Coxsackievirus A21 Synergizes with Checkpoint Inhibitors

A proprietary formulation of an oncolytic common-cold virus is producing high clinical response rates—with little added toxicity—when given in combination with immune checkpoint inhibitors to treat advanced melanoma, according to preliminary results from phase Ib trials presented April 3 and 4 at the American Association for Cancer Research (AACR) Annual Meeting 2017 in Washington, DC.

“We're really seeing that there's synergy going on,” said Dmitriy Zamarin, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, NY, who was not involved in the trials. “The true efficacy of this agent is probably going to lie in its combination.”

Coxsackievirus A21 (CVA21, or Cavatak; Viralytics) is an experimental virotherapy that infects and enters cells through a surface protein called ICAM1 that's overexpressed on many types of cancer cells. The replicating virus eventually ruptures cancer cells, releasing tumor antigens that induce anticancer immune activity.

In one clinical study, patients received injections of CVA21 directly into their melanoma lesions as well as infusions of the anti–CTLA-4 drug ipilimumab (Yervoy; Bristol-Myers Squibb). Among the first 22 participants, four experienced complete responses and seven had partial responses for an objective response rate (ORR) of 50%, with no serious adverse events related to the virus.

“The combination of CVA21 and ipilimumab is generally well-tolerated, and we've seen, I would say, remarkable tumor activity in the patients we've treated thus far,” said Brendan Curti, MD, from the Providence Cancer Center in Portland, OR, who led the trial.

Notably, four of the responders had had prior treatment with ipilimumab or another checkpoint inhibitor. That's a “very exciting observation,” remarked Louis Weiner, MD, from the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC, who was not involved in the study. It shows that “one can prime the immune response potentially with this kind of approach and basically make a tumor cell population that has been resistant to therapy become sensitive again to a checkpoint antibody.”

In another trial, Howard Kaufman, MD, from the Rutgers Cancer Institute of New Jersey in New Brunswick, and his colleagues administered the PD-1 inhibitor pembrolizumab (Keytruda; Merck), instead of ipilimumab, in addition to intratumoral injections of CVA21. Eight of the first 11 participants in that trial achieved complete or partial remission—and, according to Kaufman, “the numbers seem to be holding up” among the other 10 study subjects now enrolled.

“It's a very impressive response rate with this combination,” Kaufman said. “We are seeing at least additive therapeutic benefits when you combine the virus with the checkpoint inhibitors, but we're not seeing additive toxicity.” In earlier testing, CVA21 alone yielded an ORR of 28%, while single-agent ipilimumab and pembrolizumab demonstrated ORRs of around 33% and 11%, respectively.

A third trial also involved pembrolizumab, but in that study CVA21 was delivered intravenously to patients with melanoma, lung cancer, or bladder cancer. The combination was well tolerated, Hardev Pandha, MD, PhD, from the Royal Surrey Hospital in Guildford, UK, reported at the AACR meeting, but it's too early to say how well the dual therapy is working with this approach.

Currently, the only FDA-approved oncolytic viral therapy is talimogene laherparepvec, or T-VEC (Imlygic; Amgen). On a population level, this engineered herpes virus has shown comparable ORRs to CVA21 in clinical trials—26% as a monotherapy, at least 36% when combined with ipilimumab, and at least 48% in tandem with pembrolizumab.

For any individual patient, however, Kaufman anticipates there will be measurable differences in tumor antiviral defenses that might make them respond better to T-VEC or CVA21. “We have hit on a potential biomarker,” Kaufman said, “and we're just trying to confirm it now.” –Elie Dolgin