Molecular analyses support the safety and activity of retroviral replicating vector Toca 511 in patients
DJ Hogan, JJ Zhu, OR Diago, D Gammon… - Clinical Cancer …, 2018 - AACR
Clinical Cancer Research, 2018•AACR
Purpose: Toca 511 is a gammaretroviral replicating vector encoding cytosine deaminase
that selectively infects tumor cells and converts the antifungal drug 5-fluorocytosine into the
antineoplastic drug 5-fluorouracil, which directly kills tumor cells and stimulates antitumor
immune responses. As part of clinical monitoring of phase I clinical trials in recurrent high-
grade glioma, we have performed extensive molecular analyses of patient specimens to
track vector fate. Patients and Methods: Toca 511 and Toca FC (extended-release 5 …
that selectively infects tumor cells and converts the antifungal drug 5-fluorocytosine into the
antineoplastic drug 5-fluorouracil, which directly kills tumor cells and stimulates antitumor
immune responses. As part of clinical monitoring of phase I clinical trials in recurrent high-
grade glioma, we have performed extensive molecular analyses of patient specimens to
track vector fate. Patients and Methods: Toca 511 and Toca FC (extended-release 5 …
Abstract
Purpose: Toca 511 is a gammaretroviral replicating vector encoding cytosine deaminase that selectively infects tumor cells and converts the antifungal drug 5-fluorocytosine into the antineoplastic drug 5-fluorouracil, which directly kills tumor cells and stimulates antitumor immune responses. As part of clinical monitoring of phase I clinical trials in recurrent high-grade glioma, we have performed extensive molecular analyses of patient specimens to track vector fate.
Patients and Methods: Toca 511 and Toca FC (extended-release 5-fluorocytosine) have been administered to 127 high-grade glioma patients across three phase I studies. We measured Toca 511 RNA and DNA levels in available body fluids and tumor samples from patients to assess tumor specificity. We mapped Toca 511 integration sites and sequenced integrated Toca 511 genomes from patient samples with detectable virus. We measured Toca 511 levels in a diverse set of tissue samples from one patient.
Results: Integrated Toca 511 is commonly detected in tumor samples and is only transiently detected in blood in a small fraction of patients. There was no believable evidence for clonal expansion of cells with integrated Toca 511 DNA, or preferential retrieval of integration sites near oncogenes. Toca 511 sequence profiles suggest most mutations are caused by APOBEC cytidine deaminases acting during reverse transcription. Tissue samples from a single whole-body autopsy affirm Toca 511 tumor selectivity.
Conclusions: Toca 511 and Toca FC treatment was not associated with inappropriate integration sites and clonal expansion. The vector is tumor-selective and persistent in patients who received Toca 511 injections. Clin Cancer Res; 24(19); 4680–93. ©2018 AACR.
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