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

Abstract

Background.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.Methods.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.Results.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.Conclusions.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.

Therapeutic activity of retroviral replicating vector-mediated prodrug activator gene therapy for pancreatic cancer

“…As 5-FU has a very short half-life and is generated locally within the tumor itself, there have been no clinically meaningful adverse effects typically associated with conventional systemic chemotherapy, such as myelotoxicity. Also durable anti-tumor immunity was activated through bystander effects on immunosuppressive stromal cells adjacent to infected cancer cells [24,25]. In multi-center Phase I dose escalation trials for patients with recurrent high-grade glioma, Toca 511 and Toca FC (an extended release formulation of 5-FC) prodrug activator gene therapy showed no clinical meaningful toxicity and highly promising evidence of clinical activity [22], and is now being evaluated in a registrational Phase II/III clinical trial (NCT02414165).…”

“…Finally, we have recently shown in animal models that, as well as killing cancer cells, Toca 511 and 5-FC treatment depletes local myeloid derived suppressor cells (MDSC) in infected tumors, leading to robust anti-tumor immune responses [24,25]. Pancreatic cancer is known to carry a significant population of MDSC both in tumors and the blood stream [34].…”

Molecular Analyses Support the Safety and Activity of Retroviral Replicating Vector Toca 511 in Patients

“…In animal models, Toca 511-infected tumor cells are killed by 5-FU converted from 5-FC. The diffusible 5-FU also kills susceptible neighboring cells, including immune suppressor myeloid cells that contribute to the immune-suppressed tumor microenvironment (51,52). After several cycles of Toca FC, treated immunocompetent animals that clear tumor are resistant to tumor rechallenge (12) and this resistance is T-cell mediated (51,52).…”

Oncolytic Viruses as a Platform for the Treatment of Malignant Brain Tumors

“…This strategy has also been used with the design of the nonlytic retroviral replicating vector (RRV) Toca 511 (Vocimagene amiretrorepvec), based on a modified murine leukemia virus. Toca 551 has been shown to elicit durable T cell-mediated antitumor immune responses in mouse glioma models [ 45 , 46 ].…”