Co-opting Innate and Adaptive Immunity against Cancer

Researchers at the Massachusetts Institute of Technology in Cambridge have devised a way to eradicate large, established tumors in mice. Their strategy co-opts both nonspecific innate immunity and antigen-specific, memory-promoting adaptive immunity for tumor destruction.

Darrell Irvine, PhD, a co–senior author of this study, explains that his team had been exploring a way to enhance cancer vaccine potency: By linking a vaccine's antigens to albumin-binding lipids, they used albumin in the bloodstream as a chaperone to more efficiently traffic the vaccine to the lymph nodes, where it stimulated robust T-cell production by the adaptive immune system.

Meanwhile, researchers from a neighboring lab, led by co–senior author Dane Wittrup, PhD, had observed strong synergy between tumor-specific antibodies and the cytokine IL2. In various mouse models, this combination induced antitumor responses driven by elements of innate immunity, including natural killer (NK) cells and macrophages. However, the tumors weren't eradicated, only halted in their growth.

“We decided to combine both approaches, adding immune checkpoint blockade to boost our vaccine,” Irvine says. Dubbed AIPV, their strategy includes four components: tumor-specific antibody; IL2; anti–PD-1 therapy; and lymph node–targeting vaccine, also tumor-specific.

The researchers tested AIPV in mice implanted with melanoma, breast cancer, or cervical cancer cells. Across all three models, tumor elimination was observed in more than 70% of mice, the majority of which rejected a rechallenge with new tumor cells several months later, suggesting the development of immunologic memory.

“We waited for tumors to reach about 50mm² before starting treatment—a size where adoptive T-cell transfer would be the only other way to cure these mice,” Irvine adds. “Whether the endogenous immune system could eliminate large tumors on its own—with the right combination of signals—was an unanswered question that I think our study has addressed.”

Examining their melanoma model more closely, the team found that AIPV substantially rewired the tumor microenvironment. It induced the expression of chemokines such as MIP1α, RANTES, and eotaxin, which in turn aided the recruitment of adaptive and innate immune cells, including cytotoxic T cells, neutrophils, and NK cells, to assist in tumor destruction. Irvine also notes that epitope spreading primed new T-cell responses to additional tumor antigens not encoded by AIPV, which is “likely important in the therapeutic efficacy we've seen.”

Irvine acknowledges that moving AIPV to the clinic will be challenging. In melanoma, however, he thinks a three-component permutation may be worth pursuing. The agents are readily available: IMC-20D7S (Eli Lilly), a recombinant human form of the melanoma-specific TYRP1 antibody he and Wittrup used; anti–PD-1 therapy; and IL2 (Proleukin; Prometheus Therapeutics). IMC-20D7S's safety and moderate activity were recently demonstrated in a phase I/II study of patients with advanced melanoma, Irvine adds.

That trial was led by Jedd Wolchok, MD, PhD, chief of the Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center in New York, NY. To him, approaches combining innate and adaptive immune mechanisms are “a logical next step for immuno-oncology” and, although complex, still feasible.

“We're seeing increasing collaborations between industry, academia, and regulators to make the process of combining novel agents more efficient and eliminate any barriers involved,” Wolchok says. –Alissa Poh