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 that 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.
"When we did that, we saw only mild toxicity," Ravetch says.
Those findings became the basis of the phase 1 clinical trial described in the current study, which aimed to determine a starting clinical dose of the drug and better understand the mechanisms underlying its effectiveness.
Inducing remission
The trial included 12 patients representing myriad metastatic cancer types: melanoma, renal cell carcinoma, and different types of breast cancer. Of those 12, none suffered the serious side effects seen with other CD40 drugs. Six experienced systemic tumor reduction, of which two had a complete response—meaning their cancer disappeared entirely.
The two patients who experienced complete remission had melanoma and breast cancer, respectively—both notoriously aggressive and recurring.
"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. 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."
Tissue samples from the tumor sites revealed the immune activity that the drug stimulated. "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."
The presence of tertiary lymphoid structures (TLS) is associated with improved prognosis and response to immunotherapy, Osorio notes.
They also found TLS in the tumors they didn't inject. "Once the immune system identifies the cancer cells, immune cells migrate to the non-injected tumor sites," he says.
Improving immunotherapy
The findings have sparked a number of other clinical trials that the Ravetch lab is currently collaborating on with researchers at Memorial Sloan Kettering and Duke University. Now in either phase 1 or phase 2 study, the trials are investigating 2141-V11's effect on specific cancers, including bladder cancer, prostate cancer, and glioblastoma—all aggressive and hard to treat. Collectively, nearly 200 people are enrolled in the studies.
These studies will help to illuminate why some patients respond to 2141-V11 and others do not—and how to potentially change that.
For example, the two patients in the clinical trial whose cancer disappeared both had a high clonality of T cells—key cancer-cell killers—when they began the study. "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."
"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?"
