Molecular and Immunologic Signatures are Related to Clinical Benefit from Treatment with Vocimagene Amiretrorepvec (Toca 511) and 5-Fluorocytosine (Toca FC) in Patients with Glioma.

Autor:	Accomando WP; Tocagen Inc., San Diego, California., Rao AR; Tocagen Inc., San Diego, California., Hogan DJ; Tocagen Inc., San Diego, California., Newman AM; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California.; Department of Biomedical Data Science, Stanford University, Stanford, California., Nakao A; CiberMed Inc., Palo Alto, California., Alizadeh AA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California.; Stanford Cancer Institute, Stanford University, Stanford, California.; Division of Oncology, Department of Medicine, Stanford University, Stanford, California.; Division of Hematology, Department of Medicine, Stanford University, Stanford, California., Diehn M; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California.; Stanford Cancer Institute, Stanford University, Stanford, California.; Department of Radiation Oncology, Stanford University, Stanford, California., Diago OR; Tocagen Inc., San Diego, California., Gammon D; Tocagen Inc., San Diego, California., Haghighi A; Tocagen Inc., San Diego, California., Gruber HE; Tocagen Inc., San Diego, California., Jolly DJ; Tocagen Inc., San Diego, California., Ostertag D; Tocagen Inc., San Diego, California. dereko879@abintusbio.com.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2020 Dec 01; Vol. 26 (23), pp. 6176-6186. Date of Electronic Publication: 2020 Aug 18.
DOI:	10.1158/1078-0432.CCR-20-0536
Abstrakt:	Purpose: High-grade gliomas (HGGs) 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 anticancer 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 antitumor immune activity. Therefore, we sought to elucidate this immune-related mechanism of action in humans, and to investigate potential molecular and immunologic indicators of clinical benefit from therapy. Patients and Methods: In a phase I clinical trial (NCT01470794), patients with recurrent HGG treated with Toca 511 and Toca FC showed improved survival relative to historical controls, and some had durable complete responses to therapy. As a part of this trial, we performed whole-exome DNA sequencing, RNA-sequencing, and multiplex digital ELISA measurements on tumor and blood samples. Results: 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. Conclusions: These results support an immune-related mechanism of action for Toca 511 and Toca FC, and suggest that molecular and immunologic signatures are related to clinical benefit from treatment. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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