The advent of chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment landscape of refractory B-cell malignancies. Real-world evidence has highlighted the high incidence of hematological toxicity, including prolonged and profound cytopenia. In a collaboration with the Neal Young lab (NIH, NHLBI), the Subklewe group leveraged single-cell technologies to dissect a case of bone marrow (BM) failure in a 57-year old man with DLBCL-type Richter transformation receiving tisagenlecleucel in a standard-of-care setting. His clinical course was notable for underlying BM infiltration, severe cytokine release syndrome, and multiple infectious complications in the setting of prolonged, profound neutropenia. Cytokine profiling revealed a signature consistent with acquired aplastic anemia – including downregulation of CD40-L and EGF. Flow cytometric analyses demonstrated migration of CAR T-cells to the BM, as well as peripheral blood expansion of both CAR and non-CAR bearing CD8+CD57+ T-cells, an immunophenotype linked to oligoclonality in aplastic anemia. From single-cell level transcriptomics, this cytotoxic T-cell population was characterized by T-cell receptor Vβ oligoclonal expansion and post-CAR clonal drift. Gene expression profiling revealed upregulation of exhaustion markers on (CAR) T-cells and decreased expression of genes involved in STAT signalling and inflammatory response. Kai Rejeski, the lead author of the publication, notes that these data “highlight the complex nature of CAR-T-related hematological toxicity and introduce oligoclonal (CAR) T-cell expansion as a potential contributing pathophysiologic mechanism.” The clinician-scientist notes that future work will “focus on elucidating the relationship between host hematopoiesis and clinical outcomes after CAR T-cell therapy.”
Oligoclonal T-cell expansion in a patient with bone marrow failure after CD19 CAR-T for Richter transformed DLBCL.
Rejeski K, Wu Z, Blumenberg V, Kunz WG, Mueller S, Kajigaya S, Gao S, Buecklein V, Frölich L, Schmidt C, von Bergwelt-Baildon M, Feng X, Young NS, Subklewe M.
Blood. 2022 Jul 1:blood.2022017015. doi: 10.1182/blood.2022017015