Issue Archive

In this Blood Spotlight, Calabretta and colleagues describe the mechanism of action of loncastuximab tesirine, an anti-CD19 antibody-drug conjugate. They discuss data from the first phase 1 and 2 trials of the drug in patients with relapsed or refractory diffuse large B-cell lymphoma contributing to its recent approval by the US Food and Drug Administration.

Ganuza et al provide a concise review on the origin of hematopoietic stem cells (HSCs) in mammals. They illustrate how the field is moving away from dependence on classic transplantation assays and utilizing new culture and lineage-tracing technologies to better understand and characterize HSC numbers and function from early points in development.

Development of chimeric antigen receptor (CAR) T-cell therapies for T-cell malignancies has been compromised by the problem of T-cell fratricide. Lu et al describe a novel approach, generated through natural selection of fratricide-resistant CD7 CAR T cells. In preliminary phase 1 trial data from 20 patients with relapsed/refractory T-acute lymphoblastic leukemia or lymphoma, the authors report that infusions are well-tolerated, with the majority of patients achieving minimal residual disease-negative complete remisssion.

Despite improvements in outcomes for patients with Philadelphia chromosome positive (Ph⁺) B-cell acute lymphoblastic leukemia (Ph⁺ B-ALL) with the addition of tyrosine kinase inhibitors to chemotherapy, secondary resistance is common. Using a nonirradiated immunocompetent murine model and primary patient samples, Tracy and colleagues describe the functional defects in exhausted CD4⁺ T cells associated with the loss of anti-leukemic effects, and they demonstrate that anti-PD-L1 blockade improves the efficacy of nilotinib in a CD4⁺ T-cell–dependent manner by reducing exhaustion. These data encourage clinical testing of regimens incorporating these 2 targeted therapies.

CD19-directed chimeric antigen receptor (CAR) T cells are becoming part of the standard of care for relapsed/refractory large B-cell lymphoma. Bethge and colleagues report the real-world experience of 356 patients receiving CAR T cells to explore risk factors influencing outcomes. They detail outcomes similar to those in reported trials and identify failure of bridging therapy, elevated lactate dehydrogenase, CAR T product selection, and absence of prolonged neutropenia and/or severe neurotoxicity as significant influences on progression-free survival.

Abnormal growth factor signaling is a feature of myeloproliferative neoplasms (MPNs). Focusing on mitogen-activated protein kinase-1, also known as ERK2, Zhang and colleagues reveal that its 2 substrate binding domains have opposing roles in mouse models of JAK2V617F-driven MPNs. The ERK2-D domain may be a promising therapeutic target while conversely, the other domain, ERK2-DBP, blocks progression of the disease. This changes the perception that inhibiting the catalytic activity of ERK in MPNs will be an effective therapeutic strategy.

Early intervention with recombinant tissue plasminogen activator (rtPA) improves outcomes in acute ischemic stroke, but benefits can be limited by hemorrhagic transformation. Goncalves et al used animal models to reveal a mechanism behind the hemorrhage and provide a proof-of-concept interventional approach that reduces this risk by targeting phosphorylation of occludin in the cerebrovascular endothelium after rtPA. Translation of this work into clinical trials may improve safety and expand the time window for rtTPA therapy.