Improving Immunotherapy Responses by Approaching on Two Fronts

Two therapies can be better than one for treating some cancers, concludes a Yale study published Oct. 22 in the Journal of Clinical Investigation Insight that finds promise in pairing a drug that blocks a distinct immunosuppressive arm of the immune response with an established therapy that boosts the immune system to fight cancer.

The protein called MIF, or macrophage migration inhibitory factor, is usually associated with regulation of inflammation, but in certain conditions, such as cancer, MIF fuels cancer growth. MIF suppresses the body’s initial immune response, called innate immunity, which helps the body recognize abnormal cells and educates T cells to directly attack the tumor. MIF-supported tumor growth makes the work that much harder for first-line checkpoint inhibitor immunotherapies.

Approaching the problem on two fronts—blocking MIF and activating T lymphocytes—could enhance the response to immune checkpoint inhibitor therapy, the researchers theorized. This is a critical area for oncologists because nearly half of patients treated with immune checkpoint inhibitors do not benefit clinically, due to resistance mechanisms that enable ongoing cancer growth.

“MIF is increased in multiple cancers and has been shown to be a driver of immune resistance and cancer aggressiveness in multiple independent, non-biased genetic screening studies. MIF can both directly promote tumor growth and establish a tumor environment that suppresses anti-tumor immunity,” says the study’s first author Thuy Tran, MD, PhD, assistant professor of medicine (medical oncology) at Yale School of Medicine.

“Although prior attempts at blocking MIF in the clinic have yielded modest responses, the rationale to capitalize on MIF’s potential in enhancing innate immune responses with existing therapies that augment adaptive T cell immunity made biological sense. One arm of the immune system could work better if supported by the other, and not alone,” Tran says.

The researchers found that the synergy of an anti-MIF approach in tandem with existing PD-1 inhibitors (i.e. drugs like Pembrolizumab, Nivolumab, and Cemiplimab, which are already FDA-approved) proved more beneficial in pre-clinical models of melanoma and colon cancer than either was alone.

The combination approach led to more complete tumor regression, slower tumor growth, and improved survival, the study found. Enhanced responses were associated with an expansion of a unique population of macrophages capable of presenting tumor-related proteins to T cells. The researchers also found that the high expression form of the MIF gene, which occurs commonly, was more likely to occur in individuals with melanoma than in those without cancer.

“Finding methods to boost innate immunity is an area of intensive research in oncology,” says Tran. “Our work demonstrates that MIF could be an innate checkpoint inhibitor. Coupling MIF and T cell targeting strategies could enhance anti-cancer responses in multiple diseases and provide another treatment option to individuals in the future.”

Tran noted that the anti-MIF therapy developed by senior author Richard Bucala, MD, PhD, her mentor, has already been tested in cancer patients and found to be safe. The present findings provide a way forward to apply anti-MIF in those clinical settings most likely to benefit.

Tran and Bucala, both members of Yale Cancer Center, are actively collaborating with Yale Ventures to generate next-generation drugs that can be applied to the clinic.

The research reported in this news article was supported by the NIH National Cancer Institute (NCI) Yale SPORE in Skin Cancer P50 CA121974, the Yale SPORE in Skin Cancer Career Enhancement Program, NIH grants AR078334, T32AR07107, R01 CA269286, DE033038, by NIH grant NCI T32 CA193200-5, the Karin Bain and John Kukral Foundation, the Kuni Foundation, and Yale University.