Two-pronged response

MIT advancement in immunotherapy fights cancer in mice

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CAMBRIDGE, Mass.—Between August 1, 2015, and July 31, 2016, the U.S. Food and Drug Administration approved 13 new anticancer therapeutics, including four new immunotherapeutics and four new molecularly targeted agents, according to the AACR Cancer Progress Report 2016. Activation immunotherapies induce or amplify an immune response and are used in vaccines and as cancer immunotherapies, explains Nature Medicine.
An article in the latter (“Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses”) by Kelly D. Moynihan, Cary F. Opel and colleagues, published online in late October, demonstrates how a new advancement from the Massachusetts Institute of Technology (MIT) could bring cancer immunotherapy closer to the fore in oncology therapeutics. Researchers used a combination of four different therapies to activate both of the immune system’s two branches, producing a coordinated attack that led to the complete disappearance of large, aggressive tumors in mice, according to MIT. Potentially allowing the targeting of many types of cancer, the approach may enable the immune system to “remember” the target and destroy new cancer cells that appear after the original treatment.
Because tumor cells usually secrete chemicals that suppress the immune system, it can be difficult for the body to attack tumors on its own. In order to overcome that, scientists have attempted to discover ways to provoke the immune system into action. Most of the efforts have been focused on the innate immune system and the adaptive immune system. The innate system includes nonspecific defenses such as antimicrobial peptides, inflammation-inducing molecules and cells such as macrophages and natural killer cells. Researchers have attempted to enable this system to attack tumors by delivering antibodies that latch onto tumor cells and recruit the other cells and chemicals needed for a successful attack.
“We have shown that with the right combination of signals, the endogenous immune system can routinely overcome large immunosuppressive tumors, which was an unanswered question,” explained Darrell Irvine, a professor of biological engineering and of materials science and engineering and a member of MIT’s Koch Institute for Integrative Cancer Research. Irvine and Dane Wittrup, the Carbon P. Dubbs Professor of Chemical Engineering and Bioengineering and a member of the Koch Institute, are the senior authors of the study
While therapy with antibodies specific for certain kinds of tumors causes “durable tumor regression in metastatic cancer,” these “dramatic responses (programmed cell death) are confined to a minority of patients,” the article said. “This suboptimal outcome is probably due in part to the complex network of immunosuppressive pathways present in advanced tumors, which are unlikely to be overcome by intervention at a single signaling checkpoint.”
Instead, the researchers used “a combination immunotherapy that recruits a variety of innate and adaptive immune cells to eliminate large tumor burdens in syngeneic tumor models and a genetically engineered mouse model of melanoma.” The methodology used four components: a tumor-antigen-targeting antibody, a recombinant interleukin-2 with an extended half-life, anti-PD-1 and a powerful T cell vaccine. The treatment “induced infiltration of immune cells and production of inflammatory cytokines in the tumor, enhanced antibody-mediated tumor antigen uptake and promoted antigen spreading.”
The MIT researchers tested the combination treatment in mice implanted with three different types of tumors: melanoma, lymphoma and breast cancer. Such engineered tumors are harder to treat than human tumors implanted in mice because they suppress the immune response against them. Researchers found that in all of these strains of mice, about 75 percent of the tumors were completely eliminated. When the researchers injected tumor cells into the same mice six months later, they found that their immune systems were able to completely clear the tumor cells.
The research was funded by the Koch Institute support core grant from the National Cancer Institute, the National Institutes of Health, the Bridge Project partnership between the Koch Institute and the Dana-Farber/Harvard Cancer Center, the V Foundation and the Ragon Institute of MGH, MIT and Harvard.

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