A groundbreaking phase 1 clinical trial has demonstrated that an engineered CD40 agonist antibody can eliminate aggressive metastatic cancers, with two patients achieving complete remission after direct tumor injection. The results, published in Cancer Cell, represent a significant advancement in overcoming the historical limitations of CD40-based immunotherapies.
The drug, designated 2141-V11, was developed by Jeffrey V. Ravetch's team at Rockefeller University following two decades of disappointing results with CD40 agonist antibodies. While these drugs showed promise in animal models, previous clinical trials resulted in limited efficacy and dangerous side effects including systemic inflammatory responses, low platelet counts, and liver toxicity.
Enhanced Engineering Approach
The breakthrough came through two key modifications to the traditional CD40 approach. First, researchers engineered 2141-V11 to bind more tightly to human CD40 receptors while enhancing crosslinking through engagement with specific Fc receptors, making it 10 times more powerful in eliciting antitumor immune responses compared to previous versions.
Second, the team abandoned intravenous administration in favor of direct intratumoral injection. "When we did that, we saw only mild toxicity," Ravetch explained. This approach avoided the widespread activation of non-cancerous cells that had caused severe adverse reactions in earlier trials.
Remarkable Clinical Outcomes
The phase 1 trial enrolled 12 patients with various metastatic cancers including melanoma, renal cell carcinoma, and different types of breast cancer. Six patients experienced systemic tumor reduction, with two achieving complete remission despite having notoriously aggressive and recurring cancers.
"The melanoma patient had dozens of metastatic tumors on her leg and foot, and we injected just one tumor up on her thigh," Ravetch noted. "After multiple injections of that one tumor, all the other tumors disappeared. The same thing happened in the patient with metastatic breast cancer, who also had tumors in her skin, liver, and lung."
The systemic response observed when only single tumors were injected represents an unusual and significant finding. "This effect—where you inject locally but see a systemic response—that's not something seen very often in any clinical treatment," Ravetch emphasized.
Immune System Transformation
Tissue analysis revealed the mechanism behind the drug's effectiveness. The treatment transformed tumor microenvironments by recruiting diverse immune cell populations including dendritic cells, T cells, and mature B cells that formed organized structures resembling lymph nodes.
"We were quite surprised to see that the tumors became full of immune cells that formed aggregates resembling something like a lymph node," said first author Juan Osorio, a visiting assistant professor in Ravetch's lab and medical oncologist at Memorial Sloan Kettering Cancer Center. "The drug creates an immune microenvironment within the tumor, and essentially replaces the tumor with these tertiary lymphoid structures."
These tertiary lymphoid structures (TLS) are associated with improved prognosis and enhanced response to immunotherapy. Importantly, TLS formation was observed even in non-injected tumor sites, indicating systemic immune activation and migration of cancer-targeting immune cells throughout the body.
Expanding Clinical Investigation
The promising results have catalyzed multiple follow-up studies. Nearly 200 patients are currently enrolled in phase 1 and phase 2 trials investigating 2141-V11's effectiveness against specific aggressive cancers including bladder cancer, prostate cancer, and glioblastoma. These studies represent collaborations between Ravetch's team and researchers at Memorial Sloan Kettering Cancer Center and Duke University.
The expanded trials aim to identify biomarkers that predict treatment response. Analysis of the two patients who achieved complete remission revealed high T cell clonality at baseline, suggesting specific immune system characteristics may be required for optimal drug effectiveness.
"As a general rule, only 25 to 30% of patients will respond to immunotherapy, so the biggest challenge in the field is to try to determine which patients will benefit from it," Osorio explained. "What are the indicators or predictors of response? And how can we convert non-responders into responders?"
The research represents a significant step forward for patients with advanced metastatic disease who have limited treatment options. As cancer biologist Katelyn Byrne from Oregon Health and State University noted, "Especially for patients where we don't have any options on the table, to be able to put this on the table now — it's amazing."
