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October 25, 2016

Large Tumors Destroyed by Innate/Adaptive Immunotherapy Combo

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    Immunosuppressive tumors in mice have been eradicated by an immunotherapy that incorporates four parts: an antibody targeted to the tumor; a vaccine targeted to the tumor; IL-2; and a molecule that blocks PD1, a receptor found on T cells. In this image, the top row shows few T cells in untreated mice, while the bottom rows show many T cells produced after immunotherapy treatment. [K. Dane Wittrup and Darrell J. Irvine/MIT]

    If combination immunotherapies show promise against established tumors, why not try super-combo immunotherapies? That’s the question that occurred to MIT scientists, who had achieved partial successes with various biomolecular drugs. By combining all four drugs, the MIT scientists found that they could stimulate both arms of the immune system, the innate and the adaptive, and eradicate large, immunosuppressive tumors in mouse models of melanoma, lymphoma, and breast cancer.

    The scientists, led by K. Dane Wittrup, Ph.D., and Darrell J. Irvine, Ph.D., published their results October 24 in Nature Medicine, in an article entitled, “Eradication of Large Established Tumors in Mice by Combination Immunotherapy That Engages Innate and Adaptive Immune Responses.” The article noted that only a minority of patients afflicted with metastatic cancer experience dramatic responses to interventions such as checkpoint blockade.

    Presumably, most patients are burdened by tumors that take advantage of complex networks of immunosuppressive pathways. Such tumors are unlikely to be overcome by intervention at a single signaling checkpoint. Consequently, the study’s authors decided to attack established tumors by using the right combination of signals.

    “Maximal antitumor efficacy required four components: a tumor-antigen-targeting antibody, a recombinant interleukin-2 with an extended half-life, anti-PD-1 [programmed cell death 1], and a powerful T cell vaccine,” wrote the authors of the Nature Medicine article. “Depletion experiments revealed that CD8+ T cells, cross-presenting dendritic cells, and several other innate immune cell subsets were required for tumor regression."

    "Effective treatment," the authors continued, "induced infiltration of immune cells and production of inflammatory cytokines in the tumor, enhanced antibody-mediated tumor antigen uptake, and promoted antigen spreading."

    The four-component cancer immunotherapy built on once-separate lines of research, one led by Dr. Wittrup and one by Dr. Irvine. Last year, Dr. Wittrup showed that delivering antibodies and interleukin-2 (IL-2), a signaling molecule that helps to boost immune responses, could halt the growth of aggressive melanoma tumors in mice for as long as the treatment was given. However, this treatment worked much better when the researchers also delivered T cells along with their antibody–IL-2 therapy.

    Around the same time, Dr. Irvine's lab developed a new type of T-cell vaccine that hitches a ride to the lymph nodes by latching on to the protein albumin, found in the bloodstream. Once in the lymph nodes, these vaccines can stimulate production of huge numbers of T cells against the vaccine target.

    After both of those studies came out, Dr. Irvine and Dr. Wittrup decided to see if combining their therapies might produce an even better response.

    "We had this really good lymph-node-targeting vaccine that will drive very strong adaptive immunity, and they had this combination that was recruiting innate immunity very efficiently," Dr. Irvine explained. "We wondered if we could bring these two together and try to generate a more integrated immune response that would bring together all arms of the immune system against the tumor."

    The researchers tested this combination treatment in mice that were implanted with three different types of tumors—melanoma, lymphoma, and breast cancer. These types of engineered tumors are much more difficult to treat than human tumors implanted in mice, because they suppress the immune response against them.

    The researchers found that in all of these strains of mice, about 75% of the tumors were completely eliminated. Furthermore, 6 months later, the researchers injected tumor cells into the same mice and found that their immune systems were able to clear the tumor cells completely. Apparently, the new combination approach helps the immune system to “remember” its target and destroy new cancer cells that appear after the original treatment.

    "To our knowledge, nobody has been able to take tumors that big and cure them with a therapy consisting entirely of injecting biomolecular drugs instead of transplanting T cells," Dr. Wittrup stated.

    Using this approach as a template, researchers could substitute other types of antibodies and vaccines to target different tumors. Another possibility that Dr. Irvine's lab is working on is developing treatments that could be used against tumors even when scientists don't know of a specific vaccine target for that type of tumor.

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