An investigational immunotherapy drug, 2141-V11, has demonstrated remarkable success in a Phase 1 clinical trial, leading to complete remission in some patients with aggressive metastatic cancers. Its promising results have already spurred further clinical investigations, including studies for prostate cancer and other notoriously difficult-to-treat malignancies. Developed by the laboratory of Rockefeller University’s Jeffrey V. Ravetch, this enhanced CD40 agonist antibody overcomes the significant toxicity and limited efficacy that plagued previous drugs in its class.
For two decades, a class of cancer drugs called CD40 agonist antibodies have shown immense promise in preclinical models for their ability to activate the immune system against cancer. However, their translation to human trials was often met with disappointment, as patients experienced severe systemic inflammatory responses, low platelet counts, and liver toxicity, even at low doses, while showing limited impact on tumors.
This modified antibody was designed to bind tightly to human CD40 receptors and enhance its crosslinking by engaging a specific Fc receptor, making it ten times more powerful in eliciting an antitumor immune response. Crucially, the researchers also altered its administration method from the traditional intravenous infusion to direct injection into tumors. This localized approach drastically reduced the widespread uptake by non-cancerous cells, mitigating the previously observed toxic side effects.
Of the 12 patients enrolled, none suffered the serious side effects seen with other CD40 drugs. Six patients experienced systemic tumor reduction, with two achieving complete remission – meaning their cancer entirely disappeared. These two patients had notoriously aggressive and recurring cancers: melanoma and breast cancer.

Even better, the drug’s effect was not limited to the injected tumors. Tumors elsewhere in the body either shrank or were destroyed by immune cells, indicating a powerful systemic response.
One melanoma patient, for example, had dozens of metastatic tumors on her leg and foot, but only one tumor on her thigh was injected. After multiple injections, all other tumors disappeared. A similar outcome was observed in a breast cancer patient with tumors in her skin, liver, and lung; injecting only the skin tumor led to the disappearance of all tumors.
Tissue analysis from the tumor sites revealed the drug’s profound impact on the immune microenvironment, the tumors became full of immune cells,including different types of dendritic cells, T cells, and mature B cells, that formed aggregates resembling something like a lymph node. This process effectively replaced the tumor with tertiary lymphoid structures (TLS), which are known to be associated with improved prognosis and response to immunotherapy. Notably, TLS were also found in tumors that were not directly injected, indicating that once the immune system identifies the cancer cells, immune cells migrate to the non-injected tumor sites.
These groundbreaking findings have initiated several other clinical trials in collaboration with researchers at Memorial Sloan Kettering and Duke University. These Phase 1 or 2 studies are now investigating 2141-V11’s efficacy in treating other aggressive and hard-to-treat cancers, including bladder cancer, prostate cancer, and glioblastoma, with nearly 200 patients currently enrolled across these studies.

Source.

Clinical  trial.