Chimeric Antigen Receptor Cancer Therapies Can Now Target Solid Tumors

If the research community is to win in the fight to cure cancer, and win soon enough to matter for all of us, then the focus must be on technology platforms that can be easily and cheaply adapted to many different types of cancer. The biggest strategic problem in the field is that most of the expensive, time-consuming efforts to develop new therapies are only applicable to one or a few of the hundreds of types of cancer. Immunotherapies based on the use of chimeric antigen receptors are an incremental step towards solving this problem, an improvement on the present situation because this technology may cut the cost of tailoring an immunotherapy to each specific type of cancer. This approach has worked very well in trials targeting leukemia, but there was some question as to how to adapt it for use in solid tumors, and whether it would work in this context. Fortunately, it seems that this next step forward has now been accomplished, at least in a preliminary animal study:

Chimeric antigen receptor (CAR) T cell therapy, which edits a cancer patient's T cells to recognize their tumors, has successfully helped patients with aggressive blood cancers but has yet to show the ability to treat solid tumors. To overcome this hurdle, researchers genetically engineered human T cells to produce a CAR protein that recognizes a glycopeptide found on various cancer cells but not normal cells, and then demonstrated its effectiveness in mice with leukemia and pancreatic cancer. "This is the first approach using a patient's own immune cells that can specifically target this class of cancer-specific glycoantigens, and this has the great advantage of applicability to a broad range of cancers. Future cancer immunotherapies combining the targeting of cancer-specific carbohydrates and cancer proteins may lead to the development of incredibly effective and safe new therapies for patients."

T cells are collected from the patient's blood and genetically engineered to express cell-surface proteins called CARs, which recognize specific molecules found on the surface of cancer cells. The modified T cells are then infused into the patient's bloodstream, where they target and kill cancer cells. In recent clinical trials, CAR T cell therapy has dramatically improved the outcomes of blood cancer patients with advanced, otherwise untreatable forms of leukemia and lymphoma. But the full potential of CARs for treating solid tumors has not been reached because they have targeted molecules found on the surface of both normal cells and cancer cells, resulting in serious side effects.

The cancer cell marker the team identified was a specific change in protein glycosylation, that is, a unique pattern of sugars decorating a protein found on the cell surface. The researchers developed novel CAR T cells that express a monoclonal antibody called 5E5, which specifically recognizes a sugar modification - the Tn glycan on the mucin 1 (MUC1) protein - that is absent on normal cells but abundant specifically on cancer cells. The 5E5 antibody recognized multiple types of cancer cells, including leukemia, ovarian, breast, and pancreatic cancer cells, but not normal tissues. "This is really the first description of a CAR that can target multiple different solid or liquid tumors, without apparent toxicity to normal cells. While it may not be a universal CAR, it is currently the closest thing we have." Moreover, injection of 5E5 CAR T cells into mice with leukemia or pancreatic cancer reduced tumor growth and increased survival. All six mice with pancreatic cancer were still alive at the end of the experiment, 113 days after treatment with 5E5 CAR T cells. Meanwhile, only one-third of those treated with CAR T cells that did not target Tn-MUC1 survived until the end of the experiment.



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