The drug dupilumab, which blocks IL-4’s activity, has been approved by the Food and Drug Administration and is already used to treat asthma and eczema. This new study suggests dupilumab or similar drugs could be repurposed to enhance immunotherapy for ovarian cancer.

Ovarian cancer is one of the deadliest cancers: 50 percent of patients die within five years of diagnosis. While immunotherapy drugs such as pembrolizumab, which target the PD-1 molecule, have demonstrated efficacy in treating melanoma and lung cancer, they have not significantly improved survival rates in ovarian cancer. This is partly because ovarian tumors have fewer mutations, making them harder for the immune system to recognize. Additionally, research suggests that these tumors may resist immunotherapy by creating barriers that prevent immune cells from infiltrating their borders. The critical question, according to the investigators, has been: how do tumors establish these protective environments?

To address this question, the research team, led by Alessia Baccarini, PhD, and Brian D. Brown, PhD, used a novel genomics technology known as Perturb-map. Perturb-map enhances traditional gene-editing CRISPR screening, where hundreds of genes are simultaneously “perturbed” by incorporating state-of-the-art spatial imaging. This enables each gene’s role in controlling the tumor environment to be elucidated. Their experiments revealed that removing the IL-4 gene from ovarian cancer cells rendered tumors susceptible to anti-PD-1 therapy.

“Surprisingly, the IL-4-deficient cancer cells were eliminated by the immune system even when mixed within tumors containing IL-4-producing cancer cells, a phenomenon known as intratumoral heterogeneity, which also contributes to drug resistance in cancer,” says Dr. Brown, who is the senior author of the study.

The researchers then tested a combination of anti-PD-1 and IL-4 receptor-blocking drugs in mice with aggressive metastatic ovarian cancer and found that this combination treatment significantly extended their survival.

Additional preclinical studies demonstrated that ovarian cancer uses IL-4 to program macrophages, a type of immune cell, into protectors of the cancer cells. The IL-4-programmed macrophages prevented T cells from killing the cancer cells. However, when IL-4 was blocked, the local environment surrounding the cancer cells changed, and this left the malignant cells susceptible to being eliminated by the immune system.

To further validate their findings, the team examined specimens from human ovarian tumor resections and saw that the patients’ cancer cells also produced IL-4. Moreover, analysis of single-cell RNA sequencing data from patient tumors, which examines how genes are expressed in cells, revealed that the macrophages displayed a strong IL-4 signature, suggesting that IL-4 plays a similar role in human ovarian cancer and may be one of the reasons patients have not benefited from immunotherapy.

“Ovarian cancer has almost been written off as non-responsive to existing immunotherapy, so it was quite stunning to us that by just blocking this one molecule, IL-4, and altering the tumor’s microenvironment, we could make these difficult-to-treat tumors more treatable,” adds Dr. Brown. “This is further evidence that targeting the tumor’s neighborhood, not just the cancer cells, can be beneficial.”

While these findings are encouraging, the investigators stress that clinical trials are essential to determine whether targeting IL-4 can enhance patient outcomes. Given that dupilumab is already FDA-approved for asthma and eczema, there is potential for swift clinical testing alongside immunotherapy to enhance survival in ovarian cancer patients. Thomas Marron, MD, PhD, Director of the Early Phase Trial Unit at the Mount Sinai Tisch Cancer Center, and a colleague of Drs. Brown and Baccarini, is already running a clinical study to test whether dupilumab can improve anti-PD-1 immunotherapy in patients with lung cancer. Several patients have shown beneficial responses.

“Ovarian cancer is a disease that’s so hard to catch early and once diagnosed, it’s often too late. I am excited that these findings may make a difference in patients’ lives. The IL-4 pathway is already targeted for diseases like eczema, and I am hopeful that if we target it in ovarian cancer, we can help women facing this terrible disease,” says Dr. Baccarini.

The work was supported by NIH awards R01AT011326, R01CA254104, R01CA257195, U2C-CA233262, U01CA284207, U01CA282114, and funding from the Cancer Research Institute, the Feldman Family Foundation, the Applebaum Foundation, and Ludwig Cancer Research.