Quality Over Quantity: New Insights into the Role of Certain CAR-T Cells in Cancer Therapy

Immunotherapies strengthen patients’ own immune response to cancer, in some cases with a high degree of specificity. For example, in therapies using so-called CAR-T cells (chimeric antigen receptor T cells), certain immune cells from the patient are genetically modified and “targeted” at the individual cancer cells. Until now, it was not understood why low-dose CAR-T cell therapy is successful in some patients, while others do not benefit from it. A research consortium based at Medical Clinic V of Heidelberg University Hospital and at the Berlin Institute of Health at Charité (BIH) has now identified key biological factors that influence the effectiveness of CAR-T cell therapy using smaller numbers of cells. These findings could help improve treatment outcomes for individual patients, further personalize cancer therapies, and reduce treatment costs.

CAR-T cell therapies can be used to treat certain advanced forms of blood and lymph node cancers when other treatments, such as chemotherapy or radiation, have failed or in cases of disease recurrence. For this therapy, the body’s own immune cells are genetically modified in the laboratory so that they can recognize a target structure on the surface of cancer cells, specifically attack them, and kill them. In many patients, no cancer is detectable for an extended period after CAR-T cell therapy. The production and expansion of these therapeutic immune cells is complex and time-consuming—and it is not always possible to produce the largest possible number of cells required for treatment. Patients then either receive therapy with uncertain prospects of success—which may involve accepting potentially severe side effects—or the CAR-T cells produced are not used at all due to the small quantity available.

Highly Functional CAR-T Cells Determine Treatment Success

The study, now published in "Nature Communications", is based on data and samples from the HD-CAR-1 trial, which was conducted by researchers at Heidelberg University’s Faculty of Medicine, the German Cancer Research Center (DKFZ), and the National Center for Tumor Diseases (NCT) in Heidelberg. The scientists analyzed both the original blood samples from patients with malignant blood cancers and the CAR-T cell products derived from these blood samples. Using high-resolution single-cell analyses, they examined, among other things, the composition of the CAR-T cell products—which varied in dosage across the respective therapies—and analyzed which types of immune cells they contained and how active these cells were. They then compared these results between patients who responded to treatment and those who did not.

The researchers identified a subgroup of CAR-T cells whose number was directly linked to the success of low-dose therapies. These cells are characterized by a molecular profile that makes them particularly effective at killing tumor cells, as well as the absence of two specific surface markers that make them detectable. “The more of these specific CAR-T cells were present, the more effective the therapy was—even when the total number of all cells was relatively low,” says DKTK researcher Michael Schmitt, Professor of “Cellular Immunotherapy” at Heidelberg University’s Faculty of Medicine, Head of the Cell and Immunotherapy Research Unit at the Department of Hematology, Oncology, and Rheumatology at Heidelberg University Hospital (UKHD), and one of the two corresponding authors of the study. “Our results suggest that the absolute number of these highly functional cells could serve as a biomarker for the success of low-dose CAR-T cell therapy.”

“We have also shown that treatment success does not depend solely on the CAR-T cells. Another crucial factor is the state of the patients’ immune systems before cell production begins,” adds Professor Dr. Simon Haas. He conducts research at the Center of Genomic Medicine at the Berlin Institute of Health at Charité, the Max Delbrück Center for Molecular Medicine in Berlin, and Queen Mary University of London (England), and is the last author of the study together with Professor Schmitt. “In patients whose blood contained larger quantities of functional immune cells, it was more likely that effective CAR-T cell products could be produced.” If, on the other hand, the baseline blood sample contained a high proportion of cells that suppress the immune response, fewer highly functional CAR-T cells were generated—and the patients were less likely to respond to the therapy. “Our analyses show that clues as to how well the CAR-T cells produced later will function can already be found in the baseline blood,” summarizes Schayan Yousefian, a doctoral student in Professor Haas’s group and the study’s first author.

New Approaches for Personalized CAR-T Cell Therapies

According to the study authors, the results represent an important step toward further personalized cancer immunotherapies. “Further research is needed to better understand the underlying mechanisms, validate the biomarker, and integrate it into routine care in the long term,” said Professor Schmitt. Among other things, it is necessary to determine the minimum number of highly functional CAR-T cells required for a therapy to be promising.

Professor Haas added that the findings also have implications for health policy and health economics. CAR-T therapies can cost several hundred thousand euros per patient treated. “If our findings are confirmed in further studies, CAR-T cells could be produced in a much more targeted manner in the future. This would not only benefit patients but also conserve resources.”

SOURCE: UKHD

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