ABSTRACT
Introduction
The use of tumor-selectively replicating viruses is a rapidly expanding field that is showing considerable promise for cancer treatment. Retroviral replicating vectors (RRV) are unique among the various replication-competent viruses currently being investigated for potential clinical utility, because they permanently integrate into the cancer cell genome and are capable of long-term persistence within tumors. RRV can mediate efficient tumor-specific delivery of prodrug activator genes, and subsequent prodrug treatment leads to synchronized cell killing of infected cancer cells, as well as activation of antitumor immune responses.
Areas Covered
Here we review preclinical studies supporting bench-to-bedside translation of Toca 511, an optimized RRV for prodrug activator gene therapy, the results from Phase I through III clinical trials to date, and potential future directions for this therapy as well as other clinical candidate RRV.
Expert Opinion
Toca 511 has shown highly promising results in early-stage clinical trials. This vector progressed to a registrational Phase III trial, but the results announced in late 2019 appeared negative overall. However, the median prodrug dosing schedule was not optimal, and promising possible efficacy was observed in some prespecified subgroups. Further clinical investigation, as well as development of RRV with other transgene payloads, is merited.
Article highlights
• Retroviral replicating vectors (RRV), currently under clinical investigation for the treatment of recurrent high-grade glioma, permanently integrate into the cancer cell genome, and each infected cancer cell constitutively produces new virions that bud from the cell surface and spread to adjacent cancer cells.
• The initial rationale for the use of these vectors in cancer was their selectivity for dividing cells, as the majority of normal cells in vivo are quiescent, but it is now appreciated that additional mechanisms of tumor-selectivity include cancer cell-intrinsic defects in innate immunity, and tumor microenvironment-mediated suppression of adaptive immunity, which both act to restrict retroviral replication in normal cells and tissues.
• Preclinical studies demonstrated that RRV can mediate efficient and tumor-specific delivery of transgenes encoding prodrug activating enzymes in a variety of cancer models, and that subsequent prodrug treatment leads to synchronized cell killing of infected tumor cells, as well as activation of antitumor immune responses due to ‘bystander’ killing of adjacent immunosuppressive myeloid-derived cells residing within the tumor.
• Optimization of the viral backbone and therapeutic transgene resulted in an improved clinical candidate RRV, Toca 511, for delivery of an optimized yeast cytosine deaminase prodrug activator gene, which converts the prodrug 5-fluorocytosine (5-FC) to the active drug 5-fluorouracil (5-FU). This therapy has shown highly promising results in early-stage clinical trials for recurrent high-grade glioma.
• This vector progressed to a registrational Phase III trial, but the results announced in late 2019 found that the therapy failed to meet primary and secondary endpoints. However, the median 5-FC dosing schedule was not optimal, and promising signals were observed upon analysis of predetermined subgroups. These signals are to be validated in future clinical trials.
• Additional directions for further clinical and translational development include the application of Toca 511/Toca FC to systemic malignancies such as colorectal cancer and bladder cancer in situations where there is sufficient survival expectation to allow four courses of 5-FC prodrug and induction of anticancer immune responses (a minimum of 6-8 months), and development of RRV for tumor-selective delivery of immune checkpoint inhibitors.
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Declaration of interest
N Kasahara was previously a consultant for Tocagen Inc., and D Ostertag and DJ Jolly are former employees of Tocagen, Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Acknowledgments
We thank all the trial subjects for volunteering to participate in the Phase I and Phase II/III trials and the clinical investigators and their staff members who recruited them and carried out the trials.
Reviewer Disclosures
Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.