A longstanding challenge for the development of oncolytic virotherapies has been immune attack on the viruses themselves. Adaptive or acquired immunity to oncolytic viruses has limited the promise of systemic administration of viruses because immune cells encounter them in the bloodstream before they reach and enter tumor cells, giving the immune system a chance to recognize and attack them. Until recently, that was assumed to limit the utility of multi-dosing virotherapy regimens.
“The thought has always been that multi-dosing viruses would not be possible due to antiviral immune responses and neutralizing antibodies that would prevent entry of the virus into cancer cells,” Dr Zamarin said. “That’s particularly important when the virus is delivered intravenously.”
Acquired immunity can be circumvented to some degree by injecting viruses directly into solid tumors. But recent research suggests that longstanding concerns about adaptive immunity were based partly on an incomplete understanding of how oncolytic viruses work.
“Until fairly recently, these viruses’ mechanism of action was thought to be tumor debulking effect — virus replication in infected cancer cells continues until no more cancer cells are left,” Dr Zamarin explained. “We see that in the petri dish when we infect cancer cells with a virus. Conceptually, it makes sense. But on an organismal level, it has never been shown to completely eliminate tumor cells in an immunocompetent host.”
Preclinical research with intratumoral injections of NDV and clinical research with intratumoral talimogene laherparepvec (T-VEC, an oncolytic herpesvirus) puzzlingly suggested that repetitive dosing might sometimes be associated with stronger antitumor responses.7,8
“The virus was dosed for many months and some responses came not right away but later on,” noted Dr Zamarin. “Not an immediate response but a delayed one. If the mechanism of action was only direct tumor lysis, responses would have been immediate, so this was indicative of immune activation.”
“That raised a question: how much virus replication and cell entry is really required to achieve antitumor efficacy,” he said. “Is some minimal viral entry into cancer cells enough to activate the antitumor immune response? Can the immune system then take over and drive antitumor immunity?”
Using mice, Dr Zamarin and colleagues sought to assess how prior exposure and resulting acquired antiviral immunity to NDV modulates immune attacks on tumor cells.7
“Surprisingly, rather than diminishing antitumor activity, we saw an enhanced response,” Dr Zamarin said.