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Review
. 2021 Sep;21(9):1199-1214.
doi: 10.1080/14712598.2021.1902982. Epub 2021 May 6.

Clinical development of retroviral replicating vector Toca 511 for gene therapy of cancer

Sara A Collins  1 , Ashish H Shah  2 , Derek Ostertag  3 , Noriyuki Kasahara  1   4 , Douglas J Jolly  3
Affiliations
Review

Clinical development of retroviral replicating vector Toca 511 for gene therapy of cancer

Sara A Collins et al. Expert Opin Biol Ther. 2021 Sep.

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.

Keywords: Retroviral vector; cancer; gene therapy; immunotherapy.

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Figures

Figure 1.
Figure 1.
Toca 511 design and mechanism of action: A. Toca 511 is a Retroviral Replicating Vector (RRV) based on an amphotropic mouse gamma-retrovirus which also encodes an optimized yeast cytosine deaminase (CD) and preferentially infects tumors (LTR: long terminal repeat sequences, gag/pol/env: retroviral structural genes, IRES-CD: transgene expression cassette consisting of internal ribosome entry site linked to CD gene). B. Upon 5-FC administration, optimized CD metabolizes the antifungal prodrug Toca FC (a proprietary formulation of 5-FC) to the active anticancer drug 5-FU directly within infected cancer cells. C. Illustration of mechanism of action of Toca 511 & Toca FC causing antitumor immune activation via the tumor microenvironment: (1) Gamma-retrovirus Toca 511 selectively infects tumor, persists, and further spreads through tumor while delivering the CD gene; (2) Toca FC prodrug locally converts to 5-FU chemotherapeutic drug within the tumor, killing cancer cells and resulting in activation of antigen-presenting cells and T cell priming; (3) “Bystander effect” of locally generated intratumoral 5-FU also eliminates adjacent immunosuppressive myeloid cells (myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs)), thereby activating antitumor immunity.
Figure 2.
Figure 2.
“Swim lane” representation of data from the Phase 1 resection study in recurrent High Grade Glioma patients, higher dose cohorts (“Phase 3 eligible”): Toca 511 & Toca FC leads to 26% long-term survival and 22% durable complete response (CR) rate. All responses are durable CRs and associated with long-term survival (see ).
Figure 3.
Figure 3.
“TOCA 5” Phase 2/3 clinical trial of Toca 511 / Toca FC for recurrent High Grade Glioma (HGG). A. Study design of TOCA 5 trial. This was the largest randomized study conducted in the setting of recurrent HGG. GBM: glioblastoma multiforme, AA: anaplastic astrocytoma, IDH1: isocitrate dehydrogenase-1, KPS: Karnofsky Performance Score, SOC: standard of care. B. Kaplan-Meier plot of overall survival by time from last Temozolomide treatment to randomization (ITT population). C. Kaplan-Meier plot of overall survival by number of Toca FC cycles in the Phase 2/3 trial (Intention-to-Treat (ITT) population).
Figure 4.
Figure 4.
Overall survival in patient subgroup with two or more recurrences (Intention-to-Treat population). Left panel: Kaplan-Meier plot of overall survival in the Second Recurrence Subgroup; Toca 511 & Toca FC showed 57% reduction in risk of death (~2X median survival over standard-of-care (SOC)). HR: hazard ratio, OS: overall survival. Right panel: Key parameters of the Toca 511 / Toca FC treatment vs. SOC groups, showing good comparability. KPS: Karnofsky Performance Score, IDH: isocitrate dehydrogenase.
Figure 5.
Figure 5.
Overall survival by tumor histology in patient subgroup with two or more recurrences (Intention-to-Treat population). Left panel: Kaplan-Meier plot of overall survival in Second Recurrence Subgroup patients with glioblastoma multiforme (GBM). Right panel: Kaplan-Meier plot of overall survival in Second Recurrence Subgroup patients with anaplastic astrocytoma (AA). HR: hazard ratio, OS: overall survival.
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