For twenty years, a class of cancer drugs called CD40 agonist antibodies has promised a lot and delivered little. In animal models they switched on the immune system and helped it kill tumor cells. In people, the benefit was limited, and the side effects were serious: body-wide inflammation, low platelet counts, liver toxicity. Even low doses caused trouble.
A phase 1 trial published in Cancer Cell now offers the first encouraging human data for a reworked version, a drug known as 2141-V11. The numbers are small, and they deserve to be read that way. Twelve patients took part. Tumors shrank in six of them, and in two the cancer disappeared completely.
What changed after 2018
In 2018, the lab of Jeffrey V. Ravetch at Rockefeller University showed it could engineer a stronger CD40 antibody. It binds tightly to human CD40 receptors and is modified to engage a specific Fc receptor, which boosts crosslinking. The team found it was ten times more powerful at driving an antitumor immune response. That work was done in mice genetically engineered to mimic the relevant human pathways.
The second change was how the drug is given. The standard route had been intravenous. But CD40 receptors are everywhere, so too many healthy cells pick up the drug, and that explains the toxic effects seen earlier. Ravetch’s group injected it straight into tumors instead. “When we did that, we saw only mild toxicity,” Ravetch says.
The trial
The study aimed to find a starting clinical dose and to understand why the drug works. Its 12 patients had several metastatic cancers, among them melanoma, renal cell carcinoma and different types of breast cancer. None had the serious side effects associated with other CD40 drugs.
The two complete responses were in a woman with melanoma and a patient with metastatic breast cancer, both cancers known for being aggressive and prone to return. Ravetch described the melanoma case: dozens of metastatic tumors on her leg and foot, and the team injected just one, on her thigh. After several injections, all the others disappeared. The breast cancer patient had tumors in the skin, liver and lung. Only the skin tumor was injected, yet all of them vanished.
“This effect, where you inject locally but see a systemic response, that’s not something seen very often in any clinical treatment,” Ravetch says. He called it another dramatic and unexpected result.
Tissue samples showed why. The injected tumors had filled with immune cells, including dendritic cells, T cells and mature B cells, arranged in clusters that resembled lymph nodes. “The drug creates an immune microenvironment within the tumor,” says first author Juan Osorio, a visiting assistant professor in Ravetch’s laboratory and a medical oncologist at Memorial Sloan Kettering Cancer Center. Structures of this kind, called tertiary lymphoid structures, are linked to a better prognosis and a better response to immunotherapy. The researchers found them in tumors that had not been injected too, which suggests immune cells travel to those sites once they have identified the cancer.
Why it is too early to call it a cure
Half of twelve patients is six people. A phase 1 trial is built to test dose and safety, not to prove a drug works for everyone, and 2141-V11 remains experimental. The question the field now faces is who responds. As Ravetch notes, only 25 to 30 percent of patients typically respond to immunotherapy. Both patients whose cancer vanished had a high clonality of T cells, key cancer-killing cells, when they started, which hints that the immune system has to meet certain conditions for the drug to work.
Larger studies are under way to sort that out. The Ravetch lab is working with researchers at Memorial Sloan Kettering and Duke University on phase 1 and phase 2 trials in bladder cancer, prostate cancer and glioblastoma. Nearly 200 people are enrolled across them.
The early findings are genuinely hopeful, and they are a reason for patience rather than a reason to change any treatment plan. Anyone living with cancer should talk to their doctor or oncologist about which clinical trials might suit them, and consult your doctor before acting on headlines about a miracle shot.
Sources
- The rockefeller university
- Scientists inject one tumor and watch cancer vanish across the body
- This Experimental Cancer Drug Made Tumors Vanish, Without the Dangerous Side Effects
- List of Internet phenomena
- Iran, the plan against the US: diplomats and submarine communication cables targeted
Photo: Kenneth C. Zirkel (CC BY-SA 4.0)
