For years, this kind of cancer drug looked like a dead end. It fired up the immune system, sure, but it also caused enough damage to make doctors hesitate.
Now, a small trial is flipping that story on its head.
Scientists testing a redesigned version of a long-studied therapy say it shrank tumors in half of the patients involved, and in two cases, wiped the cancer out completely. Even more surprising, the treatment was injected into just one tumor, yet tumors elsewhere in the body also disappeared.
That kind of ripple effect is rare.
“Seeing these significant shrinkages and even complete remission in such a small subset of patients is quite remarkable,” says Juan Osorio, a visiting assistant professor in Jeffrey Ravetch’s lab at Rockefeller University and a medical oncologist at Memorial Sloan Kettering Cancer Center.
The drug, known as 2141-V11, belongs to a class called CD40 agonist antibodies. Scientists have been studying them for more than 20 years. Early lab work showed promise. These drugs can push the immune system into attack mode, helping it recognize and destroy cancer cells.
But when researchers tried them in people, the results were underwhelming. Tumor responses were limited, and side effects were hard to ignore. Patients developed widespread inflammation, dangerously low platelet counts, and liver damage. And that was at relatively low doses.
So Ravetch and his team took a different approach.
Back in 2018, they re-engineered the antibody itself. The goal was simple: make it better at activating the immune system while dialing down the collateral damage. Using specially designed mice that mimic human immune responses, they tested a version that binds more tightly to CD40 receptors and interacts more effectively with another immune component known as an Fc receptor.
In lab tests, the redesigned drug was about 10 times more potent at triggering an immune response against tumors.
But the real shift came in how they delivered it.
Traditionally, these drugs were given through an intravenous drip, spreading throughout the body. The problem is CD40 receptors are everywhere, not just on tumors. So healthy cells would soak up the drug too, leading to toxic side effects.
Instead, the team injected the therapy directly into a tumor.
“When we did that, we saw only mild toxicity,” Ravetch says.
That decision set the stage for the first human trial.
The phase 1 study included 12 patients with advanced cancers, including melanoma, breast cancer, and kidney cancer. These were metastatic cases, meaning the disease had already spread.
Six of those patients saw their tumors shrink. Two experienced complete remission.
What caught researchers off guard wasn’t just the response rate. It was where the response showed up.
“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.”
In one case, a patient with melanoma had dozens of tumors on her leg and foot. Doctors injected just one tumor in her thigh.
“The melanoma patient had dozens of metastatic tumors on her leg and foot, and we injected just one tumor up on her thigh,” Ravetch says. “After multiple injections of that one tumor, all the other tumors disappeared.”
A similar outcome played out in a patient with metastatic breast cancer.
“The same thing happened in the patient with metastatic breast cancer, who also had tumors in her skin, liver, and lung. And even though we only injected the skin tumor, we saw all the tumors disappear.”
To understand why, researchers looked closely at treated tumors.
What they found looked less like cancer and more like an immune training ground.
“We were quite surprised to see that 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,” Osorio says. “The drug creates an immune microenvironment within the tumor, and essentially replaces the tumor with these tertiary lymphoid structures.”
These formations, called tertiary lymphoid structures, are often linked to stronger responses to immunotherapy. They act like mini command centres, helping the immune system organize and coordinate its attack.
What’s more, these structures showed up not just in the injected tumors, but in others throughout the body.
“Once the immune system identifies the cancer cells, immune cells migrate to the non-injected tumor sites,” Osorio explains.
In other words, the initial injection seems to teach the immune system what to look for. After that, it takes over.
The trial was small and designed mainly to test safety, not to prove effectiveness. But the early signals were strong enough to push the research forward.
Larger trials are already underway, involving nearly 200 patients across phase 1 and phase 2 studies. Researchers are testing the therapy against several hard-to-treat cancers, including bladder cancer, prostate cancer, and glioblastoma.
Now the focus is shifting to a familiar challenge in cancer care: figuring out who benefits most.
The two patients who experienced complete remission had one thing in common. At the start of the trial, their immune systems already showed high levels of T cell clonality, meaning their T cells were primed to recognize specific targets.
“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.”
That question matters because immunotherapy doesn’t work for everyone. In many cases, only about a quarter to a third of patients respond.
“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?”
For now, the results offer something researchers have been chasing for years: a way to activate the immune system against cancer without setting off alarms everywhere else in the body.
And it all starts with a single shot.
A tiny antibody built at the University of Missouri could help show which cancer patients are most likely to respond to certain targeted treatments.
Barry Edwards, an associate professor of biochemistry in the School of Medicine, designed the antibody to seek out EphA2, a protein frequently present in cancer tumors. After creating it, he attached a radioactive marker so the molecule can be seen during a positron emission tomography, or PET, scan.
In experiments using mice, Edwards found the cancer-detecting “flashlight” clearly lit up tumors that produced EphA2. The findings suggest that tagging the antibody could help doctors identify cancers that contain the protein and work out which patients might respond to therapies aimed at EphA2-positive tumor cells while leaving healthy tissue unharmed.
“By finding out which patients have high or low amounts of EphA2, we can determine who is most likely to benefit from a targeted cancer treatment,” Edwards said.
Edwards also has an appointment in the College of Arts and Science. He said the approach could also cut back on treatment that is unlikely to help.
“There is no sense in giving a treatment that won’t work to a patient, so this new process we created saves time and money while advancing precision medicine,” he said.
Doctors currently rely on biopsies and MRI scans to assess tumors in cancer patients. According to the university, those methods can be invasive, take significant time and often give limited insight into the specific proteins inside cancer cells.
Edwards uses advanced imaging technology at Mizzou’s Molecular Imaging and Theranostics Center for his research. He hopes to move the technique from preclinical studies into human clinical trials within the next seven years.
“This new targeted approach is noninvasive, and you can get results from the imaging in hours rather than days, which can be huge for patients traveling long distances to seek treatment,” Edwards said.
“By making the process easier and faster for both patients and clinicians, we’re showing that precision medicine is a win-win.”
The study is titled “Preclinical evaluation of anti-EphA2 minibody-based immunoPET agent as a diagnostic tool for cancer,” and it was published in Molecular Imaging and Biology.
