Engineered Antibody Shrinks Tumors & Achieves Remission in Cancer Trial

For decades, cancer researchers have sought ways to harness the body’s own immune system to fight tumors. A recent clinical trial offers a potentially significant step forward, demonstrating remarkable responses in a small group of patients with advanced cancers following a novel approach using modified CD40 agonist antibodies. The findings, published in the journal Cancer Cell, suggest that injecting the therapy directly into tumors—rather than through traditional intravenous infusion—can minimize side effects while triggering a systemic anti-cancer immune response, even in tumors distant from the injection site.

The Challenge with CD40 Agonist Antibodies

CD40 is a receptor protein found on immune cells like B cells, macrophages and dendritic cells. Activating CD40 essentially signals the immune system to ramp up its activity, prompting it to recognize and attack cancer cells. For over twenty years, scientists have been exploring CD40 agonist antibodies – drugs designed to bind to and activate this receptor. However, early clinical trials were hampered by significant toxicity. Patients experienced widespread inflammation, dangerously low platelet counts, and liver damage, even at relatively low doses. These side effects limited the potential of CD40-targeted therapies.

As explained in a review in Drug Discovery Today, the key issue was that CD40 receptors are present throughout the body, not just on immune cells involved in fighting cancer. Systemic administration of CD40 agonists meant that healthy cells were also activated, leading to the observed toxicity.

A Redesigned Antibody and a New Delivery Method

In 2018, researchers at Rockefeller University, led by Jeffrey V. Ravetch, announced a potential breakthrough. They redesigned a CD40 agonist antibody, dubbed 2141-V11, to improve its effectiveness and reduce harmful side effects. The redesigned antibody binds more tightly to human CD40 receptors and interacts with a specific Fc receptor, enhancing its ability to trigger an immune attack against tumors. Crucially, they also changed the delivery method. Instead of intravenous infusion, the team injected the treatment directly into the tumors themselves.

This localized approach proved to be a game-changer. By delivering the drug directly to the tumor microenvironment, researchers significantly reduced systemic exposure and, toxicity. As Ravetch notes in the Cancer Cell publication, “When we did that, we saw only mild toxicity.”

Early Clinical Trial Results: Tumor Shrinkage and Remission

The phase 1 clinical trial, involving 12 participants with various types of metastatic cancer – including melanoma, renal cell carcinoma, and breast cancer – demonstrated encouraging results. Six patients experienced tumor shrinkage, and remarkably, two achieved complete remission, meaning all detectable cancer disappeared. These findings are particularly noteworthy given the small sample size and the advanced stage of the patients’ cancers.

The researchers observed an unusual phenomenon: the treatment didn’t just affect the injected tumors. Tumors located elsewhere in the body also shrank or were eliminated by immune cells. This systemic response, where local injection leads to widespread anti-cancer effects, is rarely seen in cancer treatment. As Juan Osorio, the first author of the study and a medical oncologist at Memorial Sloan Kettering Cancer Center, explains, “Seeing these significant shrinkages and even complete remission in such a small subset of patients is quite remarkable.”

How the Therapy Transforms the Tumor Environment

Analysis of samples taken from treated tumors revealed a significant influx of immune cells, including dendritic cells, T cells, and B cells. These cells aggregated within the tumor, forming structures resembling tertiary lymphoid structures (TLS). TLS are often associated with better outcomes in cancer treatment and stronger responses to immunotherapy. The drug essentially transforms the tumor environment, replacing cancer cells with these immune-rich structures.

researchers found TLS developing even in tumors that weren’t directly injected with the drug, suggesting that the immune response triggered by the localized injection can spread throughout the body, targeting distant cancer cells. This migration of immune cells is key to the systemic effect observed in the trial.

What’s Next: Larger Trials and Biomarker Research

The promising results from the phase 1 trial have paved the way for larger clinical trials. Ravetch’s group is collaborating with scientists at Memorial Sloan Kettering and Duke University to further evaluate the therapy in patients with several difficult-to-treat cancers, including bladder cancer, prostate cancer, and glioblastoma. Nearly 200 patients are currently participating in these phase 1 and phase 2 trials.

Researchers are also focused on identifying biomarkers – measurable indicators – that can predict which patients are most likely to respond to the treatment. The initial trial suggested that patients with high clonality of T cells at the start of treatment may be more likely to benefit. Understanding these factors will be crucial for optimizing the therapy and maximizing its effectiveness. As Ravetch’s team notes, a major challenge in immunotherapy is determining which patients will respond, and identifying these predictors is a key focus of ongoing research. A recent article in Cytokine Growth Factor Review highlights the ongoing efforts to harness the potential of CD40 agonism in cancer therapy.

The National Cancer Institute provides information on clinical trials studying anti-CD40 agonist monoclonal antibody CDX-1140, allowing patients to search for trials based on age and location: NCI Clinical Trials Information.

While these early results are encouraging, it’s important to remember that this is still a relatively new therapy. Larger, more comprehensive trials are needed to confirm these findings and determine the long-term safety and efficacy of this approach. However, the initial data suggest that targeted delivery of modified CD40 agonist antibodies could represent a significant advance in cancer immunotherapy, offering hope for patients with limited treatment options.