Over the past 20 years, a class of cancer drugs called CD40 agonist antibodies have shown great promise—and induced great disappointment. While effective at activating the immune system to kill cancer cells in animal models, the drugs had limited impact on patients in clinical trials and caused dangerously systemic inflammatory responses, low platelet counts, and liver toxicity, among other adverse reactions—even at a low dose.
But in 2018, the lab of Rockefeller University’s Jeffrey V. Ravetch demonstrated it could engineer an enhanced CD40 agonist antibody so that it improved its efficacy and could be administered in a manner to limit serious side effects. The findings came from research on mice, genetically engineered to mimic the pathways relevant in humans. The next step was to have a clinical trial to see the drug’s impact on cancer patients.
Now the results from the phase 1 clinical trial of the drug, dubbed 2141-V11, have been published in Cancer Cell. Of 12 patients, six patients saw their tumors shrink, including two who saw them disappear completely.
“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 Center.
Notably, the effect wasn’t limited to tumors that were injected with the drug; tumors elsewhere in the body either got smaller or were destroyed by immune cells.
“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.”
Engineering enhancements
CD40 is a cell surface receptor and member of the tumor necrosis factor (TNF) receptor superfamily, proteins that are largely expressed by immune cells. When triggered, CD40 prompts the rest of immune system to spring into action, promoting antitumor immunity and developing tumor-specific T cell responses.
In 2018, Ravetch’s lab—which has been supported in this line of research by Rockefeller’s Therapeutic Development Fund, founded by trustee Julian Robertson and continued by the Black Family Foundation—engineered 2141-V11, a CD40 antibody that binds tightly to human CD40 receptors and is modified to enhance its crosslinking by also engaging a specific Fc receptor. It proved to be 10 times more powerful in its capacity to elicit an antitumor immune response.
They then changed how they administered the drug. The long-time approach had been to give it intravenously. But CD40 receptors are widespread, so too many non-cancerous cells pick it up, leading to the well-known toxic side effects. Instead, they injected the drug directly into tumors.
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