Phenotypic Composition of Commercial Anti-CD19 CAR T Cells Affects In Vivo Expansion and Disease Response in Patients with Large B-cell Lymphoma.

PURPOSE: In clinical trials, the expansion and persistence of chimeric antigen receptor (CAR) T cells correlate with therapeutic efficacy. However, properties of CAR T cells that enable their in vivo proliferation have still to be consistently defined and the role of CAR T bag content has never been investigated in a real-life setting. EXPERIMENTAL DESIGN: Residual cells obtained after washing 61 anti-CD19 CAR T product bags were analyzed to identify tisagenlecleucel/Tisa-cel and axicabtagene ciloleucel/Axi-cel phenotypic features associated with postinfusion CAR T-cell in vivo expansion and with response and survival. RESULTS: While Tisa-cel was characterized by a significant enrichment in CAR+CD4+ T cells with central memory (P < 0.005) and effector (P < 0.005) phenotypes and lower rates of CAR+CD8+ with effector memory (P < 0.005) and naïve-like (P < 0.05) phenotypes as compared with Axi-cel, the two products displayed similar expansion kinetics. In vivo CAR T-cell expansion was influenced by the presence of CAR T with a CD8+ T central memory signature (P < 0.005) in both Tisa-cel and Axi-cel infusion products and was positively associated with response and progression-free survival (P < 0.05). CONCLUSIONS: Our data indicate that despite the great heterogeneity of Tisa-cel and Axi-cel products, the differentiation status of the infused cells mediates CAR T-cell in vivo proliferation that is necessary for antitumor response.

Targeting the DNA Damage Response to Increase Anthracycline-Based Chemotherapy Cytotoxicity in T-Cell Lymphoma.

Mature T-cell lymphomas (MTCLs) represent a heterogeneous group of aggressive non-Hodgkin lymphomas comprising different entities. Anthracycline-based regimens are considered the standard of care in the front-line treatment. However, responses to these approaches have been neither adequate nor durable, and new treatment strategies are urgently needed to improve survival. Genomic instability is a common feature of cancer cells and can be caused by aberrations in the DNA damage response (DDR) and DNA repair mechanisms. Consistently, molecules involved in DDR are being targeted to successfully sensitize cancer cells to chemotherapy. Recent studies showed that some hematological malignancies display constitutive DNA damage and intrinsic DDR activation, but these features have not been investigated yet in MTCLs. In this study, we employed a panel of malignant T cell lines, and we report for the first time the characterization of intrinsic DNA damage and basal DDR activation in preclinical models in T-cell lymphoma. Moreover, we report the efficacy of targeting the apical kinase ATM using the inhibitor AZD0156, in combination with standard chemotherapy to promote apoptotic cell death. These findings suggest that DDR is an attractive pathway to be pharmacologically targeted when developing novel therapies and improving MTCL patients' outcomes.