The progression of multiple myeloma (MM), an incurable malignancy of plasma cells, is often associated with the suppression of ferroptosis, a type of cell death driven by iron-dependent lipid peroxidation. The mechanisms underlying this suppression remain largely unknown. Here, we identified STK17B kinase as a critical suppressor of ferroptosis in MM. Elevated levels of STK17B are associated with poor overall survival in MM patients and STK17B expression is significantly higher in relapsed vs newly diagnosed MM cases. We found that inhibiting STK17B in MM cells increased the labile iron pool, enhanced lipid peroxidation, and sensitized cells to conventional anti-MM therapies. Notably, an orally available, in-house-generated STK17B inhibitor induced ferroptosis and significantly reduced tumor growth in MM xenograft mouse models. Mechanistically, proximity labeling assay combined with the phospho-proteomic analysis identified two major regulators of iron uptake and transport as direct targets of STK17B: iron-responsive element binding protein 2 (IREB2) and heat shock protein family B member 1 (HSPB1). We demonstrated that STK17B phosphorylates critical regulatory sites on IREB2 (S157) and HSPB1 (S15), thereby modulating the balance between IREB2 and HSPB1 downstream effectors, pro-ferropototic transferrin receptor and anti-ferroptotic ferritin heavy chain proteins. Furthermore, we demonstrated that STK17B indirectly maintains activating phosphorylation of STAT3, a ferroptosis suppressor and a major driver of MM pathobiology. Our findings uncovered a clinically relevant and targetable STK17B-pIREB2S157/pHSPB1S15 signaling axis that suppresses ferroptosis and contributes to drug resistance in MM.

The IELSG37 trial enrolled 545 patients with primary mediastinal B-cell lymphoma (PMBCL) and demonstrated that consolidation radiotherapy (RT) can be omitted in patients with complete metabolic response (CMR), defined by the Lugano classification as Deauville score (DS) 1-3. This report evaluates outcomes following different frontline rituximab- and doxorubicin-based immunochemotherapy regimens chosen according to local practice. Patients treated with R-CHOP21 showed a significantly higher percentage of DS 5 than those on other regimens (23.8% vs. 8.2% average, P< 0.001) as well as a trend toward additional unplanned treatments (53.2% vs. 46.9%, P=0.30). The increased risk of poor response was confirmed in a multinomial logistic regression analysis adjusted for age, sex, IPI score, and performance status. R-CHOP21 was also associated with smaller reductions in MTV and less pronounced decreases in SUVmax. Patients with DS 5 more often received additional treatment (RT and/or salvage chemotherapy with or without autologous consolidation) after induction immunochemotherapy (96% vs. 41%, P< 0.001) and experienced significantly poorer outcomes. Although differences in progression-free and overall survival between R-CHOP21 and more aggressive regimens were not statistically significant, R-CHOP21 may increase the risk of additional treatments and may be inadvisable as frontline therapy for PMBCL. NCT01599559.

HHV-6 reactivation in CAR T-cell recipients is reported to be rare. Our patient cohort (n=119) experienced a seven-fold higher incidence of viraemia than a previous study and 2 encephalitis cases. Further studies are needed to determine risk factors for infection.

Isatuximab is an IgG1k monoclonal antibody that binds with high affinity to CD38 expressed on plasma cells. Anti-CD38 antibodies have shown efficacy as monotherapy and in combination in a variety of settings for patients with multiple myeloma and light chain (AL) amyloidosis. This multi-center, cooperative group phase 2 trial was designed to evaluate hematologic response, organ response, and safety of isatuximab monotherapy for the treatment of relapsed AL amyloidosis. Isatuximab at 20 mg/kg was administered intravenously weekly during the first 28-day cycle and then every other week during cycles 2-24. Forty-three patients were registered, with 35 patients being evaluable for response. The overall hematologic response rate was 77.1%, with 57% of patients achieving a VGPR or better. The median time to partial response or better was 1.1 months. Renal response occurred in 50% (7/14) of patients with renal involvement and cardiac response occurred in 57% (8/14) of patients who were evaluable utilizing NT-pro-BNP with cardiac involvement. The most common treatment related grade ≥3 adverse events included lymphopenia (n=3, 8.5%) and infection (n=2, 6%). Isatuximab demonstrated substantial efficacy in previously treated patients with AL amyloidosis and was associated with a good safety profile. This trial was registered at www.clinicaltrials.gov as NCT#03499808.

Hepcidin is the key hyposideremic hormone produced primarily by the liver. However, recent reports reveal extra-hepatic functional sources of hepcidin, including the intestine, the site of dietary iron absorption. To determine whether intestinal hepcidin may play a role in plasma iron lowering, we generated transgenic mice overexpressing the peptide specifically in this tissue. At one month of age, transgenic mice exhibited severe iron deficiency along with decreased haematological indices and a drastic suppression of liver hepcidin in response to hyposideremia. Mechanistically, we showed that intestinal hepcidin was produced in the intestine lumen, inducing a striking down-regulation of Divalent Metal Transporter 1 (DMT1) protein at the enterocyte. To confirm the capacity of hepcidin to decrease DMT1, we developed food-grade recombinant lactic acid bacteria (recLAB) genetically modified to deliver hepcidin directly into the intestinal lumen. These recLAB induced a rapid decrease of duodenal DMT1 and, most importantly, when daily orally administrated, protected against iron overload in a mouse model of hemochromatosis. Taken together, our data reveal a previously unrecognized role of intestinal hepcidin as a regulator of systemic iron homeostasis, acting on DMT1 on the apical side of enterocytes, with potential therapeutics relevance for haematological or iron disorders.

Long-term maintenance of somatic stem cells relies on precise regulation of self-renewal and differentiation. Understanding the molecular framework for these homeostatic processes is essential for improved cellular therapies and treatment of myeloid neoplasms. CUX1 is a widely expressed, dosage-sensitive transcription factor crucial in development and frequently deleted in myeloid neoplasia in the context of -7/(del7q). Here, using novel mouse models and single-cell approaches, we report that dynamic and distinct CUX1 levels are integral to hematopoietic stem cell (HSC) activity. Knockdown of CUX1 reverses HSC differentiation and strikingly re-endows progenitors with stem cell function, accompanied by restoration of the HSC transcriptome and DNA accessibility landscape. CUX1 mediates these activities, in part, via suppressing endogenous retroelements (EREs) and the ensuing interferon-stimulated gene expression program. Both EREs and the interferon response are upregulated in CUX1-deficient acute myeloid leukemia (AML), suggesting a conserved role of CUX1 in regulating these elements. These data establish an unexpected entwinement of stem cell-intrinsic innate immune activation and the transcriptional programs of stem cell identity. Further, we reveal the profound effects of transcription factor levels in cell fate.

Hematopoietic stem cells (HSCs) responsible for blood cell production and their bone marrow regulatory niches undergo age-related changes, impacting immune responses and predisposing individuals to hematologic malignancies. Here, we show that the age-related alterations of the megakaryocytic niche and associated downregulation of Platelet Factor 4 (PF4) are pivotal mechanisms driving HSC aging. PF4-deficient mice display several phenotypes reminiscent of accelerated HSC aging, including lymphopenia, increased myeloid output, and DNA damage, mimicking physiologically aged HSCs. Remarkably, recombinant PF4 administration restored old HSCs to youthful functional phenotypes characterized by improved cell polarity, reduced DNA damage, enhanced in vivo reconstitution capacity, and balanced lineage output. Mechanistically, we identified LDLR and CXCR3 as the HSC receptors transmitting the PF4 signal, with double knockout mice showing exacerbated HSC aging phenotypes similar to PF4-deficient mice. Furthermore, human HSCs across various age groups also respond to the youthful PF4 signaling, highlighting its potential for rejuvenating aged hematopoietic systems. These findings pave the way for targeted therapies aimed at reversing age-related HSC decline with potential implications in the prevention or improvement of the course of age-related hematopoietic diseases.

Multiple myeloma (MM) continues to be an incurable malignancy, even with recent therapeutic advancements. While epigenetic dysregulation at cis-regulatory elements is known to drive disease progression, the complete molecular mechanisms underlying these alterations are poorly understood. Using ATAC-seq analysis combined with computational footprinting of CD138+ cells from 55 MM patients, we depicted the dynamic changes in chromatin accessibility during disease progression and identified Nuclear Respiratory Factor 1 (NRF1) as a master regulator of vital MM survival pathways. We demonstrated that NRF1 maintains proteasome homeostasis by orchestrating the ubiquitination pathway, which is essential for MM cell survival. We discovered a novel enhancer element that physically interacts with the NRF1 promoter, sustaining its expression. Targeting this enhancer RNA reduced NRF1 levels and increased tumor cell sensitivity to bortezomib (BTZ), suggesting therapeutic potential. In xenograft models, we showed that antisense oligonucleotides (ASOs) targeting the NRF1 enhancer, either alone or combined with BTZ, significantly decreased tumor burden and improved survival. Our findings reveal a previously unknown NRF1-dependent mechanism regulating MM cell survival and present a promising therapeutic approach through manipulation of its regulatory network.

Epcoritamab is a subcutaneous CD3xCD20 bispecific antibody approved as monotherapy for relapsed/refractory (R/R) follicular lymphoma (FL). We evaluated fixed-duration epcoritamab with rituximab plus lenalidomide (R2) in R/R FL in arm 2 of EPCORE® NHL-2 (phase 1b/2; NCT04663347). Patients received epcoritamab (2 step-up doses, then 48-mg full doses) for up to 2 years and R2 for up to 12 cycles (28 days/cycle). Primary endpoint was overall response rate (ORR) per investigator assessment (Lugano criteria). As of September 21, 2024, 108 patients received ≥1 epcoritamab dose in expansion (median follow-up, 28.2 months). Median age was 65 years; 57% had 1 prior line of therapy. ORR and complete response (CR) rate were 96% and 88%; CR rates in patients with high-risk features were 90% (primary refractory), 82% (refractory to anti-CD20 and an alkylating agent), and 83% (disease progression within 24 months of first-line therapy). Two-year estimates for remaining in CR, progression-free survival, overall survival, and not starting next antilymphoma therapy were 82%, 76%, 90%, and 84%, respectively. Minimal residual disease negativity was observed in 86% of evaluable patients (clonoSEQ® assay). Common treatment-emergent adverse events (TEAEs) included neutropenia (65%), COVID-19 (59%), and cytokine release syndrome (CRS; 51%). Grade (G) ≥3 TEAEs occurred in 87% of patients; 5 had G5 TEAEs (all COVID-19). CRS events were mostly low grade (38% G1, 11% G2, 2% G3), all resolved, and none led to epcoritamab discontinuation. Fixed-duration epcoritamab plus R2 demonstrated deep, durable responses with manageable safety and favorable outcomes in R/R FL, irrespective of risk features.

Von Willebrand disease (VWD)-type 1 is a bleeding disorder characterized by a quantitative deficiency of functional von Willebrand factor (VWF). We designed a novel bispecific nanobody, named KB-V13A12, that aims to increase endogenous VWF levels by bridging it to albumin. KB-V13A12 comprises two single-domain antibodies, one targeting VWF and one targeting albumin. VWF bound efficiently to the albumin/KB-V13A12 complex (2.0±0.4 nM) in immunosorbent assays and binding was stable at pH 5.6 and 7.4. VWF ristocetin activity and factor VIII binding remained unaffected in the presence of a 100 to 200-fold molar excess of KB-V13A12/albumin. Humanized VWD-type 1 mice were used for in vivo analysis. A single subcutaneous dose of KB-V13A12 (5 mg/kg) was associated with a nanobody half-life of 3.0±0.7 days and dose-dependently increased VWF in VWD-type 1 mice 1.4 to 2.1-fold for up to 14 days. FVIII activity was also increased during this period. The VWF-propeptide/VWF-antigen ratio (a marker for VWF clearance) was significantly reduced in the presence of KB-V13A12, suggesting that delayed clearance contributes to increased VWF levels. Clearance experiments in wild-type mice using recombinant VWF pre-incubated with KB-V13A12 indeed confirmed a prolonged survival, while this prolongation was absent in FcRn-deficient-mice. Finally, treatment with KB-V13A12 resulted in a significantly improved bleeding tendency in VWD-type 1 mice when using the saphenous vein puncture-model. In conclusion, KB-V13A12 is a bispecific nanobody that efficiently increases functional levels of endogenous VWF, and could be a therapeutic option to treat VWD-type 1.

Platelets in peripheral blood critically drive clot formation in health and disease. Previously considered to uniformly respond to vascular injury and inflammatory cues, recent studies have highlighted that circulating platelets exhibit marked heterogeneity, with distinct populations contributing differentially to hemostasis, thrombosis, and inflammation. In this Review, we highlight platelet diversity as a consequence of origin (i.e., megakaryocyte diversity), of circulatory age (i.e., young vs. aged platelets), and, specifically, as a sequela of and contributing factor to cardiovascular and inflammatory diseases. This diversity includes reticulated platelets, newly released from the bone marrow, RNA-rich, and highly prothrombotic, versus aged platelets, which exhibit altered receptor expression and pro-inflammatory rather than hemostatic features. We further describe how platelet subsets actively shape disease progression: Hyperreactive reticulated platelets drive arterial thrombosis, while procoagulant platelets amplify fibrin formation in venous thromboembolism. In chronic inflammation, interactions of immune-responsive platelets with leukocyte subsets facilitate their recruitment and impact on polarization, but can also promote endothelial dysfunction and immune hyperactivation, perpetuating thromboinflammatory dysregulation. Moreover, platelet phenotypes are dynamically regulated by disease states, with systemic inflammation, altered shear forces, and metabolic stress influencing platelet turnover, activation thresholds, and functional specialization. Recognizing platelet heterogeneity in disease pathogenesis could provide new opportunities for precision medicine, potentially allowing stratification of thrombotic risk and differential tailoring of antiplatelet and anti-inflammatory therapies.

Because frail and patients ≥80 years with CLL are still underrepresented in clinical trials, the CLL-Frail trial aimed to evaluate the efficacy and safety of acalabrutinib in these patients. The primary endpoint was the overall response rate (ORR) after 6 cycles of treatment to test the null hypothesis of ORR ≤ 65%.53 patients were included into the trial and 34 patients are still on therapy. Adverse events (AEs) were the most frequent reason for early discontinuation (ten patients), whereas five patients stopped treatment because of death. Median age was 81 years and 47.2% of patients were frail. The ORR for the 46 patients receiving ≥3 cycles of treatment was 93.5% (95% confidence interval 82.1 - 98.6) meeting the primary endpoint of this trial (p < 0.001). The estimated 12-month progression-free and overall survival rates were 93.3% and 95.7%, respectively, after a median follow-up of 19 months. 53.5% of patients reported an improvement in their self-perceived frailty. Although all patients experienced AEs and severe (CTC° ≥ 3) events were reported in 63.5% of patients, there were no events of severe bleeding and atrial fibrillation was rare (two cases of CTC° 2 and 3). Five patients died, of which four deaths happened during or <28 days after treatment. Infections/COVID-19 were the cause of death in three cases. This is the first prospective trial in older and/or frail CLL patients demonstrating a high efficacy and safe treatment with acalabrutinib monotherapy. ClinicalTrials.gov ID: NCT04883749 EUDRA-CT: 2020-002142-17.

The significance of endogenous immune surveillance in acute lymphoblastic leukemia (ALL) remains controversial. Using clinical B-ALL samples and a novel mouse model, we show that neoantigen-specific CD4+ T-cells are induced to adopt type-1 regulatory (Tr1) function in the leukemia microenvironment. Tr1s then inhibit cytotoxic CD8+ T-cells, preventing effective leukemia clearance. Leukemic cells induce Tr1s by phenocopying hematopoietic stem cells, which normally are subject to effective surveillance by this CD4+ subset. This mechanism effectively redirects Tr1 cells from a role in preventing cancer to maladaptively promoting clinical relapse. In mouse models, addition of IL10R blockade to cytotoxic therapy modestly affected Tr1 development but was insufficient to improve leukemia control. In contrast, combined therapy with a cytotoxic agent and anti-PDL1 blockade eradicated measurable residual disease. This correlates with polarization of the neoantigen-specific CD4+ T-cell population from Tr1 towards Th1 states. Our findings uncover a mechanism that enables leukemic relapse and resolves existing controversies on the role of immune surveillance towards this cancer type. Therapeutic polarization of neoantigen-specific CD4+ T-cells away from Tr1 and towards Th1 states may improve contemporary immune therapies by reshaping the immune microenvironment towards states permissive for cytotoxic attack of residual leukemia.

ABSTRACTInnate lymphoid cells (ILCs) are tissue-resident lymphocytes that regulate tissue homeostasis and immune responses. How ILCs modulate T cells remains incompletely understood. To investigate the interaction between ILCs and T cells, we differentiated ILC2s and ILC3s from hematopoietic stem cells (HSCs). Both suppressed T cell proliferation, enhanced cytokine production, and upregulated T cell senescence-associated surface receptors (CD57, KLRG1, TIGIT, and TIM3). T cells exposed to ILCs also increased expression of senescence-related proteins, including p16, p21, p53, GATA4, and NF-κB. Mechanistically, ILCs produced IL-9, and IL-9 blockade prevented ILC-driven T cell senescence. Conversely, addition of exogenous IL-9 to T cells recapitulated the effects of ILC co-culture. Finally, in both human xenogeneic and murine allogeneic hematopoietic cell transplantation (HCT) models, we observed ILC-mediated T cell modulation in vivo, with evidence of T cell senescence. In conclusion, HSC-derived ILCs from both humans and mice mitigate graft-versus-host disease (GVHD) by inducing T cell senescence.

Current therapies, including autologous CAR-T immunotherapy, fail to cure half of infants with KMT2A-rearranged acute lymphoblastic leukemia (KMT2Ar-ALL), a disease characterized by frequent central nervous system involvement, poor treatment response, early relapse and lineage switching. More effective treatment strategies, including the availability of 'off-the-shelf' immunotherapies is particularly relevant in infants. PROM1/CD133 is a direct target of KMT2A-fusion oncoproteins and is expressed on leukemic cells. Allogeneic iNKT cells, 'innately' more powerful effectors than T cells can be deployed 'off-the-shelf' without risk of acute graft-versus-host disease. Here, we equip iNKT with CD19- and/or CD133-targeting CARs and investigate their anti-leukaemia activity against KMT2Ar-ALL in relevant in vitro and in vivo models. Compared to mono-specific counterparts and dual, bi-specific CAR-T, bi-specific CD19-CD133 CAR-iNKT have a more potent anti-leukemia activity, effectively targeting both CAR antigen-high and -low leukemia. Bi-specific CAR-iNKT eradicate medullary and, notably, leptomeningeal leukemia and induce sustained remissions without discernible hematologic toxicity. Mechanistically, the more potent anti-leukemia effect of CAR-iNKT over CAR-T cells is mediated by a pronounced CAR- and CAR antigen-dependent upregulation of the innate activating receptor NKG2D on CAR-iNKT and its engagement by its corresponding ligands on KMT2Ar-ALL cells. This ensures effective leukemia targeting even with downregulation of CD133 or CD19. Thus, by engaging with two different types of leukemia-associated antigens i.e., CAR antigens and NKG2D ligands, CAR-iNKT provide a powerful platform for the treatment of KMT2Ar-ALL. This approach can be readily adapted for other high-risk malignancies, including those with otherwise difficult to target leptomeningeal involvement.

The acquisition of N-glycosylation sites occupied by oligomannose-type glycans in the immunoglobulin complementarity-determining region (CDR) is an early clonal tumor-specific identifier of follicular lymphoma (FL). CDR-located N-glycosylation sites are also acquired in germinal-center-B-cell-like diffuse large B-cell lymphomas (GCB-DLBCL), but their significance is less defined. We used RNA-seq immunoglobulin assembly to determine the frequency and CDR location of the acquired N-glycosylation sites (AGS) in two large independent DLBCL cohorts. Composition of the glycans occupying the AGS was determined using liquid chromatography-mass spectrometry and correlated with cell-of-origin, FL signature (defined by EZB phenotype or BCL2 translocation), transcript profile, and clinical outcome. CDR-located AGS were observed in 41-46% of GCB-DLBCL but were rare in other DLBCL. Only CDR-located AGS of DLBCL with an FL signature were occupied by oligomannose-type glycans. These DLBCL were termed Mann-type DLBCL. Conversely, the AGS of the other DLBCL were either non-glycosylated or occupied by complex-type glycans. Mann-type status was an independent marker of short progression-free survival and overall survival. In contrast, the other GCB-DLBCL cases, including those with an FL signature but without AGS, had the best outcomes. Mann-type DLBCL overexpressed gene-sets of cell growth, survival, and cycling, and underexpressed proinflammatory and apoptotic pathways, irrespective of concomitant MYC translocations. Acquisition of Mann-type glycans is a highly selective environmental pressure, identifying an aggressive GCB-DLBCL type with an origin related to FL. The detection of AGS in the CDR of GCB-DLBCLs with an FL signature defines Mann-type DLBCLs, refines prognosis and marks a precise tumor interaction to block early therapeutically.

Genomic profiling in chronic-phase chronic myeloid leukemia (CP-CML) patients demonstrated somatic variants in blood cancer-related genes (CGVs) and rearrangements associated with the formation of the Philadelphia-chromosome (Ph-associated rearrangements) at diagnosis, collectively termed additional genetic abnormalities (AGA). AGAs had a negative impact on failure-free survival and molecular response in imatinib-treated patients. We investigated whether treatment with more potent therapies could overcome the negative impact of AGAs at diagnosis. Targeted RNA-based next generation sequencing (NGS) was performed on diagnostic samples of 315 patients consecutively enrolled in four clinical trials of frontline potent tyrosine kinase inhibitors (TKIs) in CP-CML. AGAs were present in 34% of patients at diagnosis, including 20% with CGVs and 18% with Ph-associated rearrangements (4% had both). While the negative impact of Ph-associated rearrangements was overcome by more potent inhibitors, patients with CGVs continued to have inferior outcomes. This was largely attributable to patients with ASXL1 variants, observed in 7% overall. Comparing patients with ASXL1 variants to ASXL1 wildtype: 12-month major molecular response 55% versus 83% (P=0.001); 2-year failure-free survival 61% versus 91% (P<0.001); and notably, development of treatment emergent BCR::ABL1 kinase domain mutations at 2 years, 35% versus 1% (P<0.001). In multivariable models, CGVs and ASXL1 variants were predictors of each of these outcomes. Treatment with frontline potent TKIs overcame the negative impact of Ph-associated rearrangements observed with frontline imatinib. However, inferior outcomes were still associated with the presence of CGVs. The acquisition of TKI-resistant BCR::ABL1 mutations was almost exclusively associated with mutated ASXL1 at diagnosis.

Histone deacetylase inhibitors (HDACi) are valued treatment options for patients with T-cell malignancies. Romidepsin is a selective Class I HDACi initially approved for patients with relapsed or refractory (R/R) CTCL and PTCL. Romidepsin was withdrawn from its PTCL indication following a negative randomized Phase IV study (Ro-CHOP) that showed no benefit over CHOP alone, further diminishing options for patients. Herein, we describe the development of a first-in-class polymer nanoparticle (PNP) of romidepsin using an innovative amphiphilic di-block copolymer-based nanochemistry platform. Nanoromidepsin exhibited superior pharmacologic properties with improved tolerability and safety in murine models of T-cell lymphoma (TCL). The PNP also exhibited superior anti-tumor efficacy in multiple models including in vitro -TCL cell lines, ex vivo LGL leukemia patient samples, and murine TCL xenografts. Nanoromidepsin demonstrated greater accumulation in tumors and a statistically significant improvement in overall survival compared to romidepsin in murine xenograft models. These findings justify the clinical development of Nanoromidepsin in patients with T-cell malignancies.

Success of chimeric antigen receptor (CAR) T-cell therapy in lymphoid malignancies has not yet been recapitulated in acute myeloid leukemia (AML). We developed CAR T-cells targeting CD371 with a mutated CD28 costimulatory domain to limit T-cell exhaustion, and constitutive interleukin-18 secretion to enhance immune function (CD371/SAVVY/IL-18 CAR). We initiated a phase I trial (NCT06017258), successfully manufactured and administered CD371/SAVVY/IL-18 CAR T-cells in 5 patients with relapsed/refractory AML and observed expansion following a single infusion of 3x104 or 3x105 CAR T-cells/kg; three patients refractory to ≥5 lines of therapy and post-allogeneic transplant exhibited AML clearance and no evidence of graft-versus-host disease. Dose-limiting toxicity in the two patients treated with 3x105 CAR T-cells/kg dose (prolonged cytopenias with marrow hypoplasia; severe cytokine release syndrome) led to dose reduction to 3x104 CAR T-cells/kg in the following three patients. Single-cell analyses revealed that circulating CAR T-cells in responders included predominantly cytotoxic CD8+ effector T-cells 2 weeks post-infusion while co-existing NK-cells expressed markers of activation. This pilot study highlights the activity of low-dose IL-18 "armored" CAR T-cells against refractory AML and their potential to promote CAR T-cell cytotoxicity and innate endogenous anti-tumor immunity. NCT06017258.

Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare thrombotic microangiopathy mediated through inherited deficiency in ADAMTS13 (a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13). To date more than 200 ADAMTS13 genetic variants have been associated with cTTP. We report longitudinal follow up from the UK TTP registry in 104 confirmed cTTP cases (91 consented for follow-up) in a large multi-ethnic national cTTP patient cohort, including a large Black African cTTP cohort. 71 ADAMTS13 variants were identified, with N-terminal variants associated with earlier age at presentation. During the follow-up period (median 63 months (range 1-179), 80.2% of patients received regular (plasma derived) prophylaxis which reduced end-organ damage, including stroke/TIA (19.0% to 1.5%) and renal impairment during follow-up. Post presentation acute TTP episodes were reduced with prophylaxis (0.68 vs 0.06 acute episodes/follow-up year) Despite regular prophylaxis, symptom control remained apparent on plasma-derived therapy (including headache 42.6%, depression/anxiety 13.2%, fatigue 16.2% and abdominal pain 13.2%). The majority of cTTP patients in the UK have now switched to recombinant ADAMTS13 (n=43, 58.9%), owing to inadequate symptom control (53.5%), plasma reactions (30.2%), or subclinical disease activity (16.3%). This work shows the breadth of ADAMTS13 genetic variants in cTTP, and demonstrates efficacy of regular prophylaxis in (i) reducing acute TTP episodes, and (ii) preventing end organ damage, but despite advances, cTTP related symptoms and the use of blood products, remained problematic.