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BackgroundCD19-directed chimeric antigen receptor T-cell therapy (CAR-T) represents a promising treatment modality for an increasing number of B-cell malignancies. However, prolonged cytopenias and infections substantially contribute to the toxicity burden of CAR-T. The recently developed CAR-HEMATOTOX (HT) score—composed of five pre-lymphodepletion variables (eg, absolute neutrophil count, platelet count, hemoglobin, C-reactive protein, ferritin)—enables risk stratification of hematological toxicity.MethodsIn this multicenter retrospective analysis, we characterized early infection events (days 0–90) and clinical outcomes in 248 patients receiving standard-of-care CD19 CAR-T for relapsed/refractory large B-cell lymphoma. This included a derivation cohort (cohort A, 179 patients) and a second independent validation cohort (cohort B, 69 patients). Cumulative incidence curves were calculated for all-grade, grade ≥3, and specific infection subtypes. Clinical outcomes were studied via Kaplan-Meier estimates.ResultsIn a multivariate analysis adjusted for other baseline features, the HT score identified patients at high risk for severe infections (adjusted HR 6.4, 95% CI 3.1 to 13.1). HThigh patients more frequently developed severe infections (40% vs 8%, p<0.0001)—particularly severe bacterial infections (27% vs 0.9%, p<0.0001). Additionally, multivariate analysis of post-CAR-T factors revealed that infection risk was increased by prolonged neutropenia (≥14 days) and corticosteroid use (≥9 days), and decreased with fluoroquinolone prophylaxis. Antibacterial prophylaxis significantly reduced the likelihood of severe bacterial infections in HThigh (16% vs 46%, p<0.001), but not HTlow patients (0% vs 2%, p=n.s.). Collectively, HThigh patients experienced worse median progression-free (3.4 vs 12.6 months) and overall survival (9.1 months vs not-reached), and were hospitalized longer (median 20 vs 16 days). Severe infections represented the most common cause of non-relapse mortality after CAR-T and were associated with poor survival outcomes. A trend toward increased non-relapse mortality in HThigh patients was observed (8.0% vs 3.7%, p=0.09).ConclusionsThese data demonstrate the utility of the HT score to risk-stratify patients for infectious complications and poor survival outcomes prior to CD19 CAR-T. High-risk patients likely benefit from anti-infective prophylaxis and should be closely monitored for potential infections and relapse.

Despite the tremendous progress in the clinical management of autoimmune diseases, many patients do not respond to the currently used treatments. Autoreactive B cells play a key role in the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. B-cell-depleting monoclonal antibodies, such as rituximab, have poor therapeutic efficacy in autoimmune diseases, mainly due to the persistence of autoreactive B cells in lymphatic organs and inflamed tissues. The adoptive transfer of T cells engineered to target tumour cells via chimeric antigen receptors (CARs) has emerged as an effective treatment modality in B-cell malignancies. In the last 2 years treatment with autologous CAR T cells directed against the CD19 antigen has been introduced in therapy of autoimmune disease. CD19 CAR T cells induced a rapid and sustained depletion of circulating B cells, as well as in a complete clinical and serological remission of refractory systemic lupus erythematosus and dermatomyositis. In this paper, we discuss the evolving strategies for targeting autoreactive B cells via CAR T cells, which might be used for targeted therapy in autoimmune diseases.

Previous studies indicated a role of the reconstituting immune system for disease outcome upon high-dose chemotherapy (HDCT) and autologous stem cell transplantation (auto-SCT) in multiple myeloma (MM) and lymphoma patients. Since immune cell metabolism and function are closely interconnected, we used flow-cytometry techniques to analyze key components and functions of the metabolic machinery in reconstituting immune cells upon HDCT/auto-SCT. We observed increased proliferative activity and an upregulation of the glycolytic and fatty acid oxidation (FAO) machinery in immune cells during engraftment. Metabolic activation was more pronounced in T-cells of advanced differentiation stages, in CD56 bright NK-cells, and CD14 ++ CD16 + intermediate monocytes. Next, we investigated a potential correlation between the immune cells’ metabolic profile and early progression or relapse in lymphoma patients within the first twelve months following auto-SCT. Here, persistently increased metabolic parameters correlated with a rather poor disease course. Taken together, reconstituting immune cells display an upregulated bioenergetic machinery following auto-SCT. Interestingly, a persistently enhanced metabolic immune cell phenotype correlated with reduced PFS. However, it remains to be elucidated, if the clinical data can be confirmed within a larger set of patients and if residual malignant cells not detected by conventional means possibly caused the metabolic activation.

Allogeneic-hematopoietic stem cell transplantation (allo-HSCT) represents the only curative treatment option for numerous hematological malignancies. Elimination of malignant cells depends on the T-cells’ Graft- versus -Tumor (GvT) effect. However, Graft- versus -Host-Disease (GvHD), often co-occurring with GvT, remains an obstacle for therapeutic efficacy. Hence, approaches, which selectively alleviate GvHD without compromising GvT activity, are needed. As already explored for autoimmune and inflammatory disorders, immuno-metabolic interventions pose a promising option to address this unmet challenge. Being embedded in a complex regulatory framework, immunological and metabolic pathways are closely intertwined, which is demonstrated by metabolic reprograming of T-cells upon activation or differentiation. In this review, current knowledge on the immuno-metabolic signature of GvHD-driving T-cells is summarized and approaches to metabolically interfere are outlined. Furthermore, we address the metabolic impact of standard medications for GvHD treatment and prophylaxis, which, in conjunction with the immuno-metabolic profile of alloreactive T-cells, could allow more targeted interventions in the future.

Chronic graft-versus-host disease (cGVHD) remains the most significant long-term complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT), despite increasing insights into its pathogenesis. The development of reliable prognostic biomarkers is essential for identifying patients at high risk of developing cGVHD which may benefit from pre-emptive intervention. However, valid biomarkers remain elusive, and cGVHD is typically treated after clinical onset only, when irreversible manifestations such as ocular involvement may already be present. In this exploratory study, we identified ten cytokines and chemokines with potential prognostic value for predicting subsequent cGVHD. Using bead-based multiplex analysis, we assessed serum samples from 60 adult allo-HSCT recipients at day +90 and day +180 post-transplant to identify proteins distinguishing patients who later developed cGVHD from those who remained tolerant. Significant differences were found in the serum levels of BAFF, CCL4, CXCL9, and sRAGE between patients with de novo cGVHD and those without GVHD. In contrast, elevated IL-6, IL-17A, PAI-1, IL-10, CX3CL1, CXCL1, and CCL4 levels were prognostic for quiescent cGVHD compared with patients with resolved acute GVHD only. These findings underscore the biological heterogeneity of cGVHD and the limited value of single-biomarker approaches, emphasizing the need to consider distinct clinical subgroups and prior disease courses in future predictive models.

Applying advanced molecular profiling together with highly specific targeted therapies offers the possibility to better dissect the mechanisms underlying immune-mediated inflammatory diseases such as systemic lupus erythematosus (SLE) in humans. Here we apply a combination of single-cell RNA-Seq and T/B cell repertoire analysis to perform an in-depth characterization of molecular changes in the immune-signature upon CD19 CAR T cell-mediated depletion of B cells in patients with SLE. The resulting data sets not only confirm a selective CAR T cell-mediated reset of the B cell response but simultaneously reveal consequent changes in the transcriptional signature of monocyte and T cell subsets that respond with a profound reduction in type I IFN signaling. Our current data, thus, provide evidence for a causal relationship between the B cell response and the increased IFN signature observed in SLE and additionally demonstrate the usefulness of combining targeted therapies and analytic approaches to decipher molecular mechanisms of immune-mediated inflammatory diseases in humans.

Cellular stress responses including the unfolded protein response (UPR) decide over the fate of an individual cell to ensure survival of the entire organism. During physiologic UPR counter-regulation, protective proteins are upregulated to prevent cell death. A similar strategy induces resistance to UPR in cancer. Therefore, we hypothesized that blocking protein synthesis following induction of UPR substantially enhances drug-induced apoptosis of malignant cells. In line, upregulation of the chaperone BiP was prevented by simultaneous arrest of protein synthesis in B cell malignancies. Cytotoxicity by immunotoxins—approved inhibitors of protein synthesis—was synergistically enhanced in combination with UPR-inducers in seven distinct hematologic and three solid tumor entities in vitro. Synergistic cell death depended on mitochondrial outer membrane permeabilization via BAK/BAX, which correlated with synergistic, IRE1α-dependent reduction of BID, accompanied by an additive fall of MCL-1. The strong synergy was reproduced in vivo against xenograft mouse models of mantle cell lymphoma, Burkitt’s lymphoma, and patient-derived acute lymphoblastic leukemia. In contrast, synergy was absent in blood cells of healthy donors suggesting a tumor-specific vulnerability. Together, these data support clinical evaluation of blocking stress response counter-regulation using inhibitors of protein synthesis as a novel therapeutic strategy.

Non-steroidal anti-inflammatory drugs such as diclofenac exhibit potent anticancer effects. Up to now these effects were mainly attributed to its classical role as COX-inhibitor. Here we show novel COX-independent effects of diclofenac. Diclofenac significantly diminished MYC expression and modulated glucose metabolism resulting in impaired melanoma, leukemia, and carcinoma cell line proliferation in vitro and reduced melanoma growth in vivo. In contrast, the non-selective COX inhibitor aspirin and the COX-2 specific inhibitor NS-398 had no effect on MYC expression and glucose metabolism. Diclofenac significantly decreased glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), and monocarboxylate transporter 1 (MCT1) gene expression in line with a decrease in glucose uptake and lactate secretion. A significant intracellular accumulation of lactate by diclofenac preceded the observed effect on gene expression, suggesting a direct inhibitory effect of diclofenac on lactate efflux. While intracellular lactate accumulation impairs cellular proliferation and gene expression, it does not inhibit MYC expression as evidenced by the lack of MYC regulation by the MCT inhibitor α-cyano-4-hydroxycinnamic acid. Finally, in a cell line with a tetracycline-regulated c-MYC gene, diclofenac decreased proliferation both in the presence and absence of c-MYC. Thus, diclofenac targets tumor cell proliferation via two mechanisms, that is inhibition of MYC and lactate transport. Based on these results, diclofenac holds potential as a clinically applicable MYC and glycolysis inhibitor supporting established tumor therapies.

Acute myeloid leukemia (AML) is the most common acute leukemia amongst adults with a 5-year overall survival lower than 30%. Emerging evidence suggest that immune alterations favor leukemogenesis and/or AML relapse thereby negatively impacting disease outcome. Over the last years myeloid derived suppressor cells (MDSCs) have been gaining momentum in the field of cancer research. MDSCs are a heterogeneous cell population morphologically resembling either monocytes or granulocytes and sharing some key features including myeloid origin, aberrant (immature) phenotype, and immunosuppressive activity. Increasing evidence suggests that accumulating MDSCs are involved in hampering anti-tumor immune responses and immune-based therapies. Here, we demonstrate increased frequencies of CD14 + monocytic MDSCs in newly diagnosed AML that co-express CD33 but lack HLA-DR (HLA-DR lo ). AML-blasts induce HLA-DR lo cells from healthy donor-derived monocytes in vitro that suppress T-cells and express indoleamine-2,3-dioxygenase (IDO). We investigated whether a CD33/CD3-bispecific BiTE® antibody construct (AMG 330) with pre-clinical activity against AML-blasts by redirection of T-cells can eradicate CD33 + MDSCs. In fact, T-cells eliminate IDO + CD33 + MDSCs in the presence of AMG 330. Depletion of total CD14 + cells (including MDSCs) in peripheral blood mononuclear cells from AML patients did not enhance AMG 330-triggered T-cell activation and expansion, but boosted AML-blast lysis. This finding was corroborated in experiments showing that adding MDSCs into co-cultures of T- and AML-cells reduced AML-blast killing, while IDO inhibition promotes AMG 330-mediated clearance of AML-blasts. Taken together, our results suggest that AMG 330 may achieve anti-leukemic efficacy not only through T-cell-mediated cytotoxicity against AML-blasts but also against CD33 + MDSCs, suggesting that it is worth exploring the predictive role of MDSCs for responsiveness towards an AMG 330-based therapy.

We have determined stable carbon isotope ratios of epifaunal and shallow infaunal benthic foraminifera in the Mediterranean Sea to relate the inferred gradient of pore water δ13CDIC to varying trophic conditions. This is a prerequisite for developing this difference into a potential transfer function for organic matter flux rates. The data set is based on samples retrieved from a well-defined bathymetric range (400–1500 m water depth) of sub-basins in the western, central, and eastern Mediterranean Sea. Regional contrasts in organic matter fluxes and associated δ13CDIC of pore water are recorded by the δ13C difference (Δδ13CUmed-Epi) between the shallow infaunal Uvigerina mediterranea and epifaunal species (Planulina ariminensis, Cibicidoides pachydermus, Cibicides lobatulus). Within epifaunal taxa, the highest δ13C values are recorded for P. ariminensis, providing the best indicator for bottom water δ13CDIC. In contrast, C. pachydermus reveals minor pore water effects at the more eutrophic sites. Because of ontogenetic trends in the δ13C signal of U. mediterranea of up to 1.04 ‰, only tests larger than 600 µm were used for the development of the transfer function. The recorded differences in the δ13C values of U. mediterranea and epifaunal taxa (Δδ13CUmed-Epi) range from −0.46 to −2.13 ‰, with generally higher offsets at more eutrophic sites. The measured δ13C differences are related to site-specific differences in microhabitat, depth of the principal sedimentary redox boundary, and TOC content of the ambient sediment. The Δδ13CUmed-Epi values reveal a consistent relation to Corg fluxes estimated from satellite-derived surface water primary production in open-marine settings of the Alboran Sea, Mallorca Channel, Strait of Sicily, and southern Aegean Sea. In contrast, Δδ13CUmed-Epi values in areas affected by intense resuspension and riverine organic matter sources of the northern to central Aegean Sea and the canyon systems of the Gulf of Lion suggest higher Corg fluxes compared to the values based on recent primary production. Taking regional biases and uncertainties into account, we establish a first Δδ13CUmed-Epi-based transfer function for Corg fluxes for the Mediterranean Sea.