Treatment of recurrent hgg patients with the retroviral replicating vector Toca 511 and Toca FC gives durable responses and survival lasting 3 years or longer: Immune mechanisms and molecular analyses of tumors
Das A, Ostertag D, Hogan D, Accomando W, Diago O, Haghighi A, Gammon D, Rodriguez-Aguirre M, Mitchell L, Kalkanis S, Mikkelsen T, Landolfi J, Carter B, Chen C, Vogelbaum M, Cloughesy T, Gruber H, and Jolly D. Treatment of recurrent hgg patients with the retroviral replicating vector Toca 511 and Toca FC gives durable responses and survival lasting 3 years or longer: Immune mechanisms and molecular analyses of tumors. Mol Ther 2018; 26(5):160.
Toca 511 is a retroviral replicating vector (RRV) based on an amphotropic gammaretrovirus that encodes an optimized humanized yeast cytosine deaminase (CD) and Toca FC is an extended release formulation of 5-Flucytosine (5-FC) which is converted to 5-Fluorouracil (5-FU) by CD, but not by any human gene activity. Toca 511 shows preferential uptake by tumor cells leading to local chemotherapy without systemic activity or toxicity. We have shown in animals that this treatment leads to high 5-FU levels in infected tumors, disruption of the immune suppressive tumor microenvironment, depletion of myeloid immune suppressive cells and robust anti-tumor CD4 and CD8 T cell responses. A phase 1 dose escalation trial (NCT01470794) with Toca 511 and Toca FC in patients with recurrent High Grade Glioma who underwent resection and injection of Toca 511 into the resection bed followed by cyclic treatment with Toca FC has completed enrollment and we continue to follow patient outcomes. Typically these tumors recur rapidly and median survival of such patients is around 8-9 months. The treatments were well-tolerated with no dose-limiting toxicities observed. Among 53 patients that were efficacy evaluable we report on the long term outcomes for 23 patients in the highest dose group where more than 25% of patients continue to survive (the two longest are currently over 50 months) and 5 of the long term survivors have durable ongoing complete responses lasting longer than 36 months. The late-occurring durable clinical responses suggest that these responses have a strong immune component, as seen in animal models. We now report on the initial analyses of the immune status of tumors before treatment, including neo-antigen load, in responding versus non-responding patients, and on the search for changes in systemic markers post treatment We also report on the molecular analyses of the virus recovered from treated patients in this trial and after iv administration of Toca 511 (NCT01985256), and preclinical data showing that efficacy can be observed with low levels of tumor transduction. These data support the ongoing Phase 3 “Toca 5” trial (NCT02414165) in recurrent high grade glioma patients.