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Vocimagene amiretrorepvec/flucytosine

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Toca 511 and Toca FC, developed by Tocagen, is a combination treatment currently being investigated in a phase 2/3 trial for patients with recurrent high grade glioma (HGG) including anaplastic astrocytoma (WHO grade III) and glioblastoma (WHO grade IV)1. Toca 511 (vocimagene amiretrorepvec) is an investigational, conditionally lytic, retroviral replicating vector (RRV) that encodes the transgene cytosine deaminase (CD). RRVs preferentially infect cancer cells not only because of the immune suppressed tumor microenvironment, but also because of the specificity of the RRV for infection of replicating cells. Thus CD is expressed almost exclusively in tumors. The CD enzyme catalyzes the conversion of Toca FC, an investigational orally administered, extended-release formulation of the prodrug 5-fluorocytosine (5-FC), into an antineoplastic drug 5-fluorouracil (5-FU) within infected cancer cells. This results in direct cancer cell killing, destruction of the immune-suppressive microenvironment, and activation of the immune system against the cancer. The FDA has granted Toca 511 & Toca FC Breakthrough Therapy Designation and Fast Track designation for the treatment of patients with recurrent HGG, and Orphan-Drug designation for the treatment of glioblastoma (GBM).

Proposed Mechanism of Action

Retroviruses are RNA viruses with two positive (directly encode viral proteins) single-strand genomes. They are enveloped viruses (i.e. have a non-rigid lipid outer membrane surface) with embedded ligands for binding to cell surface target molecules. The cell and viral membranes fuse, releasing the virus inner core particle which packages the RNA genomes, the reverse transcriptase and integrase enzymes. Once inside the target cell, the reverse transcriptase copies the RNA into DNA and then to double stranded DNA, the complex moves to the nucleus and the DNA is inserted into the host genome by the viral integrase. Toca 511 is a RRV derived from a mouse gammaretrovirus and has an amphotropic envelope, meaning that it can infect both mouse cells and cells of other species, including human cells. RRVs selectively infect and integrate into the DNA of cancer cells, which then serve as factories to produce more RRVs by budding. These progeny RRVs infect neighboring cancer cells, providing long-term presence of the encoded therapeutic gene or genes. Toca 511 infects human cells with selectivity for cancer cells in vivo, because genome integration is dependent on cell division and viral replication is inhibited by innate and adaptive immune responses, defective in malignant tissues. Toca 511 spreads through cancer cells and stably delivers the transgene CD. The CD enzyme therefore converts courses of the oral prodrug Toca FC into high concentrations of 5-FU only in the infected tumor cell microenvironment, thus avoiding toxic side-effects. In addition to the direct killing of Toca 511-infected cancer cells, 5-FU can kill neighboring uninfected cancer cells and immune-suppressive myeloid cells, including myeloid-derived suppressor cells (MDSCs), as well as tumor associated macrophages (TAMs). Cancer cell death releases previously immune-invisible cancer antigens, and causes release of inflammatory damage-associated molecular signals, resulting in antigen presentation and activation of CD4 (helper) and CD8 (killer) T cells. This activation results in acquired anti-tumor immunity, with further induction and harnessing of the T cells against the tumor, and provides durable control of the cancer. This approach is designed to selectively destroy cancer cells and the surrounding immune suppressed tumor microenvironment, while leaving healthy cells unharmed. This proposed dual mechanism of action is supported by emerging clinical and preclinical data2-5.

https://www.youtube.com/watch?v=9HmQj74Z5Xk

This short video explains the proposed mechanism of action for Toca 511 & Toca FC.

Toca 511 Design

The design of the Toca 511 RRV is based upon the vector design by Logg et al6 with improvements to the backbone of the virus to optimize the genetic stability of the RRV and the CD activity produced by the delivered transgene7. Some of the key modifications include: i) the original envelope gene has been replaced with an amphotropic envelope gene, enabling the vector to infect human cells; (ii) small repeats on either side of the internal ribosome entity site (IRES)-CD cassette were eliminated to attempt to minimize instability because of homologous recombination; (iii) a unique restriction enzyme site Psi I was introduced at the 3’ end of the IRES for convenient insertion of transgene(s) and; (iv) the yeast CD gene was optimized by modifying the codon sequence at three amino acids and optimizing the codon usage of known preferred human codons, resulting in increased CD enzyme stability at 37 °C, enzyme production and genome stability during RRV replication. The combination of these changes led to the product candidate that is currently in clinical development1, 8-10.

Clinical trials

Toca 511 and Toca FC combination therapy is being investigated for patients with recurrent high grade glioma1, 8-10 and metastatic cancers11. The treatment involves two steps: administration of Toca 511 by injection followed by cycles of Toca FC.

Results from the three Phase I studies in recurrent glioma include good tolerability; no persistent viremia; successful gene transduction within resected tumors; no evidence for clonality by vector insertion site analysis; and increased median overall survival compared to historical controls8-10. Enrollment in the Phase 2 portion of an ongoing randomized, international Phase 2/3 clinical trial for patients with recurrent high grade glioma has been completed1.

Preclinical investigations

In studies of mice models with implanted orthotropic gliomas or liver colorectal metastases, intracranial or intravenous administration of Toca 511 for the glioma model or intravenous administration of Toca 511 for the colorectal metastasis model with subsequent 5-FC treatment resulted in prolonged survival compared to the control group11-13. Furthermore, complementary findings were reported demonstrating that antitumor immune effects are T-cell dependent and correlate with depletion of immune-suppressive myeloid cells3, 4. The demonstrations that intravenous administration of Toca 511 and subsequent 5-FC also resulted in prolonged survival in a mouse model supported the feasibility of this less invasive way to deliver the virus9, 10, 12, 13. In another mouse glioma model study, Toca 511 and 5-FC treatment was demonstrated to act as a radiosensitization agent through local production of 5-FU, potentiating the anti-tumor effects of radiation in a mouse model of malignant glioma14. In addition, additive effect was observed in mice bearing a temozolomide-sensitive glioma after Toca 511 administration followed by co-administration of temozolomide and 5-FC, providing a further rationale for the investigation of this novel combination treatment strategy in patients with newly diagnosed malignant glioma in conjunction with the clinical standard of care15.

References

1. Tocagen Inc. P2/3 Randomized Study of Toca 511 & Toca FC Versus SOC in Subjects Undergoing Surgery for Recurrent GBM/AA (Toca5). Available from: https://clinicaltrials.gov/ct2/show/NCT02414165 NLM Identifier: NCT02414165.

2. Cloughesy, T.F. et al., Phase 1 trial of vocimagene amiretrorepvec and 5-fluorocytosine for recurrent high-grade glioma. Sci Transl Med. 2016, 8(341)

3. Mitchell, L. et al., Toca 511 gene transfer and treatment with the prodrug, 5-fluorocytosine, promotes durable antitumor immunity in a mouse glioma model. Neuro-Oncology, 2017 Apr 6. doi: 10.1093/neuonc/nox037. [Epub ahead of print].

4. Hiraoka, K. et al., Retroviral replicating vector-mediated gene therapy achieves long-term control of tumor recurrence and leads to anti-cancer immunity, Neuro-Oncology, 2017 Apr 6. doi: 10.1093/neuonc/nox038. [Epub ahead of print].

5. Ostertag, D. et al., Brain tumor eradication and prolonged survival from intratumoral conversion of 5-fluorocytosine to 5-flurouracil using a nonlytic retroviral replicating vector. Neuro-Oncology 2012, 14(2), 145-159.

6. Logg, C.R. et al., Retroviral Replicating Vectors in Cancer. Methods in Enzymology 2012, 507, 199-228.

7. Perez, O.D. et al., Design and Selection of Toca 511 for Clinical Use: Modified Retroviral Replicating Vector With Improved Stability and Gene Expression. Molecular Therapy 2012, 20(9), 1689-1698.

8. Tocagen Inc. A Phase 1 Ascending Dose Trial of the Safety and Tolerability of Toca 511 in Patients With Recurrent High Grade Glioma. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2014 June 12]. Available from: http://clinicaltrials.gov/show/NCT01156584 NLM Identifier: NCT01156584.

9. Tocagen Inc. A P1 Ascending Dose Trial of Safety and Tolerability of Toca 511, a Retroviral Replicating Vector, Administered to Subjects at the Time of Resection for Recurrent High Grade Glioma & Followed by Treatment With Toca FC, Extended-Release 5-FC. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2014 June 12]. Available from: http://clinicaltrials.gov/show/NCT01470794 NLM Identifier: NCT01470794.

10. Tocagen Inc. A P1 Ascending Dose Trial of the Safety and Tolerability of Toca 511, a Retroviral Replicating Vector, Administered Intravenously Prior to, and Intracranially at the Time of, Subsequent Resection for Recurrent HGG & Followed by Treatment With Extended-Release 5-FC. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2014 June 12]. Available from: http://clinicaltrials.gov/show/NCT01985256 NLM Identifier: NCT01985256.

11. Tocagen Inc. A Phase 1b Study of Toca 511, a Retroviral Replicating Vector, Combined With Toca FC in Subjects With Solid Tumors. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2017 March 13]. Available from: https://clinicaltrials.gov/ct2/show/NCT02576665 NLM Identifier: NCT02576665.

12. Huang, T.T. et al. Intravenous administration of retroviral replicating vector, Toca 511, demonstrates therapeutic efficacy in orthotopic immune-competent mouse glioma model. Human gene therapy 2015, 26, 82-93.

13. Yagiz K. et al. Treatment of liver and brain metastases with a retroviral replicating vector encoding cytosine deaminase followed by 5-fluorocytosine, induces anti-tumor immune responses, depletes local myeloid derived suppressor cells and prolongs survival in murine models of metastatic colon cancer. Submitted

14. Takahashi, M. et al. Radiosensitization of gliomas by intracellular generation of 5-fluorouracil potentiates prodrug activator gene therapy with a retroviral replicating vector. Cancer gene therapy 2014, 21, 405-410.

15. Huang, T.T. et al. Toca 511 gene transfer and 5-fluorocytosine in combination with temozolomide demonstrates synergistic therapeutic efficacy in a temozolomide-sensitive glioblastoma model. Cancer gene therapy 2013, 20, 544-551.


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