An Approach to Deliver Chimeric Antigen Receptor T Cells to Solid Tumors

The approaches to cancer therapies that we should pay attention to are those capable of targeting many different types of cancer. The only practical way to meaningfully accelerate progress towards robust control of cancer as a whole is for the research community to prioritize treatments that have a much broader impact for a given investment in development. Chimeric antigen receptor (CAR) methods, in which T cells are engineered to direct their attention towards markers that identify cancer cells, can plausibly be adapted to many different cancers with minimal cost. Given that, they are a step in the right direction towards making cancer research cost-effective. So far CAR T cells have proven effective against various leukemias, but adapting this form of immunotherapy to the much larger range of cancers that form solid tumors has been a challenge. Here, researchers outline one possible way forward:

Cellular immunotherapy is beginning to bring new hope to patients with certain blood cancers. Tumors that form solid masses, such as breast and pancreatic cancer, are the next frontier for the strategy - but scientists are still grappling with how to overcome the unique challenges large clusters of tumor cells present to engineered immune cells. Researchers have now shown that a dissolving biopolymer sponge packed with therapeutic ingredients can shrink tumors and extend survival in laboratory models of cancer. Loaded with engineered immune cells, molecules that help stimulate those cells' ability to eliminate cancer, and a special ingredient that recruits a patient's own immune cells for a second round of anti-cancer attacks, the spongey, lattice-like scaffold offers a new strategy for tackling genetically variable and crowded masses of tumor cells.

Cellular immunotherapies currently being tested - and showing promise - in clinical trials are delivered intravenously. This can work well in some patients with blood cancers like leukemia, as the engineered cells fan out to hunt down cancer cells circulating in the blood (or residing in the bone marrow). But because solid tumors like breast cancer present millions upon millions of diseased cells all packed together, they require a concentrated effort. Merely injecting a solution of T cells onto a tumor would result in most of them seeping away without a chance to get a toehold in the tumor. The new approach is to concentrate engineered immune cells known as CAR T cells directly at the site of the tumor using the scaffold. A T cell is a specialized type of immune cell capable of recognizing and eliminating diseased cells. Researchers genetically engineer T cells with a scientist-designed chimeric antigen receptor, or CAR, that gives them the ability to "see" cancer cells with specific targets on their surface.

The biopolymer sponge, which lasts for about a week before dissolving harmlessly in the body, gives the CAR T cells a comfortable home base and retains them right where they're needed. The synthetic T-cell headquarters is well-stocked with molecules that help energize the T cells. Because tumors release a number of molecules that switch T cells to a lethargic state, the immune boosters are necessary to ensure that the scaffold-delivered T cells are on high alert for cancer cells and ready to pounce as they exit the implant. When the researchers tested their strategy in a mouse model of pancreatic cancer, they found that CAR T cells delivered with immune-boosting nourishment via the scaffold multiplied their numbers and responded robustly to the cancer: The animals' tumors shrank. In contrast, CAR T cells that were injected into tumors (without activating molecules to support their attack) didn't expand their numbers and reacted anemically in the face of millions of tumor cells.



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