Cancer-killing viruses and drugs that inhibit the immune checkpoints CTLA-4 and PD-1 are on the market to treat a variety of cancers, but they aren’t universally effective. A team of Japanese researchers led by Astellas Pharma’s drug discovery unit is proposing a combination strategy to boost the effectiveness of both types of therapies.
The researchers engineered a piece of the vaccinia virus, which is part of the poxvirus family, so it can deliver two cytokines that stimulate anti-cancer responses from immune cells: interleukin-7 (IL-7) and IL-12. When they injected the virus directly into tumors in mice, the cancers regressed, they reported in the journal Science Translational Medicine. Combining the virus with anti-PD-1 or anti-CTLA-4 antibodies was even more effective.
The researchers observed that when the virus carrying IL-7 and IL-12 was injected into tumors, the environment surrounding the cancer became inflammatory. Tumor growth was subsequently inhibited by 93% in melanoma and 53% in colon and lung cancers.
When the mice that were treated with the cancer-killing—or “oncolytic”—virus were challenged with new tumors three months later, they seemed to be protected. “Tumors in the cured mice were completely rejected within 4 weeks, whereas all age-matched tumor-naive control mice developed tumors,” the authors wrote.
Then the researchers combined the virus with anti-PD-1 or anti-CTLA-4 antibodies in mice with immunotherapy-resistant colon cancer. It worked.
The team concluded that promoting an inflammatory environment around tumors could be the key to making combinations of oncolytic viruses and checkpoint inhibitors work. “It has been reported that in clinical studies of immunotherapy, the extent of inflammation in the tumor microenvironment … and the establishment of antitumor memory correlates with prognosis and affects the overall survival and progression-free survival,” they wrote. “This, together with our findings, suggests that further investigation in clinical studies is warranted.”
The one oncolytic virus on the market, Amgen’s Imlygic, has not proven to be a huge hit as a solo therapy for melanoma, but it is being tested in several combination trials. The company recently presented data from a phase 2 trial showing that combining the virus with Yervoy, Bristol-Myers Squibb’s CTLA-4 inhibitor, provided durable and superior response rates over Yervoy alone in patients with advanced melanoma.
And there’s still plenty of Big Pharma interest in oncolytic viruses. In December, Takeda penned a $120 million deal to co-develop Turnstone Biologic’s oncolytic virus candidate, RIVAL-01, which is an engineered form of vaccinia that encodes an anti-CTLA-4 antibody, as well as IL-12 and a ligand called Flt3.
As for Astellas, it’s been dabbling in oncolytic virus development, too. Astellas Venture Management has funded Oncorus, which recently raised $79.5 million in a series B to move two oncolytic viruses through development.