Immunological activation in responding patients with recurrent HGG after treatment with toca 511 & toca FC: Results from a phase 1 trial
Ostertag D, Accomando W, Hogan D, Diago O, Gammon D, Haghighi A, Mitchell L, Rodriguez-Aquirre M, Cloughesy T, Kalkanis S, Mikkelsen T, Landolfi J, Chen C, Vogelbaum M, Gruber H, Das A, and Jolly D. Immunological activation in responding patients with recurrent HGG after treatment with toca 511 & toca FC: Results from a phase 1 trial. Neuro-Oncology 2017; 19(suppl 6):vi31-vi32.
A dose-escalation clinical study (NCT01470794) using a retroviral replicating vector (RRV), Toca 511 (vocimagene amiretrorepvec), in combination with oral Toca FC (extended-release 5-fluorocytosine, 5-FC) is ongoing to evaluate safety, mechanism of action, and preliminary efficacy of this investigational therapy in patients with recurrent HGG. Toca 511 encodes a yeast-derived, codon-optimized, heat-stabilized cytosine deaminase that converts 5-FC to the anti-cancer drug 5-FU in infected tumors. This virus replicates selectively in malignant tissue and may have broad application in cancer therapies. When Toca FC is administered, cytosine deaminase is designed to convert 5-FC to 5-FU resulting in cancer cell death. In preclinical tumor models, as infected cancer cells are killed, diffusible 5-FU also kills susceptible cells, including myeloid derived suppressor cells that contribute to immune-suppression in the tumor microenvironment. This action by Toca 511 and Toca FC in animal models generates durable anti-tumor immune responses that can be transferred to naïve, untreated animals. In the clinical study presented here, Toca 511 is injected into resection cavity walls at time of resection followed by multiple courses of oral Toca FC. Multi-year durable and ongoing objective responses are observed, including four complete responses and two partial responses. We plan to report temporal changes in peripheral immune cells between responding and non-responding patients, including baseline differences in peripheral blood cell populations as well as temporal shifts in leukocyte subsets, T-cell receptor clonality, and serum cytokine levels. Sustained markers of proliferation and immune activation are observed in patients with response or stable disease compared to those that progressed. Immunohistochemistry analysis of resident T-cells in patient tumors taken at time of resection show fewer T-cells in responding and stable disease patients before treatment compared to those that did not respond. Data are consistent with the induction of anti-tumor immune response after Toca 511 and Toca FC administration.