Viruses come to help T cells in fighting tumors

by Dr. Saman Maleki

Oncolytic viruses are emerging as promising therapeutic agents in the fight against cancer.

Last year, the U.S. FDA approved Talimogene laherparepvec (T-Vec)–a genetically modified Herpes Simplex Virus Type 1 replicating in tumor cells and producing GM-CSF–for the local of treatment of patients with unresectable metastatic melanoma^1. Tumor cells often have a defective intrinsic antiviral response because of their immune evasive and neoplastic characteristics, which makes them ideal hosts for viral infections^2. Furthermore, viruses preferential targeted replication in cancer cells has shown acceptable safety profile in clinical trials^2.

Perhaps the most important feature of an oncolytic viral infection of a tumor is its capacity to activate a robust antitumor immune response, which plays a vital role in the efficacy of these viruses in the clinic^3. Interestingly, this important aspect of oncolytic virus therapies was initially overlooked and the robust antitumor effect was mostly attributed to the capacity of the viruses to replicate and lyse tumor cells.

Today, however, these viruses are mostly regarded as agents that can enhance antitumor immunity and can perhaps be used in combination with other immunotherapeutics in the clinic.

This is what a phase Ib study (n=21 patients) published recently in Cell demonstrated^4. Ribas and his colleagues showed that the combination of T-Vec and pembrolizumab – an anti-programmed cell death 1 checkpoint inhibitor – was safe and well-tolerated in metastatic melanoma patients^4. Notably, patients showed 62% objective response rate with a complete response rate of 32%.

Mechanistically, intratumoral injection of T-Vec increased the number of tumor-infiltrating CD8+ T cell and IFN-g signature of those tumors. This is important since previously patients with low tumor-infiltrating CD8+ T cells responded poorly to anti-PD-1 therapy^5.

Perhaps the most exciting finding in this study was the capacity of tumor-reactive T cells to destroy non-injected distal lesions. This study shows that combination of oncolytic viral therapy with checkpoint inhibitors can increase patient response without added toxicities. There is an ongoing phase III study (ClinicalTrials.gov: NCT02263508) that is comparing the combination of systemic pembrolizumab to T-Vec or placebo.

There are currently many other oncolytic viruses being developed for the treatment of various types of cancers for single agent monotherapy or combination with other drugs (NCT02285816, NCT03004183, NCT03206073, NCT02977156).

References:

1. Rehman H, Silk AW, Kane MP, Kaufman HL. Into the clinic: Talimogene laherparepvec (T-VEC), a first-in-class intratumoral oncolytic viral therapy. J Immunother Cancer. 2016;4:53.
2. Pikor LA, Bell JC, Diallo JS. Oncolytic Viruses: Exploiting Cancer's Deal with the Devil. Trends Cancer. 2015;1(4):266-277.
3. Lawler SE, Speranza MC, Cho CF, Chiocca EA. Oncolytic Viruses in Cancer Treatment: A Review. JAMA Oncol. 2017;3(6):841-849.
4. Ribas A, Dummer R, Puzanov I, et al. Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy. Cell. 2017;170(6):1109-1119 e1110.
5. Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515(7528):568-571.