SUMOylation is a biochemical process that peppers proteins with small ubiquitin-like modifiers (SUMOs). Earlier studies have shown SUMOylation suppresses type I interferon (IFN1) signaling that helps mobilize innate and acquired immune response against cancer.

A new preclinical study led by scientists at Takeda and Jounce Therapeutics shows TAK-981, a potent and selective small-molecule inhibitor of SUMOylation, reactivates IFN1 signaling, promoting innate and acquired immune responses against cancers.

“We have preclinical evidence that SUMOylation inhibition can reactivate interferon signaling that is deficient in a “cold,” or immunosuppressive, tumor setting, and transform it into one that is “hot,” or immunologically activated, potentially re-engaging the immune system to fight against cancer,” said Chris Arendt, PhD, Takeda’s head, oncology cell therapy and therapeutic area unit. “SUMOylation has been the subject of exciting research studies by groups across the world, but we are the first to have developed a compound to address the pathway.”

“Our first-in-class TAK-981 program is currently exploring inhibition of SUMOylation in several Phase I/II studies, which include both combination and single-agent approaches. Our most recent preclinical data, published this month in Science Translational Medicine, indicate potential synergistic mechanisms between TAK-981 and other immunomodulatory agents. We look forward to sharing more on our clinical studies, once more data are available.”

These findings are published in an article titled, “A small-molecule SUMOylation inhibitor activates antitumor immune responses and potentiates immune therapies in preclinical models.” The study demonstrates that TAK-981 promotes antitumor immune responses by activating IFN1 signaling and protects the IFN1 pathway from inactivation within the tumor.

In recent decades, immune checkpoint inhibitors (ICIs) that block inhibitory T cells and mobilize an immune attack against tumors have revolutionized cancer treatment. But many advanced cancer patients do not respond to these drugs or develop resistance against them.

A complementary strategy in cancer treatment is to promote innate and acquired immunity by targeting potent immunomodulatory molecules such as IFN1s. However, earlier studies attempting to inject IFN1s or increase their synthesis in the body, have been stymied by systemic dose-limiting toxicity and the loss of IFN1 receptors.

In this study, the researchers decided to explore the potential for pharmacological inhibition of IFN1 SUMOylation to stimulate IFN1-driven mechanisms of innate and adaptive antitumor immunity. They hypothesized that this approach in up-regulating the IFN1 pathway would be less toxic and better tolerated.

“We believe there is great potential in exploring innate immune responses because they involve the orchestration of a broad arsenal of different immune cell types and mechanisms that may help to overcome the attempts of cancer cells to evade immune recognition,” said Arendt.

Injecting TAK-981 intravenously in two independent tumor-bearing strains of mice strongly induces genes in the IFN1 pathway in peripheral blood leukocytes, spleen cells, and in the cancerous tissues, the researchers observed.

Dendritic cells are accessory cells of the mammalian immune system that act like billboards presenting cancer-protein fragments (antigens) that allow immune cells to recognize the presence of the tumor. Treating mouse and human dendritic cells in the dish with TAK-981 promotes their IFN1-dependent activation, the authors noted.

Vaccination in mice with TAK-981 alone, or together with an adjuvant (ovalbumin)—an ingredient used in some vaccines to create a stronger immune response—increases antigen presentation and priming of naïve T cells into effector cells. The authors showed TAK-981 directly stimulates T cell activation, increases T cell sensitivity and their response to antigen, ex vivo.

In mice, TAK-981 inhibits the growth of two syngeneic tumors—tumors that are generated by grafting mouse cancer cell lines derived from the same inbred strain of mice. The authors further showed the suppression of tumor growth by TAK-981 depends on the IFN1 pathway and adaptive immunity.

“We have also observed increased cell surface expression of the IFN1 receptor IFNAR1 in the tumor microenvironment in response to treatment with TAK-981,” the authors noted. The mechanism by which this occurs, and the cell types in which this occurs, remain to be explored.

Combining TAK-981 with anti-PD1 or anti-CTLA4 antibodies—prevalent checkpoint inhibitor therapies for cancer that activate subsets of T cells—improves the survival of mice with syngeneic colorectal and colon tumors. When combined with anti-PD1 antibodies, TAK-981 also shows increased activation of natural killer cells—an innate immune cell, and T cells marked by CD8 protein expression, that are part of the adaptive immune response.

In their in vivo experiments, the authors exposed tumor cells to the drug transiently, once or twice weekly for a few hours. “Under these conditions, we anticipate that anti-proliferative responses to periodic and temporally limited loss of SUMOylation are likely contributing minimally to antitumor activity,” the authors noted, indicating TAK-981 primarily acts through regulating the IFN1 pathway. However, SUMOylation also promotes cancer development, earlier studies report. It is therefore possible that TAK-981 mediates non-immune antitumor mechanisms that remain unknown.

The safety and efficacy of TAK-981 in treating patients with solid tumors and lymphomas are currently being investigated in several Phase I clinical trials (NCT03648372, NCT04074330, NCT04776018, and NCT04381650). TAK-981, a first-in-class small molecule inhibitor of SUMOylation, is the only SUMOylation inhibitor currently in clinical development.

“Our immuno-oncology programs include several first-in-class investigational medicines that fall into two categories: our ‘cold-to-hot’ portfolio of immunomodulators, and our redirected immunity platforms that include novel cell therapies and immune cell-engaging biologics. In addition to TAK-981, our ‘cold-to-hot’ portfolio includes an antibody-targeted STING (STimulator of INterferon Genes) agonist and a CD38 antibody-targeted attenuated type I interferon,” said Arendt. “We are excited about the potential these programs have to improve the lives of patients.”

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