Date Published: March 16, 2017
Publisher: Public Library of Science
Author(s): Roberto Cattaneo, Stephen J. Russell, Richard C. Condit.
Viruses have shaped human history through devastating infections. In addition, virus infection may be responsible for up to 15% of cancer deaths . Nevertheless, certain viruses can be our “friends.” At the end of the 18th century, Edward Jenner used cowpox to protect humans against infection with a lethal pathogen, smallpox. Based on the effectiveness of this “vaccination” process, in the 1960s, the World Health Organization mounted a global vaccination campaign that resulted in the eradication of smallpox .
Shortly after the discovery of animal viruses, observing physicians reported cancer regressions coincident with natural infections, most notably in patients with lymphomas and leukemias who were suffering from viral hepatitis, glandular fever, chickenpox, or measles. Intentional transmission of virus infections was then pursued in a range of cancer types using several different virus isolates (most notably West Nile, mumps, and adenovirus) and led to definite tumor regressions but sometimes also to fatal encephalitis, as with West Nile virus in immunosuppressed lymphoma patients . When tissue culture systems for animal cells were established, it became clear that many viruses grow much better in cancer cell lines than in primary cells. In retrospect, the multistep process of tumor pathogenesis  accounts for preferential virus spread by weakening multiple cellular responses to viral infections.
Reasons for success or failure of early clinical trials with oncolytic viruses were difficult to assess because viral replication could not be easily monitored in humans. Many second-generation oncolytic viruses express reporter proteins that allow noninvasive monitoring of viral infection. For example, one oncolytic MeV (MV-CEA) expresses the soluble carcinoembryonic antigen (CEA) that is secreted in the blood stream, providing for noninvasive monitoring of the total amount of viral replication in the body. Another virus (MV-NIS) expresses the human thyroidal natrium iodine symporter (NIS), the physiological function of which is to transport iodide ions into cells. When NIS is expressed from the genome of an oncolytic virus, infected cells concentrate iodide or similar isotopes. Thus, NIS expression, which has been exploited for decades in clinical practice for thyroid imaging and ablation, can provide anatomical information about the location of virus-infected cells. Production of clinical grade MV-CEA and MV-NIS stocks was nontrivial because cancer trials operate with the equivalent of up to 108 vaccine doses (1011 infectious units) per individual (Table 1) .
Efficacy of oncolysis can be enhanced by pharmacological down-modulation of preexisting and induced antiviral immune responses, as demonstrated preclinically . Nevertheless, more incisive solutions to overcome the neutralization barrier are sought. These include virus delivery through carrier cells and replacement or resurfacing of viral capsids or envelopes so that preexisting neutralizing antibodies are not effective.
With some exceptions, cancer therapies based on replicating viruses have been tolerated well after both local and systemic administration . No virus transmission from treated patients to medical personnel or other contacts has been reported, although viral RNA sequences (but not infectious virus) have been detected in saliva and urine, especially after high-dosage systemic administration.
While producing and validating new recombinant viruses for clinical use is complex and slow, the combination of already approved oncolytic viruses with anticancer drugs is easier to implement. Immune checkpoint inhibitors are a particularly attractive new class of anticancer drugs. They were developed based on the observation that the immune system recognizes and is poised to eliminate cancer cells as well as virus-infected cells but is held in check by inhibitory receptors and their ligands . Drugs interrupting these immune checkpoints can elicit antitumor immunity and mediate durable cancer regression. Can these checkpoint inhibitors be combined with replication-competent viruses to enhance their efficacy while limiting tissue damage of antiviral immune responses?