Preexisting immunity to NDV did limit viral replication within tumors, his team found. But tumor clearance and antitumor immune attacks were not diminished.
Nor were antitumor immune effects limited to the injected tumor. Animals’ immune systems also attacked distant, untreated tumors — so-called abscopal effects.7
Local effects are mediated by inflammation, Dr Zamarin said.
“In the immediate vicinity of infected cells, cells can die via bystander effects, meaning a lot of local inflammation that nonspecifically kills proximate cancer cells,” he explained. “An inflammatory effect modifies the tumor microenvironment. Tumors that are resistant to antitumor immune response are modified and rendered vulnerable. You have recognition of the tumor and viral epitopes.”
Even after viral infection is resolved, and viral antigens no longer appear on tumor cell surfaces, immune cells have learned to recognize persisting tumor antigens that were frequently encountered with viral ones — a phenomenon known as epitope spreading.
Systemically, epitope spreading also contributes to abscopal effects, Dr Zamarin believes.
Because oncolytic viruses have different antitumor mechanisms of action, they should slow the evolution of tumor resistance.
“More interestingly, can we use oncolytic viruses to overcome resistance to immune checkpoint inhibition? This will be a very interesting area of evaluation in patients who don’t respond or progress on immune checkpoint inhibition ― which is unfortunately the case for the majority of patients and the majority of cancer types,” Dr Zamarin noted.
“Viruses can get around tumors’ resistance mechanisms,” he explained. “The hope is that viruses can actually be used as a strategy to overcome resistance—or to even prevent resistance from happening in the first place.”
Authors of a recent study of intratumoral injection of prostate tumors and bone metastases in mice with an engineered version of the oncolytic rhabdovirus VSV-GP reported long-term remissions.14
“One criticism of intratumoral therapy is the logistical challenge of delivery,” Dr Zamarin acknowledged. “Most of the data so far is for readily accessible tumors or enlarged lymph nodes that can be injected with bedside ultrasound.”
Research is under way for other mechanisms of delivery, however, such as intraperitoneal or pleural infusion via catheter. Viruses might also be infused directly into the liver via the hepatic artery, under interventional radiology (IR) guidance.
“If a tumor can be biopsied, it can be injected with IR guidance,” he said.
“Obviously, there is a limitation to how many times it can be done,” he acknowledged. But if viral potentiation of antitumor immune effects can be achieved with only two or three doses, that might be a viable approach, he argued.
“With modern radiology and endoscopy techniques, I think it will become more and more possible to deliver these viruses directly to tumor sites,” Dr Zamarin concluded.
- Lichty BD, Breitbach CJ, Stojdl DF, Bell JC. Going viral with cancer immunotherapy. Nat Rev Cancer. 2014;14:559-567. doi: 10.1038/nrc3770
- Lee P, Gujar S. Potentiating prostate cancer immunotherapy with oncolytic viruses. Nat Rev Urol. 2018;15:235-250. doi: 10.1038/nruol.2018.10
- Chaurasiya S, Chen NG, Fong Y. Oncolytic viruses and immunity. Curr Opin Immunol. 2018;51:83-90. doi: 10.1016/j.coi.2018.03.008
- Achard C, Surendran A, Wedge ME, et al. Lighting a fire in the tumor microenvironment using oncolytic immunotherapy [published April 20, 2018]. EBioMed. doi: 10.1016/j.ebiom.2018.04.020
- Hou W, Sampath P, Rojas JJ, Thorne SH. Oncolytic virus-mediated targeting of PGE2 in the tumor alters the immune status and sensitizes established and resistant tumors to immunotherapy. Cancer Cell. 2016;30:108-119. doi: 10.1016/j.ccell.2016.05.012
- Russell SJ, Baber GN. Oncolytic viruses as antigen-agnostic cancer vaccines. Cancer Cell. 2018;33(4):599-605.
- Ricca JM, Oseledchyk A, Walther T, et al. Pre-existing immunity to oncolytic virus potentiates its immunotherapeutic efficacy. Molec Ther. 2018;26(4):1008-1019. doi: 10.1016/j.ymthe.2018.01.019
- Ribas A, Dummer R, Puzanov I, et al. Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy. Cell. 2017;170:1109-1119. doi: 10.1016/j.cell.2017.08.027
- Robert C. Checkpoint blockade plus oncolytic virus: a hot therapeutic cancer strategy. Trends Molec Med. 2017;23(11):983-984. doi: 10.1016/j.molemed.2017.09.008
- Scherwitzl I, Hurtado A, Pierce CM, Vogt S, Pampeno C, Meruelo D. Systematically administered Sindbis virus in combination with immune checkpoint blockade induces curative anti-tumor immunity in solid tumors [published April 28, 2018]. Molec Ther Oncolytics. doi: 10.1016/j.omto.2018.04.004
- Zamarin D, Holmgaard RB, Subudhi SK, et al. Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy. Sci Transl Med. 2014;6(226):226ra32.
- Zamarin D, Holmgaard RB, Ricca J, et al. Intratumoral modulation of the inducible co-stimulator ICOS by recombinant oncolytic virus promotes systemic anti-tumor immunity. Nat Comm. 2017;8:14340.
- Zamarin D, Ricca JM, Sadekova S, et al. PD-L1 in tumor microenvironment mediates resistance to oncolytic immunotherapy. J Clin Invest. 2018;128(4):1413-1428.
- Urbiola C, Santer FR, Petersson M, et al. Oncolytic activity of the rhabdovirus VSV-GP against prostate cancer [published April 26, 2018]. doi: 10.1002/ijc.31556