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Molecular and immunological signatures are related to clinical benefit from treatment with Vocimagene amiretrorepvec (Toca 511) and 5-fluorocytosine (Toca FC) in patients with glioma.
Molecular and immunological signatures are related to clinical benefit from treatment with Vocimagene amiretrorepvec (Toca 511) and 5-fluorocytosine (Toca FC) in patients with glioma. Clinical cancer research : an official journal of the American Association for Cancer Research Accomando, W. P., Rao, A. R., Hogan, D. J., Newman, A. M., Nakao, A. n., Alizadeh, A. A., Diehn, M. n., Diago, O. R., Gammon, D. K., Haghighi, A. n., Gruber, H. E., Jolly, D. J., Ostertag, D. n. 2020Abstract
High grade gliomas are central nervous system tumors with poor prognoses and limited treatment options. Vocimagene amiretrorepvec (Toca 511) is a retroviral replicating vector encoding cytosine deaminase, which converts extended-release 5-fluorocytosine (Toca FC) into the anti-cancer agent 5-fluorouracil. According to preclinical studies, this therapy kills cancer cells and immunosuppressive myeloid cells in the tumor microenvironment, leading to T-cell mediated anti-tumor immune activity. Therefore, we sought to elucidate this immune-related mechanism of action in humans, and to investigate potential molecular and immunological indicators of clinical benefit from therapy.In a Phase I clinical trial (NCT01470794), recurrent high grade glioma patients treated with Toca 511 and Toca FC showed improved survival relative to historical controls, and some had durable complete responses to therapy. As part of this trial, we performed whole exome DNA sequencing, RNA sequencing and multiplex digital ELISA measurements on tumor and blood samples.Genetic analyses suggest mutations, copy number variations and neoantigens are linked to survival. Quantities of tumor immune infiltrates estimated by transcript abundance may potentially predict clinical outcomes. Peak values of cytokines in peripheral blood samples collected during and after therapy could indicate response.These results support an immune-related mechanism of action for Toca 511 and Toca FC, and suggest that molecular and immunological signatures are related to clinical benefit from treatment.
View details for DOI 10.1158/1078-0432.CCR-20-0536
View details for PubMedID 32816892