Researchers tested a redesigned CD40 agonist antibody, 2141-V11, by injecting it directly into tumors of 12 patients with metastatic cancers. Six patients saw tumor shrinkage, with two achieving complete remission, including effects on untreated tumors elsewhere in the body. The trial reported only mild side effects, unlike prior CD40 therapies.
For over two decades, CD40 agonist antibodies have shown promise in lab settings by activating the immune system against cancer but disappointed in human trials due to modest benefits and severe side effects like inflammation and liver damage, even at low doses. In 2018, Jeffrey V. Ravetch's team at Rockefeller University engineered antibody 2141-V11 to bind tightly to human CD40 receptors and improve crosslinking via a specific Fc receptor, making it about 10 times more effective in lab studies using engineered mice. Supported by Rockefeller's Therapeutic Development Fund, they shifted delivery from intravenous to direct tumor injection to minimize toxicity on healthy cells. A phase 1 clinical trial tested this in 12 patients with metastatic cancers including melanoma, renal cell carcinoma, and breast cancer. Results, published in Cancer Cell, showed tumors shrank in six patients, with complete remission—no detectable cancer—in two: one with melanoma and one with breast cancer. Notably, injecting a single tumor triggered immune responses that shrank or eliminated distant tumors. As Ravetch described, the melanoma patient had dozens of metastatic tumors on her leg and foot; after injecting one on her thigh, all others disappeared. Similarly, the breast cancer patient's skin, liver, and lung tumors vanished after skin tumor injection. Juan Osorio, first author and oncologist at Memorial Sloan Kettering Cancer Center, noted: “Seeing these significant shrinkages and even complete remission in such a small subset of patients is quite remarkable.” Tumor samples revealed infiltration by dendritic cells, T cells, B cells, and tertiary lymphoid structures (TLS), mimicking lymph nodes, even in non-injected sites. Ravetch highlighted the rarity: “This effect—where you inject locally but see a systemic response—that's not something seen very often.” No severe side effects occurred, only mild toxicity. Larger phase 1 and 2 trials with nearly 200 patients are underway at Memorial Sloan Kettering and Duke University for cancers like bladder, prostate, and glioblastoma to identify response predictors, such as high T-cell clonality.
