-expressing gliomas in a syngeneic mouse model. Flow cytometry was utilized to monitor and characterize the immune cell infiltrate in subcutaneous Tu-2449 gliomas in B6C3F1 mice treated with Toca 511 and 5-FC. Tumor-bearing animals treated with Toca 511 and 5-FC display alterations in immune cell populations within the tumor that result in antitumor immune protection. Attenuated immune subsets were exclusive to immunosuppressive cells of myeloid origin. Depletion of immunosuppressive cells temporally preceded a second event which included expansion of T cells which were polarized away from Th2 and Th17 in the CD4+ T cell compartment with concomitant expansion of interferon gamma-expressing CD8+ T cells. Immune alterations correlated with clearance of Tu-2449 subcutaneous tumors and T cell-dependent protection from future tumor challenge. Treatment with Toca 511 and 5-FC has a concentrated effect at the site of the tumor which causes direct tumor cell death and alterations in immune cell infiltrate, resulting in a tumor microenvironment that is more permissive to establishment of a T cell mediated antitumor immune response.