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Jeremy S. Abramson, MD, MMSc
Jeremy S. Abramson, MD, MMSc
Posted: Tuesday, January 21, 2025
Chimeric antigen receptor (CAR) T-cell therapy typically yields an 80% or greater complete response rate in pediatric patients with lymphoid leukemia; however, this treatment produces rates of only 30% or less in patients with chronic lymphocytic leukemia (CLL). A presentation at the 2024 American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract 2051) provided evidence on the impact of immunosenescence on CAR T-cell therapy in patients with CLL to assess the impact of aging on this treatment. Joseph A. Fraietta, PhD, of the University of Pennsylvania, Perelman School of Medicine, Philadelphia, and colleagues conducted immunophenotyping assays and chronic antigen stress tests; they found that CAR T cells derived from treatment-naive patients exhibited a decrease in co-stimulatory receptors CD27 and CD28 expression with heightened levels of senescence markers.
Included in the study were 19CAR-BBz T cells generated from 11 treatment-naive patients with CLL. Patients were age- and gender-matched with healthy controls and had a median age of 67. Immunophenotyping was performed using flow cytometric panels, which included 25 markers. Additionally, every 5 days, chronic antigen stress tests were conducted, wherein 1E6 CAR T cells were counted, phenotyped, and stimulated with fresh CD19-expressing K562 cells at a 1:1 ratio. Cytokine analyses were then conducted on the supernatant collected 24 hours after coculture.
Overall findings revealed heightened levels of senescence markers p16, p21, p53, β-galactosidase, and γ-H2AX in treatment-naive patients and a decrease in expression in co-stimulatory receptors CD27 and CD28. Additionally, a random forest prediction model revealed that CD28 was instrumental in predicting CLL from controls. Although the proliferative capacity of patient-derived CAR T cells was attenuated, according to the investigators, CLL-derived CAR T cells showed signatures of inflammaging (low-grade inflammation that occurs as people age), such as increased expression of granzyme A and B as well as perforin and production of proinflammatory factors.
Disclosure: For full disclosures of the study authors, visit ash.com.
2024 ASH Annual Meeting & Exposition
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