Oligoclonal T-cell expansion in a patient with bone marrow failure after CD19 CAR-T therapy for Richter-transformed DLBCL

Abstract

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. Here, we present 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. In conclusion, this case highlights the complex nature of CAR-T-related hematological toxicity and introduces oligoclonal (CAR) T-cell expansion as a potential contributing pathophysiologic mechanism.

Recent revelations and future directions using single-cell technologies in chronic lymphocytic leukemia

“…In fact, a recent study focusing on stereotyped subset #2 and #169 (a satellite subset to subset #2) demonstrated shared SHM patterns in both subsets at either clonal or subclonal level, reflecting ongoing intraclonal diversification compatible with a branched evolution ( 98 ). The recently developed strategy to combine immunomics ( 99 ) with global transcriptomics in individual cells, allows for B cell and/or T cell clonotypes to be linked to gene expression signatures ( 100 ). Collectively, these technologies facilitate in-depth analysis of immunogenetic features (e.g., ongoing SHM and class-switching) at single-cell level and the discovery of clone-specific phenotypes, which may in turn expedite the identification of therapeutic targets and resistance markers.…”

Current and Future Perspectives for Chimeric Antigen Receptor T Cells Development in Poland

“…Therefore, the composition of CAR-T cells’ preparation infused into patients possibly affects the efficiency of the therapy and only the products of precise cellular composition can provide uniform potency [ 30 ]. A case study by Rejeski et al [ 31 ] showed that different subpopulations of CAR-T cells not only have different biological functions but also show distinct differentiation patterns. In the presented study, the phenotype of CD4(+) CAR-T cells shifted from central memory to effector type, while CD8(+) CAR-T cells’ phenotype changed from effector memory to terminal effector cells.…”

“…In the presented study, the phenotype of CD4(+) CAR-T cells shifted from central memory to effector type, while CD8(+) CAR-T cells’ phenotype changed from effector memory to terminal effector cells. Yet, at the same time, both subpopulations of CAR-T cells underwent equivalent clonal expansion [ 31 ].…”

Identifying Early Infections in the Setting of CRS With Routine and Exploratory Serum Proteomics and the HT10 Score Following CD19 CAR-T for Relapsed/Refractory B-NHL

“…[9][10][11] Real-world evidence has further emphasized the importance of hematological toxicity as the most common high-grade toxicity of CAR-T therapy, which can present both as a syndrome of profound bone marrow aplasia, 12 or as prolonged cytopenia. [13][14][15][16][17][18] An additional expected on-target/off-tumor side effect of CD19-directed CAR-T is B-cell aplasia and hypogammaglobulinemia. 19 The combination of cellular and humoral immunodeficiency translates into a predisposition for infectious complications, which substantially contribute to the toxicity burden and drive nonrelapse mortality.…”