Cytotoxic CD4 (CD4_CTX) T cells are emerging as an important component of antiviral and antitumor immunity, but the molecular basis of their development remains poorly understood. In the context of human cytomegalovirus infection, a significant proportion of CD4 T cells displays cytotoxic functions. We observed that the transcriptional program of these cells was enriched in CD8 T cell lineage genes despite the absence of ThPOK downregulation. We further show that establishment of CD4_CTX-specific transcriptional and epigenetic programs occurred in a stepwise fashion along the Th1-differentiation pathway. In vitro, prolonged activation of naive CD4 T cells in presence of Th1 polarizing cytokines led to the acquisition of perforin-dependent cytotoxic activity. This process was dependent on the Th1 transcription factor Runx3 and was limited by the sustained expression of ThPOK. This work elucidates the molecular program of human CD4_CTX T cells and identifies potential targets for immunotherapy against viral infections and cancer.

Acute myeloid leukemia (AML) is a cancer that originates from the bone marrow (BM). Under physiological conditions, the bone marrow supports the homeostasis of immune cells and hosts memory lymphoid cells. In this review, we summarize our present understanding of the role of the immune microenvironment on healthy bone marrow and on the development of AML, with a focus on T cells and other lymphoid cells. The types and function of different immune cells involved in the AML microenvironment as well as their putative role in the onset of disease and response to treatment are presented. We also describe how the immune context predicts the response to immunotherapy in AML and how these therapies modulate the immune status of the bone marrow. Finally, we focus on allogeneic stem cell transplantation and summarize the current understanding of the immune environment in the post-transplant bone marrow, the factors associated with immune escape and relevant strategies to prevent and treat relapse.

The real-world results of chimeric antigen receptor T-cell (CAR-T) therapy for patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) substantially differ across countries. In the Netherlands, the CAR-T tumorboard facilitates a unique nationwide infrastructure for referral, eligibility assessment and data collection. The aim of this study was to evaluate real-world outcomes of axicabtagene ciloleucel (axi-cel) in the Dutch population, including the thus-far underreported effects on health-related quality of life (HR-QoL). All patients with R/R LBCL after ≥2 lines of systemic therapy referred for axi-cel treatment between May 2020–May 2022 were included (N = 250). Of the 160 apheresed patients, 145 patients received an axi-cel infusion. The main reason for ineligibility was rapidly progressive disease. The outcomes are better or at least comparable to other studies (best overall response rate: 84% (complete response: 66%); 12-month progression-free-survival rate and overall survival rate: 48% and 62%, respectively). The 12-month NRM was 5%, mainly caused by infections. Clinically meaningful improvement in several HR-QoL domains was observed from Month 9 onwards. Expert-directed patient selection can support effective and sustainable application of CAR-T treatment. Matched comparisons between cohorts will help to understand the differences in outcomes across countries and select best practices. Despite the favorable results, for a considerable proportion of patients with R/R LBCL there still is an unmet medical need.

Early identification of patients at risk of immune effector cell–associated hematotoxicity (ICAHT) is essential to minimize nonrelapse mortality. The CAR-HEMATOTOX (HT) score is an implemented risk-stratification tool for ICAHT, infections, and survival in patients with relapsed/refractory large B-cell lymphoma (R/R LBCL) receiving chimeric antigen receptor T-cell therapy (CART). Although validated in its defining study, the HT score was developed in a small cohort, necessitating independent external validation. This study externally validates the HT score in a real-world population-based cohort of adults with R/R LBCL receiving CART. The HT score, based on absolute neutrophil count (ANC), hemoglobin, platelets, C-reactive protein, and ferritin, was calculated before lymphodepleting chemotherapy. Of 245 consecutive patients, 171 (70%) had an HT score of ≥2 (HThigh). The initial end point, clinically significant neutropenia (ANC of <500/μL for ≥14 days), occurred in 21% of patients. The binary HT score was associated with clinically significant neutropenia (odds ratio [OR], 2.94; 95% confidence interval [CI], 1.27-6.80; P = .012) with a good predictive performance (area under the curve = 0.73). Similar results were achieved for early and late ICAHT grade ≥3 (OR, 2.92; 95% CI, 1.19-7.14; P = .019; and OR, 2.42; 95% CI, 1.31-4.47; P = .005). A trend toward an association with severe infections was observed (OR, 2.02; 95% CI, 0.91-4.48; P = .085). HThigh patients had a lower progression-free and overall survival (hazard ratio [HR], 1.84; 95% CI, 1.15-2.93; P = .011; and HR, 2.83; 95% CI, 1.64-4.87; P < .001, respectively). The HT score identified CART-treated patients with R/R LBCL at risk of clinically significant neutropenia, poor survival outcomes, and potentially severe infections.

Brexucabtagene autoleucel (brexu-cel) and allogeneic hematopoietic cell transplantation (alloHCT) are effective treatments for relapsed and refractory mantle cell lymphoma (r/r MCL), but the optimal choice remains unclear. We conducted an analysis of 64 patients aged ≥50 years with r/r MCL treated with brexu-cel in the ZUMA-2 study, matching them 1:1 by propensity score to 64 (of 272) patients with r/r MCL who underwent alloHCT using data from the European Society for Blood and Marrow Transplantation registry. The median follow-up time was 36.5 months for the brexu-cel cohort and 34.1 months for the matched alloHCT cohort. Patients who received brexu-cel had a significantly higher overall survival [(OS) 81.3% vs. 59.2%; HR, 0.39; P = 0.004] and lower nonrelapse mortality (3.6% vs. 21.2%; P = 0.015) 1 year after treatment. Chronic GVHD occurred within the first year in 26.9% of patients who underwent alloHCT. However, long-term progression-free survival (PFS) and OS remain comparable. Despite the limitations of this nonrandomized study, the findings indicate a superior safety profile for brexu-cel in r/r MCL. Significance: Patients aged ≥50 years with r/r MCL had superior OS and lower nonrelapse mortality 1 year after receiving brexu-cel compared with alloHCT. However, the long-term PFS and OS are similar for both treatments. Individual risk–benefit evaluation is essential to guide optimal treatment decisions.

Bispecific antibodies (BsAb) targeting CD20 and CD3 have shown efficacy for relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL), but their impact on outcomes following allogeneic hematopoietic cell transplantation (alloHCT) remains unclear. In this international, retrospective study, we compared outcomes of adult patients with R/R B-NHL undergoing first alloHCT after BsAb exposure (n = 47) versus a historical BsAb-naïve cohort (n = 101). Baseline imbalances were addressed using inverse probability of treatment weighting (IPTW) and propensity score matching (PSM). The primary end point was nonrelapse mortality (NRM); secondary end points included overall survival (OS), progression-free survival (PFS), cumulative incidence of relapse (CIR), graft-versus-host disease (GVHD), engraftment, and GVHD/relapse-free survival (GRFS). In the overall cohort, 2-year NRM did not differ significantly between BsAb-exposed and BsAb-naïve groups (IPTW: 29.1% vs 31.4%, P = 0.80; PSM: 35.8% vs. 27.9%, P = 0.43). CIR was significantly lower in BsAb-exposed patients after IPTW (7.4% vs 20.0%, P = 0.01), but not in PSM (9.5% vs 23.4%, P = 0.06). OS, GVHD, GRFS, and engraftment were comparable. In a prespecified subanalysis limited to large B-cell lymphomas, CIR differences were consistent across IPTW (6.1% vs 21.1%, P = 0.01) and PSM (9.2% vs 33.3%, P = 0.03), reinforcing a potential benefit of prior BsAb therapy. A significant improvement in PFS was observed in this subgroup with IPTW (55.5% vs 36.6%; P = 0.04), but not in PSM (P = 0.20). Prior BsAb exposure does not adversely impact alloHCT safety and may be associated with improved disease control. Prospective studies are warranted to define optimal sequencing in this high-risk population.