Novel CD3×CD20 bispecific antibody (BsAb) immunotherapies have entered the armamentarium for follicular lymphoma and diffuse large B-cell lymphoma based on accelerated approvals. The primary challenge in utilizing BsAbs lies in patient selection due to variable responses, unique toxicity, and health economics. To date, no validated biomarkers of therapy response exist, however data demonstrating potential clinical, imaging, and biological markers relating to BsAbs are growing. This review examines current prognostic and potentially predictive biomarkers and explores future directions for nuanced patient selection.

The UK Infected Blood Inquiry report was published in May 2024 after 6 years of taking oral and written evidence from patients, clinicians, blood services, government officials, and politicians about the transmission of infection by blood transfusion to thousands of patients in the 1970s through to the 1990s. The same problems with transfusion-transmitted infection occurred in many other countries in the same period, but their reviews, inquiries, and decisions about compensation occurred many years earlier than in the United Kingdom. The publication of the report has been welcomed but begs 2 important questions. Why was the inquiry so delayed in the United Kingdom? And why did it take so long to report? Furthermore, the report itself deserves scrutiny. What were its findings and lessons learned? How will the findings be implemented, and what are the implications, if any, for other countries?

ZUMA-12 is a multicenter phase 2 study evaluating axicabtagene ciloleucel (axi-cel) autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy as part of first-line treatment for high-risk large B-cell lymphoma (LBCL). In the primary efficacy analysis (n = 37; median follow-up, 15.9 months), axi-cel demonstrated a high rate of complete responses (CR; 78%) and a safety profile consistent with prior experience. Here, we assessed updated outcomes from ZUMA-12 in 40 treated patients after ≥3 years of follow-up. Eligible adults underwent leukapheresis, lymphodepleting chemotherapy, and  axi-cel infusion (2 × 106 CAR T cells/kg). Investigator-assessed CR, objective response, survival, safety, and CAR T-cell expansion were assessed. The CR rate among response-evaluable patients (n = 37) increased after the primary analysis to 86% (95% confidence interval [CI], 71%-95%), with a 92% objective response rate. After a median follow-up of 47.0 months (range, 37.1-57.8 months), 36-month estimates (95% CI) of duration of response and event-free, progression-free, and overall survival were 81.8% (63.9%-91.4%), 73.0% (55.6%-84.4%), 75.1% (57.5%-86.2%), and 81.1% (64.4%-90.5%), respectively. In total, 4 patients had new malignancies, 2 occurring after the data cutoff of the primary analysis; none were axi-cel-related. Eight patients died on study, 2 of whom died from nonrelapse mortality causes. After long-term follow-up, axi-cel demonstrated a high durable response rate, with no new safety signals after the primary analysis, suggestive of an effective first-line therapy with curative intent in high-risk LBCL. Further assessments are needed to determine its benefit vs standard of care. This trial was registered at clinicaltrials.gov, as NCT03761056.

Burkitt lymphoma (BL) is an aggressive B-cell lymphoma that is associated with poor outcomes in patients with relapsed/refractory disease. This multicenter, retrospective study evaluated real-world CD19 chimeric antigen receptor (CAR) T-cell therapy outcomes in patients with relapsed/refractory BL using data abstracted from the medical records. In total, 31 patients received CAR T cells after a median of 3 previous therapies (range, 1-6). Patients received axicabtagene ciloleucel (n = 19), lisocabtagene maraleucel (n = 4), tisagenlecleucel (n = 4), or other agents (n = 4). Grade 1 to 2 cytokine release syndrome occurred in 83.9% of patients (grade ≥3, 65%), and grade 1 to 2 immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 29% of patients (grade ≥3, 19.4%). The 28-day mortality rate was 16.1%, including 1 patient who died from grade 5 ICANS. The overall response rate at 1 month was 58.0% with a complete response (CR) rate of 41.9%; however, the 6-month CR rate was only 19.4%. The median progression-free survival was 2.3 months (95% confidence interval, 1.0-9.0), and the median overall survival was 6.0 months (95% confidence interval, 1.9-11.5). Three patients (9.7%) received consolidative allogeneic stem cell transplants, but all subsequently relapsed. In conclusion, CD19 CAR T-cell therapy infrequently delivers long-term disease control in BL. Further investigation is needed to determine the most effective alternative management strategy for these patients.

Hyperhomocysteinemia (HHcy) is strongly associated with cardiovascular diseases (CVDs), and it has been identified as a risk factor for thrombotic diseases. Most patients with HHcy die from various complications closely related to thrombotic diseases. However, the underlying mechanisms have not been fully elucidated. G protein-coupled receptors (GPCRs), the central regulators of the cardiovascular system, primarily control platelet activation. By examining the effects of HHcy on a panel of GPCRs involved in platelet aggregation, we found that HHcy systematically modulated biased GPCR signaling through the inhibition of desensitization by β-arrestins and the amplification of G protein signals. We further revealed that the N-homocysteinylation of β-arrestin1/2 at lysine (K) residues (K294/K296) disrupted the interaction between β-arrestins and GPCRs. The aforementioned phenomenon may be universal because HHcy was found to modulate the signaling bias of 9 other randomly selected GPCRs. Moreover, we found that the proinflammatory effects of homocysteine and homocysteine thiolactone were weakened in Arrb2-/- mice and that the reintroduction of wild-type but not K296R β-arrestin2 mutants (in mice) into primary peritoneal macrophages reversed these effects. Notably, in Arrb2K296R mice, HHcy-induced thrombus formation and platelet aggregation were reversed. Our results suggest that a G-biased agonist could be a better choice for disease therapy under HHcy conditions. Collectively, our findings demonstrate that the N-homocysteinylation of β-arrestin1/β-arrestin2 actively modulates the biased property of GPCR signaling, which contributes to the pathophysiology of HHcy-related CVDs and provides insight into the selection of agonists for the treatment of diseases under HHcy conditions.

Cardiovascular disease has been recognized as the main cause of death in adults with sickle cell disease (SCD). Although the exact mechanism linking SCD to cardiomyopathy remains elusive, a possible role of subclinical acute transient myocardial ischemia during acute sickle cell-related vaso-occlusive crises (VOCs) has been suggested. We approached SCD cardiomyopathy by integrated omics using humanized SS mice exposed to hypoxia/reoxygenation (H/R; 10 hours hypoxia followed by 3 hours reoxygenation) stress, mimicking acute VOCs. In sickle cell (SS) mice exposed to H/R, a neutrophil-driven cardiac hypertrophic response is initiated by cardiac proinflammatory pathways, intersecting proteins and micro RNA involved in profibrotic signaling. This response may be facilitated by local unresolved inflammation. We then examined the effect of 17(R)-resolvin D1 (17R-RvD1), a member of the specialized proresolving lipid mediator superfamily, administration on H/R-activated profibrotic and proangiogenic pathways. In SS mice, we found that 17R-RvD1 (1) modulates miRNAome; (2) prevents the activation of NF-κB p65; (3) protects against the H/R-induced activation of both platelet derived growth factor receptor and transforming growth factor (TGF)-β1/Smad2-3 canonical pathways; (4) reduces the expression of hypoxia-inducible factor-dependent proangiogenic signaling; and (5) decreases the H/R-induced proapoptotic cell signature. The protective role of 17R-RvD1 against H/R-induced maladaptive heart remodeling was supported by the reduction of galectin-3, procollagen C-proteinase enhancer-1, and endothelin-1 expression and perivascular fibrosis in SS mice at 3 days after H/R stress compared with vehicle-treated SS animals. Collectively, our data support the novel role of unresolved inflammation in pathologic heart remodeling in SCD mice in response to H/R stress. Our study provides new evidence for protective effects of 17R-RvD1 against SCD-related cardiovascular disease.

Venetoclax (Ven), when combined with intensive chemotherapy, shows promise for untreated acute myeloid leukemia (AML), but its integration with the 7+3 regimen remains underexplored. In a phase 1b study, we assessed the safety and efficacy of Ven with daunorubicin and cytarabine in patients with newly diagnosed AML. A total of 34 patients (median age, 59 years; 62% non-White) received Ven at escalating durations (8, 11, or 14 days). Adverse events included febrile neutropenia (100%), sepsis (29%), and enterocolitis (23.5%), but there were no induction deaths. The median recovery times for neutrophils (>1.0 × 103/μL) and platelets (>100 × 103/μL) were less than 30 days. Composite complete remission was achieved in 85.3% of patients, and 86.2% were negative for measurable residual disease (MRD). Responses spanned all European Leukemia Net 2022 risk categories. With a median follow-up of 9.6 (2-20) months, the median duration of response, event-free survival, and overall survival were not reached. Ven (400 mg), when combined with 7+3 chemotherapy, was safe and effective in achieving MRD-negative remissions across all durations. Ven dose optimization is being explored in the expansion phase of this trial. Future multicenter studies should confirm our findings. This trial was registered at clinicaltrials.gov as #NCT05342584.

Although described more than a decade ago, the mechanism by which the JAK2 46/1 haplotype increases the risk of developing JAK2-mutated myeloproliferative neoplasms (MPNs) remains unexplained. Inflammation and immunity are linked to MPN development and thus could be relevant to the mechanism by which 46/1 mediates its effect. Here, we show that programmed death-1 receptor ligand (PD-L1) expression is elevated in 46/1 haplotype, both in healthy carriers and in CD34+ cells from patients with MPN. Using circular chromosome conformation capture, we observed that PD-L1 and the neighboring PD-L2 loci physically interact with JAK2 in a manner that differs between 46/1 and nonrisk haplotypes. CRISPR/Cas9 genome editing identified a region within JAK2 intron 2 that influences both JAK2 and PD-L1 expression. We suggest that increased PD-L1 expression may be relevant to the mechanism by which 46/1 leads to an increased inherited risk of developing MPN.

The success of allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be limited by graft-versus-host disease (GVHD). T-cell activation is a key factor in GVHD progression. Costimulatory signals can be counterbalanced by coinhibitory signals such as the checkpoint molecule VISTA (V-domain immunoglobulin-containing suppressor of T-cell activation)/programmed death-1 homolog that restrains activation and maintains donor T-cell quiescence. A single dose of anti-VISTA monoclonal antibody (mAb) prevents acute GVHD lethality in multiple models. Naïve donor T cells express moderate VISTA levels, which transiently increase in allo-HSCT recipients in association with T-cell receptor signaling, leading to heightened susceptibility to anti-VISTA mAb-mediated depletion, in contrast to donor T cells transferred to syngeneic recipients. Anti-VISTA mAb donor T-cell depletion was compatible with rapamycin but incompatible with peritransplant tacrolimus GVHD prophylaxis. Targeting VISTA exclusively on host cells or donor CD8+ T cells was not protective against GVHD lethality. Instead, anti-VISTA mAb-mediated deletion of alloreactive donor T cells depended on targeting a third (non-T) cell type. Further mechanistic studies indicated that donor T cells concurrently exposed to anti-VISTA mAb in vivo but not preincubated in vitro before adoptive T-cell transfer were eliminated via Fc receptor (FcR)-mediated phagocytosis. In a lymphoma challenge model, a graft-versus-lymphoma (GVL) effect was fully retained when anti-human VISTA mAb exclusively targeted donor CD4+ T cells, and was delayed but mostly retained when unseparated donor T cells were infused. In a xenogeneic GVHD model, anti-human VISTA mAb reduced donor T-cell expansion, VISTA T-cell expression levels, and recipient lethality. Together, these data support a novel clinical translational pathway in which acute GVHD lethality can be mitigated without negating the GVL effect.