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Toca 511, a clinical-stage tumor-selective retroviral replicating vector (RRV), encodes optimized yeast cytosine deaminase (CD), which converts the prodrug 5-fluorocytosine (5-FC) to the active drug 5-fluorouracil (5-FU) within infected cancer cells. In preclinical models of intracerebral glioblastoma, 5-FU generated locally by Toca 511 (RRV-CD) prodrug activator gene therapy has also been shown to kill immunosuppressive myeloid cells in the tumor microenvironment, leading to anti-cancer immune activation and long-term survival. Early-phase clinical trials of Toca 511 in recurrent high-grade glioma showed highly promising evidence of therapeutic benefit, leading to a Phase III trial completed in late 2019 (n=400 patients, randomized 1:1 vs. standard chemotherapy), which appeared to show negative results overall. However, additional analysis showed possible efficacy in prespecified subgroups, and further clinical investigation is being pursued. In preclinical studies, we have also evaluated RRV for use in medulloblastoma, the most common malignant tumor of the pediatric nervous system. Both established and primary human medulloblastoma cell lines supported efficient RRV replication in vitro, with spread to &amp;gt;90% of cells by day 10 post-inoculation, and RRV-CD-transduced medulloblastoma cells showed significant dose-dependent reduction of viability upon exposure to 5-FC, compared to controls. In an intracerebellar HDMB03 medulloblastoma model, RRV-CD-treated mice exhibited long-term survival while on sequential cycles of 5-FC prodrug, until prodrug treatment was stopped, after which 25% long-term survival was observed (median survival 110 days) as compared to controls (median survival 28 days, 100% lethality) (p=0.00007). These results support further evaluation of RRV-mediated prodrug activator gene therapy for pediatric brain tumors.

neuro-oncology

THER-06. THERAPEUTIC EFFICACY OF RRV-MEDIATED PRODRUG ACTIVATOR GENE THERAPY IN CLINICAL TRIALS OF RECURRENT HIGH-GRADE GLIOMA AND IN MURINE ORTHOTOPIC MODELS OF INTRACEREBRAL GLIOMA AND INTRACEREBELLAR MEDULLOBLASTOMA