For more than 20 years, scientists have been studying a class of anti-cancer drugs known as CD40 agonist antibodies. Early experiments suggested that these treatments powerfully activate the immune system and may help destroy cancer cells. But people’s results were disappointing. Clinical trials showed only modest efficacy, and the drugs often caused severe side effects, including widespread inflammation, dangerously low platelet levels, and liver damage. These reactions occurred even at relatively low doses.
In 2018, researchers led by Jeffrey V. Ravetch of Rockefeller University reported a potential groundbreaking discovery. The research team redesigned the CD40 agonist antibody to improve efficacy while reducing harmful side effects. Their research relied on specially engineered mice that mimic the main immune pathways found in humans. This encouraging finding suggested that this treatment may work better for people if it is delivered in a different way.
The next step was to test the drug on patients.
Early clinical trials show tumor shrinkage and remission
Results from a phase 1 clinical trial of the improved drug, called 2141-V11, were published in the journal Cancer Cell. Of the 12 people in the study, six patients had their tumors shrink. Two of those patients experienced complete remission. This means that the cancer is completely gone.
“It’s very remarkable to see such a significant shrinkage and even complete remission in such a small number of patients,” said lead author Juan Osorio, a visiting assistant professor in the Leonard Wagner Institute for Molecular Genetics and Immunology at Ravetch University and a medical oncologist at Memorial Sloan Kettering Cancer Center.
Researchers also observed something unusual. The treatment didn’t just affect the tumors that were injected with the drug. Tumors elsewhere in the body are also shrunk or eliminated by immune cells.
“This effect, where you can inject it locally and still get a systemic response, is something you don’t often see in clinical therapy,” Ravetch said. “This is another very dramatic and unexpected outcome of our trial.”
How the engineered CD40 antibody works
CD40 is a receptor found on the surface of certain cells and belongs to the tumor necrosis factor (TNF) receptor superfamily. These receptors are primarily found on immune cells. When CD40 is activated, it signals the immune system to mount a stronger response, triggering anti-tumor immunity and helping to generate T cells that target cancer.
In 2018, Ravetch’s team developed antibody 2141-V11 with support from the Rockefeller Therapeutic Development Fund, established by Trustee Julian Robertson and continued by the Black Family Foundation. The redesigned antibody was modified to tightly bind to the human CD40 receptor and improve cross-linking by interacting with specific Fc receptors. Clinical studies showed that the new design was about 10 times more effective at triggering an immune attack against tumors.
Researchers also changed the way the drug was administered. Traditionally, CD40 therapy has been delivered by intravenous infusion. Because CD40 receptors are present throughout the body, many healthy cells can absorb the drug, potentially causing toxic side effects.
Instead, the team injected the treatment directly into the tumor.
“When we did that, we found only mild toxicity,” Ravetch said.
These findings laid the groundwork for a phase 1 clinical trial aimed at determining a safe starting dose and better understanding how the treatment works in patients.
Tumor disappears in some patients
The trial involved 12 people with several types of metastatic cancer, including melanoma, renal cell carcinoma, and various forms of breast cancer. None of the participants experienced severe side effects previously associated with CD40 drugs.
Six patients showed systemic tumor regression. Two patients achieved a complete response. This means that all detectable cancer has disappeared.
The two patients whose cancer disappeared had melanoma and breast cancer, respectively. Both cancers are known to be highly malignant and prone to recurrence.
“This melanoma patient had dozens of metastatic tumors in her legs and feet, but we injected just one tumor in her thigh,” Ravetch says. “After multiple injections into that one tumor, all the other tumors disappeared. The same thing happened with a patient with metastatic breast cancer. She also had tumors in her skin, liver, and lungs. And even though we only injected the skin tumor, we saw all the tumors disappear.”
Immune cells alter the tumor environment
Samples taken from treated tumors revealed how strongly the immune system responded.
“We were very surprised to see that the tumors were filled with immune cells, including different types of dendritic cells, T cells, and mature B cells, forming aggregates that resembled lymph nodes,” Osorio says. “This drug creates an immune microenvironment within the tumor, essentially replacing the tumor with these tertiary lymphoid structures.”
These structures, known as tertiary lymphoid structures (TLS), are often associated with better outcomes in cancer treatment and stronger responses to immunotherapy.
The researchers also detected TLS in tumors that were not directly injected with the drug.
“Once the immune system identifies cancer cells, they migrate to the tumor site where they were not injected,” Professor Osorio explains.
Large-scale trial aims to improve cancer immunotherapy
Promising findings led to additional clinical trials. Ravetch’s group is currently working with scientists at Memorial Sloan Kettering and Duke University to further evaluate the therapy.
Current Phase 1 and Phase 2 trials are testing 2141-V11 in several difficult-to-treat cancers, including bladder cancer, prostate cancer, and glioblastoma. Nearly 200 patients are participating in these studies.
Researchers hope that larger trials will reveal why some patients respond to treatment while others do not, and how response rates can be improved.
For example, the two patients whose cancer disappeared both had high T-cell clonality at the start of the study. These immune cells play an important role in killing cancer.
“This suggests that there are some requirements from the immune system for this drug to work, and we are in the process of dissecting these properties in more detail in these larger studies.”
Understanding these factors can help researchers predict who will benefit from treatment.
“Typically, only 25% to 30% of patients respond to immunotherapy, so the biggest challenge in this field is determining which patients will benefit from immunotherapy. What are the indicators and predictors of response? And how can we convert non-responders to responders?”
