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T cells artificially endowed with 2 cancer-seeking receptors aim to be an elite army of cancer killers

Despite high remission rates for patients treated with T cells that are supercharged in laboratories into elite cancer warriors, there is still a considerable population of patients who eventually relapse, their cancers invariably coming back.

It is estimated that CAR T cell therapy—a breakthrough form of cancer immunotherapy—has a 30 percent to 40 percent rate of success for durable remission. That means a significant number of patients aren't quite as lucky. To improve the odds, medical scientists in laboratories worldwide are searching for ways to make CAR T cell cancer therapy work more effectively.

CAR T cells—chimeric antigen receptor T cells—start out as the patients' own T cells isolated from a blood sample, but the cells are primed in a laboratory using a genetic modification process that causes T cells to express a cancer-seeking-and-destroying receptor on their surface.

That special receptor is known as the chimeric antigen receptor, or CAR, engineered to bind to a specific target— the cancer's antigen—a molecular complex known as CD19. Cancer cell destruction can be swift—indeed, so much so that the therapy has been known to quickly force some cancers into remission. CAR T cell therapy is used in the treatment of certain cancers of the blood, primarily acute lymphoblastic leukemia, B-cell lymphoma, follicular lymphoma and multiple myeloma.

CAR T cells' population is expanded into a formidable army before being transfused into the patient. A lab grows millions of altered T cells before shipping them back to the patient's hospital. Once returned, the modified T cells are stronger, bolder and cancer-seeking. Bearing the chimeric antigen receptor allows these T cells to hunt down and destroy cancer cells. Because they seek and destroy malignant cells around the clock, some doctors have referred to CAR T cell therapy as "a living drug."

Immunotherapy with chimeric antigen receptor cells has emerged as a promising therapeutic tool against cancer. Even though the therapy works best in hematological cancers, it is not recommended for all forms of these malignancies. The approach remains under study as a form of treatment for solid tumors, which don't have as high a response rate to CAR T cells as cancers of the blood, although emerging clinical studies hint at eventual success.

Most relapses occur either because the CAR T cells don't persist long enough after transfusion, according to the  researchers, or because the CAR T cells struggle to recognize cancer cells that harbor fewer antigens to target. T cell exhaustion and reduced persistence are other major factors limiting the efficacy of CAR T cell.

Now researchers  are embarking on a novel approach that involves attaching not one, but two engineered receptors to T cells.  Their aim is solve one of the biggest problems in CAR T cell cancer therapy: It doesn't work for everyone. Cancers rebound in what the scientists describe as a considerable proportion of patients. The researchers theorizes that a dual-receptor strategy can increase the effectiveness of this form of immunotherapy and lower the rate of treatment failures.

The scientists posit that T cells wielding two receptors can double the capability of CAR T cells to fight cancer. Using a dual strategy additionally enhances the persistence of CAR T cells in the blood. It is therefore hoped that this new breed of CAR T cells can track down stealthy malignant cells that elude traditional single-receptor CAR T cells. Having two receptors diminishes the possibility of cancer cells seeding a re-emergence, sending patients into a relapse, scientists say.

They  tested dual-receptor T cells in laboratory dishes and in an animal model. The cells' performance suggests that this type of modification could address the twin challenges of poor CAR T cell longevity and ineffectiveness against low-antigen density, which prevent the altered cells from working for many patients. Key to the research were the two types of receptors introduced to T cells. One was the traditional chimeric antigen receptor  and the other a chimeric costimulatory receptor, or CCR.

Compared with traditional CAR T cells, the CAR-CCR T cell combination was more sensitive "to low-antigen multiple myeloma and leukemia cells in culture," the scientists reported in their research. The new dual receptor T cells also expanded and persisted longer in mouse models of multiple myeloma and low-antigen leukemia, which extended survival times and delayed cancer progression, the researchers found.

Scientists hope the early research involving dual-receptor T cells lays the groundwork for a new way to deliver the therapy.

Afroditi Katsarou et al, Combining a CAR and a chimeric costimulatory receptor enhances T cell sensitivity to low antigen density and promotes persistence, Science Translational Medicine (2021). DOI: 10.1126/scitranslmed.abh1962

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