Metastatic cancer is often difficult to treat as it spreads to nearby organs and body parts. For decades, drugs that supercharged the immune system’s response to tumors seemed promising, but in clinical trials, they caused serious side effects and delivered modest results.
Now, researchers at Rockefeller University have redesigned one of these drugs and changed its administration, with early results.
The drug, 2141-V11, belongs to a class of treatments known as CD40 agonist antibodies. CD40, a receptor found on the surface of certain immune cells, acts as an activation switch that signals the immune system to ramp up its response and generate cancer-targeting T cells.
Earlier CD40 drugs caused inflammation, dangerous drops in platelet counts and liver damage even at low doses, side effects severe enough to halt the therapies for years.
The Rockefeller team, led by immunologist Jeffrey Ravetch, addressed both problems. They re-engineered 2141-V11 to bind more tightly to CD40 receptors while engaging a separate Fc receptor, a modification that made it roughly 10 times more effective at triggering an immune attack against tumors than its predecessors.
Instead of delivering it through the bloodstream, they injected it directly into a single tumor, keeping it concentrated rather than flooding healthy tissue.
The phase 1 trial enrolled 12 patients with metastatic cancers, including melanoma, renal cell carcinoma and different forms of breast cancer.
Results, published in the journal Cancer Cell, showed that tumors shrank in six patients, while two achieved complete remission. Crucially, none of the patients experienced the harmful side effects associated with previous CD40 treatments.
The findings were particularly striking because of what happened beyond the injection site. Tumors elsewhere in the body, never touched by the drug, also shrank or vanished. In one case, a melanoma patient with dozens of metastatic tumors across her leg and foot received only a single injection in a thigh tumor. All other tumors beyond the injection site eventually disappeared.
Tissue samples offered an explanation. Treated tumors had been effectively colonized by immune cells, filled with T cells, B cells and dendritic cells that organized into structures resembling miniature lymph nodes, known as tertiary lymphoid structures.
These formations are strongly associated with better outcomes in cancer treatment. Once assembled, they appeared to dispatch immune cells to distant tumor sites.
Not all patients responded equally. Researchers noted that two patients who achieved complete remission both showed high levels of T cell activity at the start of the trial, suggesting the immune system may need certain preconditions to fully mobilize.
Understanding those conditions is now the focus of ongoing trials at Memorial Sloan Kettering and Duke University, testing 2141-V11 against bladder cancer, prostate cancer and glioblastoma in nearly 200 patients.
The broader challenge is that only 25% to 30% of patients respond to immunotherapy in general and determining who benefits remains one of the field’s biggest challenges.
This trial does not answer the question, but it adds a promising piece to the puzzle.
