Background: Chimeric antigen receptor (CAR) T-cell therapy has demonstrated significant benefits in the treatment of relapsed/refractory multiple myeloma (RRMM). However, these outcomes can be compromised by severe complications, including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome (ICANS) and immune effector cell-associated hematotoxicity (ICAHT), predisposing for life-threatening infections. Methods: This retrospective observational study examined a total of 129 patients with RRMM who had received idecabtagene vicleucel (ide-cel) at two major myeloma centers in Germany and one center in the USA to assess the Endothelial Activation and Stress Index (EASIX) as a risk marker for an unfavorable clinical course and outcome after CAR T-cell therapy. EASIX is calculated by lactate dehydrogenase (U/L) × creatinine (mg/dL) / platelets (10⁹ cells/L) and was determined before lymphodepletion (baseline) and at the day of CAR T-cell infusion (day 0). The analysis was extended to EASIX derivatives and the CAR-HEMATOTOX score. Results: An elevated baseline EASIX (>median) was identified as a risk marker for severe late ICAHT, manifesting with an impaired hematopoietic reconstitution and pronounced cytopenias during the late post-CAR-T period. Patients with high EASIX levels (>upper quartile) were particularly at risk, as evidenced by an increased rate of an aplastic phenotype of neutrophil recovery, severe late-onset infections and ICANS. Finally, we found associations between baseline EASIX and an inferior progression-free and overall survival. Moreover, the EASIX at day 0 also demonstrated potential to serve as a risk marker for post-CAR-T complications and adverse outcomes. Conclusions: In conclusion, EASIX aids in risk stratification at clinically relevant time points prior to CAR T-cell therapy with ide-cel. Increased EASIX levels might help clinicians to identify vulnerable patients to adapt peri-CAR-T management at an early stage.

Bispecific antibodies (bsAb) and chimeric antigen receptor (CAR) T cells allow for antibody guided recruitment of T cells against tumors. Both are successfully used for treatment of CD19 expressing leukemias, but may cause cytokine release syndrome (CRS) as a major dose-limiting side effect. For CRS prevention, steroids are recommended prior to bsAb treatment, despite their well-known lymphotoxic activity. The IL-6 receptor antibody tocilizumab is established for treatment of CRS induced by CAR T cells, but was not considered for CRS prevention in bsAb therapy. We here compared the influence of dexamethasone and tocilizumab on bsAb-mediated T cell proliferation and tumor lysis in vitro and in vivo and found that dexamethasone profoundly inhibited T cell proliferation and antitumor activity as induced by two different bsAb, particularly at low effector:target ratios, whereas tocilizumab did not affect efficacy. When we applied tocilizumab early during treatment of three patients with a newly developed PSMAxCD3 bsAb, significant CRS attenuation despite high IL-6 serum levels was observed. Thus, early IL-6 blockade may reduce the undesired sequelae of CRS upon bsAb therapy without affecting therapeutic activity, allowing in turn for safe application of effective doses.

The prostate‐specific membrane antigen (PSMA) has been demonstrated in numerous studies to be expressed specifically on prostate carcinoma cells and on the neovasculature of several other cancer entities. However, the simultaneous expression of PSMA on both, tumor cells as well as tumor vessels remains unclear, even if such “dual” expression would constitute an important asset to facilitate sufficient influx of effector cells to a given tumor site. We report here on the generation of a PSMA antibody, termed 10B3, which exerts superior dual reactivity on sections of prostate carcinoma and squamous cell carcinoma of the lung. 10B3 was used for the construction of T‐cell recruiting bispecific PSMAxCD3 antibodies in Fab‐ and IgG‐based formats, designated Fabsc and IgGsc, respectively. In vitro , both molecules exhibited comparable activity. In contrast, only the larger IgGsc molecule induced complete and durable elimination of established tumors in humanized mice due to favorable pharmacokinetic properties. Upon treatment of three patients with metastasized prostate carcinoma with the IgGsc reagent, marked activation of T cells and rapid reduction of elevated PSA levels were observed.

Glofitamab, a bispecific antibody targeting CD20 and CD3, is approved for relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL) after at least 2 prior treatment lines, but real-world data are scarce. In this retrospective, multicenter, multinational study, we evaluated the outcomes of 70 patients with r/r DLBCL treated with glofitamab as part of the compassionate use patient program in Germany, Austria, and Switzerland. The median number of prior treatment lines was 4, with 71% of patients refractory to their last treatment. Cytokine release syndrome was observed in 40% of patients (grade 3-4 in 2%), immune effector cell–associated neurotoxicity syndrome in 10% (grade 3 in 1%), and infections in 31% (grade 5 in 3%). The overall response rate was 46%, with 27% achieving complete responses (CR) and 19% partial responses. The median progression-free survival (PFS) was 3.6 months, whereas the median overall survival was 5.7 months. Notably, 13 patients (19%) were in CR 6 months after initiating glofitamab and exhibited durable responses. Elevated lactate dehydrogenase is the most robust predictor of inferior outcome. Patients pretreated with bendamustine within 6 months prior to glofitamab initiation exhibited significantly reduced PFS, suggesting that bendamustine may impair T-cell fitness and hence glofitamab efficacy. In summary, glofitamab demonstrates promising efficacy and a manageable safety profile in heavily pretreated patients with r/r DLBCL in a real-world scenario and the optimal sequence of treatments should use T-cell–depleting agents before glofitamab with caution.

While several genetic and morphological markers are established and serve to guide therapy of acute myeloid leukaemia (AML), there is still profound need to identify additional markers to better stratify patients. CD105 (Endoglin) is a type I transmembrane protein reported to induce activation and proliferation of endothelial cells. In addition, CD105 is expressed in haematological malignancies and the vessels of solid tumours. Here, CD105 associates with unfavourable disease course, but so far no data are available on the prognostic relevance of CD105 in haematological malignancies. We here generated a novel CD105 antibody for analysis of expression and prognostic relevance of CD105 in a cohort of 62 AML patients. Flow cytometric analysis revealed substantial expression in the various AML FAB types, with FAB M3 type displaying significantly lower surface levels. Next we established a cut-off specific fluorescence level of 5.22 using receiver-operating characteristics, which allowed to group patients in cases with CD105^loand CD105^hisurface expression and revealed that high CD105 expression correlated significantly with poor overall and progression free survival. In conclusion, we here identify CD105 expression as a novel prognostic marker in AML, which may serve to optimize follow up and treatment decisions for AML patients.

The B-cell lymphoma 2 inhibitor venetoclax (VEN) in combination with hypomethylating agents has been approved for first-line treatment of patients with acute myeloid leukemia (AML) ineligible for intensive treatment. VEN-containing treatment strategies may also be effective in relapsed/refractory (R/R) AML; however, comparative studies with conventional therapies for fit patients as a bridge-to-transplant strategy are limited. Using propensity score matching (PSM), we compared 37 patients with R/R AML, who received VEN-based salvage therapy as bridge to allogeneic hematopoietic stem cell transplantation (allo-HCT), with 90 patients from the German Study Alliance Leukemia AML registry, who were treated with non–VEN-containing salvage therapy according to their treating physician’s choice (TPC). The overall response rate among VEN patients was higher than the TPC control cohort (62% vs 42%; P = .049). Overall, 73% of VEN-treated patients vs 63% of TPC patients were bridged to allo-HCT (P = .41). After a median follow-up of 34.3 months for the VEN and 21.0 months for the TPC cohort, the median overall survival (OS) were 15.8 months (95% confidence interval [CI], 10.6 to not evaluable) and 10.5 months (95% CI, 6.8-19.6; P = .15), respectively. PSM revealed a trend toward improved OS for VEN patients (hazard ratio, 0.70; 95% CI, 0.41-1.22; P = .20). Median event-free survival was significantly longer in the VEN cohort (8.0 months) than the TPC cohort (3.7 months; P = .006). Our data suggest that VEN-based salvage therapy is a safe and effective bridge to allo-HCT for this difficult-to-treat AML patient population.