A distinct population of CAR T cells could help predict whether products containing fewer cells than intended will still produce a therapeutic response, according to a new study.
Researchers from the Berlin Institute of Health (BIH) identified the absolute number of CD27-negative, CD39-negative CAR T cells in an infusion product as a potential biomarker of response at low doses. The findings could inform decisions about whether to administer products that do not meet their target cell count.
CAR T manufacturing does not always produce the intended dose. The researchers cite failure rates of 1–13 percent due to insufficient cell numbers, which can leave patients unable to receive treatment or require clinicians to consider using an out-of-specification product.
The study analyzed CAR T products and the corresponding leukapheresis starting materials from 28 patients enrolled in the phase I/II HD-CAR-1 trial. Participants with relapsed or refractory B-cell malignancies received third-generation CD19-directed CAR T cells at doses ranging from one million to 200 million cells per square meter of body surface area.
Low-dose responders had higher numbers of functional effector and effector memory-like CAR T cells. These cells lacked the surface markers CD27 and CD39 and demonstrated high tumor-cell killing activity in functional experiments.
“The greater the number of these specific CAR T cells, the more effective the therapy was, even when the overall number of cells was relatively low,” said senior author Michael Schmitt in a press release. “Our findings suggest that the absolute number of these highly functional cells could serve as a biomarker for predicting the success of low-dose CAR T-cell therapy.”
The researchers tested the association in an independent cohort of 42 patients treated with four commercial CD19- or BCMA-directed therapies for B-cell non-Hodgkin lymphoma or multiple myeloma. Early post-infusion samples were available from 29 patients. Higher numbers of CD27-negative, CD39-negative CAR T cells were again associated with response, although legal restrictions meant the researchers could not test the commercial infusion products directly.
Analysis of the starting material also linked treatment outcomes to the patient’s immune-cell profile before manufacturing. T-cell-rich samples containing supportive myeloid-cell states were more likely to produce functional CAR T cells. Regulatory myeloid signals were associated with dysfunctional products and treatment failure.
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