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Blood
W.B. Saunders Co., etc.]
Blood

W.B. Saunders Co., etc.]

0006-4971

Blood/Journal BloodSCIISTPAHCI
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    CD7 CAR: sword and shield

    Velasquez M.PMamonkin M
    2页
    查看更多>>摘要：In this issue of Blood, Lu et al1 describe a novel approach for generating autologous CD7-specific chimeric antigen receptor (CAR) T cells from peripheral blood T cells that can naturally overcome CD7-directed fratricide; these T cells could be useful for treating patients with T-lineage malignancies. Expression of a CD7 CAR in T cells promotes sequestration of the available CD7 antigen, resulting in an expansion of naturally selected fratricide-resistant CD7 CAR T cells. The authors report that these CD7 CAR T cells were well tolerated in 20 patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) or T-cell acute lymphoblastic lymphoma (T-LBL) and induced complete remission (CR) in most of them.
      原文链接:
    • NSTL
    • Amer Soc Hematology

    Uncovering CD4+ T-cell exhaustion in B-ALL

    Gerdemann UAlvarez-Calderon F
    3页
    查看更多>>摘要：In this issue of Blood, Tracy et al~1 describe a key subset of exhausted CD4~~+ T cells in Philadelphia chromosome positive (Ph~+) B-cell acute lymphoblastic leukemia (B-ALL) that modulates antileukemic effects. The authors use a nonirradiated immunocompetent murine model of Ph~+ B-ALL and primary patient samples to dissect the CD4 T-cell immune response and to provide a rationale for combination therapies of tyrosine kinase inhibitors that target the BCR-ABL oncoprotein and programmed death-ligandl (PD-L1) blockade to reverse the exhausted state of CD4~+ T cells and enhance the clearance of leukemia.
      原文链接:
    • NSTL
    • Amer Soc Hematology

    German CARs keeping pace

    Darnell E.PJacobson C.A
    3页
    查看更多>>摘要：In this issue of Blood, Bethge et al~1 present findings from the analysis of 356 patients treated with axicabtagene ciloleucel (axi-cel) or tisagenledeucel (tisa-cel) chimeric antigen receptor (CAR) T-cell therapy for large B-cell lymphoma (LBCL) in a non-trial setting in 21 centers throughout Germany with a median follow-up of 11 months. While corroborating the excellent results of these therapies in a real-world setting with an overall response rate (ORR) of 65% and 12-month overall survival (OS) of 52%, they also add important insights into this growing standard-of-care literature. Their analysis is the first to report response to, rather than use of, bridging therapy as a predictor of outcome. Additionally, they report an adjusted 12-month nonrelapse mortality (NRM) of 5.5% in all patients, most occurring late (67%) and due to infection (62%). While their analysis invites a comparison between axi-cel and tisa-cel, differences between the patients being selected for, and the sites offering, each product result in biases that should preclude such a comparison.
      原文链接:
    • NSTL
    • Amer Soc Hematology

    The 2 faces of ERK2 in MPNs

    Havelange VConstantinescu S.N
    3页
    查看更多>>摘要：In this issue of Blood, Zhang et al~1 reported that extracellular signal-regulated kinase 2 (ERK2) substrate-binding domains have opposing roles in Janus kinase 2 V617F (JAK2V617F)-driven myeloproliferative neoplasms (MPNs). One of the domains, ERK2-docking (ERK2-D), may be a promising therapeutic target for MPNs. Conversely, the other domain, ERK2-DEF-binding pocket (ERK2-DBP), blocks progression of the disease in a mouse model. This changes the perception that simply inhibiting the catalytic activity of ERK1/2 in MPNs would be an effective therapeutic strategy.
      原文链接:
    • NSTL
    • Amer Soc Hematology

    Fibrinolysis without intracranial hemorrhage

    Nimjee S.M
    3页
    查看更多>>摘要：In this issue of Blood, Goncalves et al1 demonstrate that targeting phosphorylation of ocdudin in the endothelium of the cerebrovasculature significantly reduces the risk of intracranial hemorrhage (ICH) after treatment with recombinant tissue plasminogen activator (rtPA) for acute ischemic stroke (AIS). Intravenous administration of rtPA improves the functional outcome of patients who present at any time up to 4.5 hours after suffering an AIS.2'3 Unfortunately, a significant number of patients who receive rtPA develop a hemorrhagic conversion of their ischemic stroke that presents as an ICH. This complication of treatment with rtPA limits its use, with less than 10% of the AIS population receiving treatment. Mitigating the risk of ICH associated with intravenous fibrinolysis can provide increased safety to patients who present with AIS. It may also expand the inclusion criteria for fibrinolysis so that more patients presenting with AIS can receive rtPA therapy.
      原文链接:
    • NSTL
    • Amer Soc Hematology

    The antibody-drug conjugate loncastuximab tesirine for the treatment of diffuse large B-cell lymphoma

    Calabretta EHamadani MZinzani P.LCaimi P...
    6页
    查看更多>>摘要：Diffuse large B-cell lymphoma (DLBCL) is a heterogenous subtype of non-Hodgkin lymphoma. Relapsed/refractory disease represents remains an unmet medical need, despite the introduction of novel cellular and targeted therapies. Loncastuximab tesirine is a cluster of differentiation19-targeting antibody-drug conjugate approved by the US Food and Drug Administration for relapsed DLBCL after 2 lines of systemic therapy based on a trial showing a 48.3% overall response rate. The spectrum of its clinical applications is expanding and is now being tested in other B-cell malignancies. ? 2022 American Society of Hematology
      原文链接:
    • NSTL
    • Amer Soc Hematology

    Specification of hematopoietic stem cells in mammalian embryos: a rare or frequent event?

    Ganuza MClements WMcKinney-Freeman S
    12页
    查看更多>>摘要：Hematopoietic stem cells (HSCs) are the blood-forming stem cells thought to be responsible for supporting the blood system throughout life. Transplantability has long been the flagship assay used to define and characterize HSCs throughout ontogeny. However, it has recently become clear that many cells emerge during ontogeny that lack transplantability yet nevertheless are fated to ultimately contribute to the adult HSC pool. Here, we explore recent advances in understanding the numbers and kinetics of cells that emerge during development to support lifelong hematopoiesis; these advances are made possible by new technologies allowing interrogation of lifelong blood potential without embryo perturbation or transplantation. Illuminating the dynamics of these cells during normal development informs efforts to better understand the origins of hematologic disease and engineer HSCs from differentiating pluripotent stem cells. ? 2022 American Society of Hematology
      原文链接:
    • NSTL
    • Amer Soc Hematology

    Naturally selected CD7 CAR-T therapy without genetic manipulations for T-ALL/LBL: first-in-human phase 1 clinical trial

    Lu PLiu YYang JZhang X...
    14页
    查看更多>>摘要：Derivation of CD7-targeted chimeric antigen receptor (7CAR) T cells often requires genetic manipulations to ablate the CD7 gene or block CD7 cell surface expression. Our novel approach deriving naturally selected 7CAR (NS7CAR) T cells from bulk T cells was able to overcome major fratricide by minimizing accessible CD7 epitopes. The CD7 molecules of NS7CAR T cells were masked or sequestered by the CD7-targeting CAR. Compared with sorted CD7-negative 7CAR T cells and CD7 knocked-out 7CAR T cells, NS7CAR exhibited similar or superior therapeutic properties, including a greater percentage of CAR+ cells and a higher proportion of CD8+ central memory T cells. In our first-in-human phase 1 trial (NCT04572308), 20 patients with relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL) (n = 14) and T-cell lymphoblastic lymphoma (T-LBL) (n = 6) were treated with NS7CAR. Nineteen patients achieved minimal residual disease negative complete remission (CR) in the bone marrow (BM) by day 28, and 5 of 9 patients achieved extramedullary CR. With a median follow-up of 142.5 (32-311) days after infusion, 14 patients subsequently received allogeneic hematopoietic stem cell transplant (10 consolidative, 4 salvage) following NS7CAR infusion with no relapses to date. Of the 6 patients who did not receive a transplant, 4 remained in CR at a median time of 54 (32-180) days. Eighteen patients experienced mild cytokine release syndrome (CRS) (grade ≤2), 1 developed grade 3 CRS, and 2 had grade 1 neurotoxicity. These results indicate that NS7CAR-T therapy is a safe and highly effective treatment for T-ALL/LBL. More patients and longer follow-up are needed for validation. ? 2022 American Society of Hematology
      原文链接:
    • NSTL
    • Amer Soc Hematology

    Combining nilotinib and PD-L1 blockade reverses CD4+ T-cell dysfunction and prevents relapse in acute B-cell leukemia

    Tracy S.IVenkatesh HHekim CHeltemes-Harris L.M...
    14页
    查看更多>>摘要：Patients with acute lymphoblastic leukemia have experienced significantly improved outcomes due to the advent of chimeric antigen receptor (CAR) T cells and bispecific T-cell engagers, although a proportion of patients still relapse despite these advances. T-cell exhaustion has been recently suggested to be an important driver of relapse in these patients. Indeed, phenotypic exhaustion of CD4+ T cells is predictive of relapse and poor overall survival in B-cell acute lymphoblastic leukemia (B-ALL). Thus, therapies that counter T-cell exhaustion, such as immune checkpoint blockade, may improve leukemia immunosurveillance and prevent relapse. Here, we used a murine model of Ph+ B-ALL as well as human bone marrow biopsy samples to assess the fundamental nature of CD4+ T-cell exhaustion and the preclinical therapeutic potential for combining anti–PD-L1 based checkpoint blockade with tyrosine kinase inhibitors targeting the BCR-ABL oncoprotein. Single-cell RNA-sequence analysis revealed that B-ALL induces a unique subset of CD4+ T cells with both cytotoxic and helper functions. Combination treatment with the tyrosine kinase inhibitor nilotinib and anti–PD-L1 dramatically improves long-term survival of leukemic mice. Depletion of CD4+ T cells prior to therapy completely abrogates the survival benefit, implicating CD4+ T cells as key drivers of the protective anti-leukemia immune response. Indeed, treatment with anti–PD-L1 leads to clonal expansion of leukemia-specific CD4+ T cells with the aforementioned helper/cytotoxic phenotype as well as reduced expression of exhaustion markers. These findings support efforts to use PD1/PD-L1 checkpoint blockade in clinical trials and highlight the importance of CD4+ T-cell dysfunction in limiting the endogenous anti-leukemia response. ? 2022 American Society of Hematology
      原文链接:
    • NSTL
    • Amer Soc Hematology

    GLA/DRST real-world outcome analysis of CAR T-cell therapies for large B-cell lymphoma in Germany

    Stelljes MGlass BBaldus C.DVucinic V...
    10页
    查看更多>>摘要：CD19-directed chimeric antigen receptor (CAR) T cells have evolved as a new standard-of-care (SOC) treatment in patients with relapsed/refractory (r/r) large B-cell lymphoma (LBCL). Here, we report the first German real-world data on SOC CAR T-cell therapies with the aim to explore risk factors associated with outcomes. Patients who received SOC axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) for LBCL and were registered with the German Registry for Stem Cell Transplantation (DRST) were eligible. The main outcomes analyzed were toxicities, response, overall survival (OS), and progression-free survival (PFS). We report 356 patients who received axi-cel (n = 173) or tisa-cel (n = 183) between November 2018 and April 2021 at 21 German centers. Whereas the axi-cel and tisa-cel cohorts were comparable for age, sex, lactate dehydrogenase (LDH), international prognostic index (IPI), and pretreatment, the tisa-cel group comprised significantly more patients with poor performance status, ineligibility for ZUMA-1, and the need for bridging, respectively. With a median follow-up of 11 months, Kaplan-Meier estimates of OS, PFS, and nonrelapse mortality (NRM) 12 months after dosing were 52%, 30%, and 6%, respectively. While NRM was largely driven by infections subsequent to prolonged neutropenia and/or severe neurotoxicity and significantly higher with axi-cel, significant risk factors for PFS on the multivariate analysis included bridging failure, elevated LDH, age, and tisa-cel use. In conclusion, this study suggests that important outcome determinants of CD19-directed CAR T-cell treatment of LBCL in the real-world setting are bridging success, CAR-T product selection, LDH, and the absence of prolonged neutropenia and/or severe neurotoxicity. These findings may have implications for designing risk-adapted CAR T-cell therapy strategies. ? 2022 American Society of Hematology
      原文链接:
    • NSTL
    • Amer Soc Hematology