Prognostic impact of peripheral eosinophil counts in patients with diffuse large B-cell lymphoma receiving chimeric antigen receptor T-cell therapy.

BACKGROUND AIMS: Chimeric antigen receptor (CAR) T-cell therapy is a breakthrough treatment for patients with relapsed or refractory diffuse large B-cell lymphoma. However, many patients do not achieve remission or relapse after remission. Previous studies have demonstrated that eosinophils have synergistic anti-tumor effects with CD8+T cells and pre-CAR T-eosinophil counts are associated with the efficacy of CAR T cells. METHODS: We retrospectively analyzed the eosinophil counts of patients with diffuse large B-cell lymphoma and found it changed remarkably pre- and post-CAR T-cell therapy. RESULTS: Patients who achieved complete remission after CAR T-cell infusion had greater post-CAR T-eosinophil counts than those who did not. Kaplan-Meier curves showed that patients with greater eosinophil counts during the second month after CAR T-cell infusion had superior progression-free survival and overall survival compared with those with lower eosinophil counts. CONCLUSIONS: For patients who responded to CAR T-cell therapy, eosinophil counts also can be used to predict 6-month duration of response. In conclusion, the post-CAR T-eosinophil count is associated with the prognosis of patients treated with CAR T-cell therapy and can be used to clinically identify patients who can achieve longer remission after CAR T-cell infusion.

Indicators describing the tumor lesion aggregation and dissemination and their impact on the prognosis of patients with diffuse large B cell lymphoma receiving chimeric antigen receptor T cell therapy.

INTRODUCTION: Chimeric antigen receptor (CAR) T cell therapy has markedly improved the prognosis of patients with diffuse large B-cell lymphoma (DLBCL). The relative positioning of tumor lesions in lymphoma varies among patients, manifesting as either aggregation (clumped together) or dissemination (spread throughout the body). Prognostic significance of factors indicating the relative positioning of tumor lesions in CAR T cell therapy remains underexplored. For aggregation, prior research proposed the tumor volume surface ratio (TVSR), linking it to prognosis in chemotherapy. Regarding dissemination, indicators such as disease stage or extranodal involvement, commonly used in clinical practice, have not demonstrated prognostic significance in CAR T cell therapy. This study aims to analyze current indicators of tumor aggregation or dissemination and introduce a novel indicator to assess the prognostic value of tumor lesions' relative positioning in DLBCL patients undergoing CAR T cell therapy. METHODS: This retrospective study included 42 patients receiving CAR T cell therapy. Lesion image information was obtained from the last PET/CT scan prior to CAR T cell infusion, including total metabolic tumor volume, total tumor surface, diameter of lymphoma masses, and the sites of tumor lesions. We evaluated TVSR and bulky disease as descriptors of tumor aggregation. We refined existing indicators, stage III&IV and >1 site extranodal involvement, to distill a new indicator, termed 'extra stage', to better represent tumor dissemination. The study examined the prognostic significance of tumor aggregation and dissemination. RESULTS: Our findings indicate that TVSR, while prognostically valuable in chemotherapy, lacks practical prognostic value in CAR T cell therapy. Conversely, bulky disease emerged as an optimal prognostic indicator of tumor aggregation. Both bulky disease and extra stage were associated with poor prognosis and exhibiting synergistic prognostic impact in CAR T cell therapy. CONCLUSIONS: Overall, the relative positioning of tumor lesions significantly influences the prognosis of patients with DLBCL receiving CAR T cell therapy. The ideal scenario involves tumors with minimal dissemination and no aggregation.

The DNA damage-independent ATM signalling maintains CBP/DOT1L axis in MLL rearranged acute myeloid leukaemia.

The long-term maintenance of leukaemia stem cells (LSCs) is responsible for the high degree of malignancy in MLL (mixed-lineage leukaemia) rearranged acute myeloid leukaemia (AML). The DNA damage response (DDR) and DOT1L/H3K79me pathways are required to maintain LSCs in MLLr-AML, but little is known about their interplay. This study revealed that the DDR enzyme ATM regulates the maintenance of LSCs in MLLr-AML with a sequential protein-posttranslational-modification manner via CBP-DOT1L. We identified the phosphorylation of CBP by ATM, which confers the stability of CBP by preventing its proteasomal degradation, and characterised the acetylation of DOT1L by CBP, which mediates the high level of H3K79me2 for the expression of leukaemia genes in MLLr-AML. In addition, we revealed that the regulation of CBP-DOT1L axis in MLLr-AML by ATM was independent of DNA damage activation. Our findings provide insight into the signalling pathways involoved in MLLr-AML and broaden the understanding of the role of DDR enzymes beyond processing DNA damage, as well as identigying them as potent cancer targets.

Challenges and optimal strategies of CAR T therapy for hematological malignancies.

ABSTRACT: Remarkable improvement relative to traditional approaches in the treatment of hematological malignancies by chimeric antigen receptor (CAR) T-cell therapy has promoted sequential approvals of eight commercial CAR T products within last 5 years. Although CAR T cells' productization is now rapidly boosting their extensive clinical application in real-world patients, the limitation of their clinical efficacy and related toxicities inspire further optimization of CAR structure and substantial development of innovative trials in various scenarios. Herein, we first summarized the current status and major progress in CAR T therapy for hematological malignancies, then described crucial factors which possibly compromise the clinical efficacies of CAR T cells, such as CAR T cell exhaustion and loss of antigen, and finally, we discussed the potential optimization strategies to tackle the challenges in the field of CAR T therapy.