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April 25, 2017

Anticancer T Cells Occupy Biopolymer Camp Sites in the Solid Tumor Wild

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    The scaffold in this illustration is loaded with CAR T cells and microspheres containing nutrients to help the cells multiply and, subsequently, venture outside to attack cancer cells. Such scaffolds may improve the effectiveness of CAR T-cell therapy in solid tumors and help protect against the emergence of escape variants. [Cognition Studio, courtesy of Fred Hutchinson Cancer Research Center]

    Merely injecting anticancer T cells into the body is like dropping Survivorman into the wilderness, leaving him stranded and hoping that he can cope with whatever dangers come his way. T cells, however, are not as hardy as Survivorman. In fact, they are downright finicky. If they find themselves in an environment that lacks the right nutrients and means of eliminating wastes, they die within a couple of days. Also, they may surrender all hope, and stop working, if they are exposed to the self-defense chemicals released by tumors.

    Perhaps T cells are more like campers than survivalists. They may need a home away from home—a cushy base that is stocked not only with goodies, but various kinds of supportive and protective equipment. A cushy base for T cells has in fact been developed and tested by scientists based at the Fred Hutchinson Cancer Research Center. These scientists, led by Matthias Stephan, M.D., Ph.D., have created a sticky, spongy, dissolvable biopolymer scaffold. It can be made into just about any size or shape. It is porous. And it is loaded with proteins that keep T cells healthy and enable them to rapidly grow and venture into a tumor—and leave devastation in their wake. Sort of like environmentally unfriendly campers.

    Not only does the biopolymer scaffold unleash T cells equipped with chimeric antigen receptors (CARs), it also puts out a substance known as STING, or stimulator of interferon genes, agonist, which ramps up the immune response to go after nearby cancer cells that aren’t recognized by CAR T cells.

    Details about the biopolymer scaffold appeared April 24 in The Journal of Clinical Investigation, in an article entitled, “Biopolymers Codelivering Engineered T Cells and STING Agonists Can Eliminate Heterogeneous Tumors.” This article describes how the Fred Hutch team, in collaboration with MIT scientists, tested implantable biopolymer devices that deliver CAR T cells directly to the surfaces of solid tumors. These devices exposed tumors to high concentrations of immune cells “for a substantial time period.”

    “In immunocompetent orthotopic mouse models of pancreatic cancer and melanoma, we found that CAR T cells can migrate from biopolymer scaffolds and eradicate tumors more effectively than does systemic delivery of the same cells,” wrote the article’s authors. “We have also demonstrated that codelivery of stimulator of IFN genes (STING) agonists stimulates immune responses to eliminate tumor cells that are not recognized by the adoptively transferred lymphocytes.”

    When placed on the tumors of mice, the scaffolds sway the tumor milieu from suppressive to permissive and effectively control disease progression in the majority of treated animals, noted Dr. Stephan.

    "The key to our scaffold is that it's not just a structure," he continued. "The components we've engineered into these scaffolds include an optimal mix of stimulating factors and other ingredients that allow the T cells to survive and proliferate and to maintain a sustained fight against cancerous cells."

    The technology is a long way from being ready for patients. The next step is for it to go through clinical trials, and Stephan is looking for an industry collaborator to develop and commercialize the technology. Then it would need to go through Food and Drug Administration approval.

    But if it succeeds in those steps, Dr. Stephan envisions that genetic profiling of a patient's tumor tissue would reveal the protein makeup of the tumor. Then, a scaffold would be created from a mix of T cells and other ingredients designed to target the variety of tumor proteins in the patient's particular tumor. The scaffold itself would dissolve after about a week, so it would not need to be removed in another surgical procedure.

    Since CAR T cells are engineered to divide and grow to keep the anticancer fight going, it's possible that patients wouldn't need much more treatment after the scaffold is implanted.

    "It's like lighting a spark at the site of the tumor," Dr. Stephan said. By putting CAR T cells on the tumor, they create that initial flicker and grow and attack tumor right away. Then the immune boost provided by the other substances in the scaffold adds fuel to the growing fire. This second wave of fighting against the tumor develops slower than the initial spark, but it maintains the blaze.

    This analogy turns Smokey Bear’s favorite line—"Only you can prevent forest fires"—on its head. It may be that in immuno-oncology, only pampered T cells will be able to fan the flames of a raging antitumor immune response.

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