Tocagen Inc (TOCA)

[gr8db8]

Targeting Myeloid Cells in Combination Treatments for Glioma and Other Tumors

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6664066/

Another creative chemotherapy with effects on the myeloid compartment utilizes the retroviral vector Toca 511. With this technique, Toca 511 selectively delivers a cytosine deaminase gene to cancer cells. Cytosine deaminase is then expressed by the infected cells, causing them to convert the pro-drug 5-fluorocytosine (5-FC), commonly delivered in the oral extended-release form of Toca FC, into the potent chemotherapeutic 5-fluorouracil (5-FU), which causes death of the tumor cells (173). Besides tumor cell death, 5-FU has also been shown by Vincent et al. to selectively kill MDSCs in tumor cells while preserving other immune populations and resulting in greater T cell IFN? production (126). Mitchell et al. then confirmed this effect in the context of Toca by pretreating tumor cells before flank implantation with Toca 511, followed by treatment with Toca FC (127). Intratumoral injection of Toca 511 in gliomas by Hiraoka et al. (128) and colorectal cancer by Yagiz et al. (129) also resulted in immunological benefit. The immunological effects were correlated with survival and long-term resistance to tumor rechallenge. Survival effects were preserved on combination therapy with both TMZ (130) and lomustine, another chemotherapeutic (131). Additionally, Takahashi et al. demonstrated a decrease in radioresistance caused by treatment of gliomas, although this was done in athymic mice, and thus the possible immunological contribution is unclear (132). The success of Toca supports the findings of Mathios et al. where localized chemotherapy was beneficial for cultivating an immune response (170). The exact mechanism of the synergistic anti-tumor effects of combining myeloid targeted therapies with chemotherapy is unclear. It has been postulated that chemotherapy, similar to radiation therapy, generates new antigenic targets and boosts antigenic uptake and presentation thereby priming the TME for adaptive anti-tumor immune responses. Combination with myeloid targeted therapies can further abrogate alternative immunosuppressive pathways to enhance anti-tumor effects of chemotherapy.