Filippo Veglia remembers the exact moment his team saw the tumors shrink—42 days in a mouse model where most animals had already died. Glioblastoma, the most aggressive brain cancer in adults, kills quickly and resists nearly every treatment thrown at it. Immunotherapy, which has revolutionized care for cancers like melanoma and lung cancer, works in only about 10% of glioblastoma patients. But now, Veglia and his team at The Wistar Institute have found a two-part strategy that could change that.
The problem lies inside the tumor’s environment. Glioblastomas are packed with myeloid cells—immune cells that should help fight disease but instead turn traitor, shutting down cancer-killing T cells. These tumors are also starved of oxygen, a condition called hypoxia, which flips a switch in myeloid cells, turning them into powerful suppressors of immunity. Even when T cells do reach the tumor, they become overworked and worn out, slipping into a state called exhaustion—too tired to attack.
Veglia’s team discovered that low oxygen levels were key to recruiting these rogue immune cells. So they tried a drug called axitinib, already approved for kidney cancer, to ease the hypoxia. It worked: oxygen levels improved, fewer myeloid cells turned suppressive, and more T cells entered the tumor. But survival only rose slightly—from 17 to 19 days on average. “By reducing hypoxia, we can impair the immunosuppressive activity of myeloid cells,” Veglia said. “But this is not enough.”
The breakthrough came when they added a second treatment: a 4-1BB agonist, an immunotherapy that boosts exhausted T cells still capable of fighting. These T cells carry a marker—4-1BB—that shows they’ve seen the cancer and are trying to respond. Activating that signal revived them. Together, axitinib and the 4-1BB agonist extended median survival to 42 days, with 40% of mice surviving long-term. When those survivors were exposed to tumor cells again, no new tumors grew—proof their immune systems had learned to recognize and destroy the cancer.
This dual approach—calming the tumor’s defenses while energizing its attackers—could be a blueprint not just for glioblastoma, but for other hypoxic, immunotherapy-resistant cancers. Veglia is now pushing to bring this combination into clinical trials for human patients. For a disease where progress has been painfully slow, this small number—40% long-term survival—feels like a door cracking open.