Preclinical and Clinical Data Supports Anti-tumor Cellular Immune Response Elicited by Toca 511 and Toca FC Therapy
Derek Ostertag, Daniel J. Hogan, Oscar R. Diago, Dawn Gammon, Ali Haghighi, William P. Accomando, Leah A. Mitchell, Asha Das, Harry E. Gruber and Douglas J. Jolly
Tocagen Inc. San Diego, CA 92109
Toca 511 (vocimagene amiretrorepvec) is a gamma-retroviral replicating vector (RRV) encoding a cytosine deaminase transgene that allows infected cells to convert antifungal drug 5-fluorocytosine (5-FC) into antineoplastic drug 5-fluorouracil (5-FU). Toca 511 can be delivered by multiple routes, selectively infects, spreads and persists in cancer cells and through multiple mechanisms of action can elicit an anti-tumor immune response. Treatment directly kills infected cancer cells. Diffusible 5-FU also kills neighboring susceptible cells that contribute to the immune-suppressed tumor microenvironment, especially myeloid immune suppressor cells. After multiple cycles of 5-FC, treated animals that clear tumor are resistant to tumor re-challenge. Splenic T cells from these treated animals can be adoptively transferred into naïve animals who then gain resistance to tumor challenge. Toca 511 and Toca FC (extended-release 5-FC) have been administered to 126 recurrent high grade glioma (rHGG) patients in three phase I studies (NCT01156584, NCT01470794, NCT01985256) and, a phase 2/3 trial (Toca 5) is ongoing (NCT02414165). Toca 511 plus Toca FC has been well tolerated in these patients. In the clinical study presented, Toca 511 is injected into resection cavity walls at time of tumor resection, and followed with multiple courses of Toca FC. In a subset of Phase I patients that mimic the phase 2/3 rHGG enrollment criteria, there were 3 CRs and 2 PRs out of 24 patients observed. The median duration of response is 26.7 months. These responders have an overall survival range from 24.0+ to 42.6+ months and ongoing. Data are consistent with induction of anti-tumor immune responses after Toca FC administration. Changes in peripheral immune populations as well as interrogation of immunogenic biomarkers in responding and non-responding patients will be presented.
Credits: None available.
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