By Morgan Nwanguma
A redesigned cancer immunotherapy has delivered striking early results, triggering widespread tumour destruction in a small clinical trial. The experimental treatment shrank cancers in half of the participants and eliminated them entirely in two cases.
After decades of limited success with similar drugs, researchers improved a class of treatments known as CD40 agonist antibodies by both enhancing their potency and changing how they are administered. Instead of delivering the drug through the bloodstream, the new approach involves injecting it directly into tumours—helping to focus the immune response where it is needed most.
In an early-stage trial involving 12 patients with metastatic cancer, six experienced significant tumour shrinkage, while two achieved complete remission.
CD40 agonist antibodies have been studied for more than 20 years because of their ability to activate the immune system against cancer. However, earlier clinical trials produced only modest benefits and were often accompanied by severe side effects, including systemic inflammation, dangerously low platelet counts, and liver toxicity—even at low doses.
A turning point came in 2018, when a team led by Jeffrey V. Ravetch at Rockefeller University re-engineered the antibody to boost its effectiveness while reducing harmful reactions. Using specially designed mouse models that replicate key aspects of the human immune system, the researchers demonstrated that altering both the drug’s structure and delivery method could significantly improve outcomes.
The newly developed therapy, known as 2141-V11, has now advanced to human testing. Findings from its phase 1 clinical trial, published in Cancer Cell, show promising signs of efficacy, with notable tumour reduction and, in some cases, complete disappearance of cancer.
“Seeing these significant shrinkages and even complete remission in such a small subset of patients is quite remarkable,” says first author Juan Osorio, a visiting assistant professor in Ravetch’s Leonard Wagner Laboratory of Molecular Genetics and Immunology and a medical oncologist at Memorial Sloan Kettering Cancer Centre.
Researchers also noted an unexpected effect: the therapy did not act only on the tumours directly injected with the drug. Tumours in other parts of the body also shrank or were completely cleared, suggesting a broader immune response.
“This effect – where you inject locally but see a systemic response – that’s not something seen very often in any clinical treatment,” Ravetch notes. “It’s another very dramatic and unexpected result from our trial.”
How the Engineered CD40 Antibody Operates
CD40 is a receptor located on the surface of certain cells and is part of the tumour necrosis factor (TNF) receptor superfamily. It is primarily found on immune cells, and when activated, it stimulates a stronger immune response, helping to drive anti-tumour activity and generate cancer-targeting T cells.
In 2018, a team led by Jeffrey V. Ravetch engineered a modified antibody known as 2141-V11, with support from Rockefeller University’s Therapeutic Development Fund, originally established by trustee Julian Robertson and later sustained by the Black Family Foundation. This redesigned antibody binds more tightly to human CD40 receptors and was further enhanced to improve crosslinking through interaction with a specific Fc receptor. Laboratory studies showed that this new version was roughly ten times more effective at activating an immune attack against tumours.
The researchers also changed how the drug is administered. Traditionally, CD40 therapies were delivered intravenously, but because CD40 receptors are widely distributed throughout the body, many healthy cells absorbed the drug – often causing toxic side effects.
To address this, the team opted to inject the therapy directly into tumours, allowing for a more targeted and controlled immune response.
“When we did that, we saw only mild toxicity,” Ravetch says.
These results paved the way for a phase 1 clinical trial designed to establish a safe starting dose and gain deeper insight into how the therapy performs in patients.
Tumours Disappear in Some Patients
The trial included 12 individuals with various forms of metastatic cancer, including melanoma, renal cell carcinoma, and different types of breast cancer. Notably, none of the participants experienced the severe side effects that had previously limited CD40-based treatments.
Six patients exhibited tumour shrinkage across multiple sites in the body, while two achieved a complete response, meaning all detectable cancer was eliminated.
The two patients whose cancers disappeared entirely had melanoma and breast cancer, respectively – both known to be aggressive and highly prone to recurrence.
“The melanoma patient had dozens of metastatic tumours on her leg and foot, and we injected just one tumour up on her thigh,” Ravetch says. “After multiple injections of that one tumour, all the other tumours disappeared. The same thing happened in the patient with metastatic breast cancer, who also had tumours in her skin, liver, and lung. And even though we only injected the skin tumour, we saw all the tumours disappear.”
Immune Cells Change the Tumour Surroundings
Samples taken from treated tumours revealed how strongly the immune system responded.
“We were quite surprised to see that the tumours 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,” Osorio says. “The drug creates an immune microenvironment within the tumour, and essentially replaces the tumour with these tertiary lymphoid structures.”
These formations, called tertiary lymphoid structures (TLS), are frequently associated with improved cancer outcomes and more robust responses to immunotherapy.
Notably, TLS were also identified in tumours that had not been directly injected with the treatment.
“Once the immune system identifies the cancer cells, immune cells migrate to the non-injected tumour sites,” Osorio explains.
Bigger Tests Aim to Advance Cancer Immunotherapy
The encouraging early results have spurred further clinical investigations. Ravetch’s team is now working alongside researchers at Memorial Sloan Kettering and Duke University to expand evaluation of the therapy.
Ongoing phase 1 and phase 2 trials are testing 2141-V11 in several hard-to-treat cancers, including bladder cancer, prostate cancer, and glioblastoma, with nearly 200 patients enrolled across studies.
Scientists hope these bigger trials will clarify why some patients respond while others do not, and identify ways to boost effectiveness.
For example, the two patients who experienced complete cancer disappearance both had high T-cell clonality at the start of the trial, suggesting a strong population of cancer-targeting immune cells may play a key role in treatment success.
“This suggests there are some requirements from the immune system in order for this drug to work, and we’re in the process of dissecting these characteristics in more granular detail in these larger studies.”
Comprehending these factors will possibly assist scientists predict who will benefit from the treatment.
“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. What are the indicators or predictors of response? And how can we convert non-responders into responders?”
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