Rorc restrains the potency of ST2+ regulatory T cells in ameliorating intestinal graft-versus-host disease

Soluble stimulation-2 (ST2) is increased during graft-versus-host disease (GVHD), while Tregs that express ST2 prevent GVHD through unknown mechanisms. Transplantation of Foxp3- T cells and Tregs that were collected and sorted from different Foxp3 reporter mice indicated that in mice that developed GVHD, ST2+ Tregs were thymus derived and predominantly localized to the intestine. ST2-/- Treg transplantation was associated with reduced total intestinal Treg frequency and activation. ST2-/- versus WT intestinal Treg transcriptomes showed decreased Treg functional markers and, reciprocally, increased Rorc expression. Rorc-/- T cells transplantation enhanced the frequency and function of intestinal ST2+ Tregs and reduced GVHD through decreased gut-infiltrating soluble ST2-producing type 1 and increased IL-4/IL-10-producing type 2 T cells. Cotransfer of ST2+ Tregs sorted from Rorc-/- mice with WT CD25-depleted T cells decreased GVHD severity and mortality, increased intestinal ST2+KLRG1+ Tregs, and decreased type 1 T cells after transplantation, indicating an intrinsic mechanism. Ex vivo IL-33-stimulated Tregs (TregIL-33) expressed higher amphiregulin and displayed better immunosuppression, and adoptive transfer prevented GVHD better than control Tregs or TregIL-33 cultured with IL-23/IL-17. Amphiregulin blockade by neutralizing antibody in vivo abolished the protective effect of TregIL-33. Our data show that inverse expression of ST2 and RORγt in intestinal Tregs determines GVHD and that TregIL-33 has potential as a cellular therapy avenue for preventing GVHD

Outcome after allogeneic stem cell transplantation with haploidentical versus HLA-matched donors in patients with higher-risk MDS.

peer reviewedAllogeneic hematopoietic stem cell transplantation remains the best curative option for higher-risk myelodysplastic syndrome. The presence of monosomal karyotype and/or complex karyotype abnormalities predicts inferior survival after allo-SCT in MDS patients. Haploidentical allo-SCT has been increasingly used in acute leukemia (AL) and has similar results as using HLA-matched donors, but data on higher-risk MDS is sparse. We compared outcomes in 266 patients with higher-risk MDS after HLA-matched sibling donor (MSD, n = 79), HLA-matched unrelated donor (MUD, n = 139) and HLA haploidentical donor (HID, n = 48) from 2010 to 2019. Median donor age differed between the three groups (p < 0.001). The overall survival was significantly different between the three groups with a better OS observed in the MUD group (p = 0.014). This observation could be explained by a higher progression-free survival with MUD (p = 0.014). The cumulative incidence of grade 2-4 acute GvHD was significantly higher in the HID group (p = 0.051). However, in multivariable analysis, patients transplanted using an HID had comparable mortality to patients transplanted using a MUD (subdistribution hazard ratio [sHR]: 0.58 [0.32-1.07]; p = 0.080) and a MSD ([sHR]: 0.56 [0.28-1.11]; p = 0.094). MUD do not remain a significant positive predictor of survival, suggesting that beyond the donor-recipient HLA matching, the donor age might impact recipient outcome

Late relapse after hematopoietic stem cell transplantation for acute leukemia: a retrospective study by SFGM-TC.

peer reviewedLate relapse (LR) after allogeneic hematopoietic stem cell transplantation (AHSCT) for acute leukemia is a rare event (nearly 4.5%) and raises the questions of prognosis and outcome after salvage therapy. We performed a retrospective multicentric study between January 1, 2010, and December 31, 2016, using data from the French national retrospective register ProMISe provided by the SFGM-TC (French Society for Bone Marrow Transplantation and Cellular Therapy). We included patients presenting with LR, defined as a relapse occurring at least 2 years after AHSCT. We used the Cox model to identify prognosis factors associated with LR. During the study period, a total of 7582 AHSCTs were performed in 29 centers, and 33.8% of patients relapsed. Among them, 319 (12.4%) were considered to have LR, representing an incidence of 4.2% for the entire cohort. The full dataset was available for 290 patients, including 250 (86.2%) with acute myeloid leukemia and 40 (13.8%) with acute lymphoid leukemia. The median interval from AHSCT to LR was 38.2 months (interquartile range [IQR], 29.2 to 49.7 months), and 27.2% of the patients had extramedullary involvement at LR (17.2% exclusively and 10% associated with medullary involvement). One-third of the patients had persistent full donor chimerism at LR. Median overall survival (OS) after LR was 19.9 months (IQR, 5.6 to 46.4 months). The most common salvage therapy was induction regimen (55.5%), with complete remission (CR) obtained in 50.7% of cases. Ninety-four patients (38.5%) underwent a second AHSCT, with a median OS of 20.4 months (IQR, 7.1 to 49.1 months). Nonrelapse mortality after second AHSCT was 18.2%. The Cox model identified the following factors as associated with delay of LR: disease status not in first CR at first HSCT (odds ratio [OR], 1.31; 95% confidence interval [CI], 1.04 to 1.64; P = .02) and the use of post-transplantation cyclophosphamide (OR, 2.23; 95% CI, 1.21 to 4.14; P = .01). Chronic GVHD appeared to be a protective factor (OR, .64; 95% CI, .42 to .96; P = .04). The prognosis of LR is better than in early relapse, with a median OS after LR of 19.9 months. Salvage therapy associated with a second AHSCT improves outcome and is feasible, without creating excess toxicity

Cellules T régulatrices avec récepteur antigénique chimérique CD19SFv dans la prévention et le traitement de la maladie du greffon contre l’hôte aiguë et chronique

La greffe de cellules souches hématopoïétiques est une option curative pour de nombreuses maladies hématologiques malignes et bénignes. Cependant, son effet bénéfique est contrebalancé par le développement de la maladie du greffon contre l'hôte (GVHD) aiguë et chronique. Les options thérapeutiques permettant de réduire l'incidence et la gravité de la GVH reposent principalement sur des médicaments pan-immunosuppresseurs qui exposent le destinataire à des infections opportunistes et à une rechute de la maladie d'origine. Les immunothérapies à base de cellules T régulatrices (Treg) se sont révélées efficaces, mais sont limitées par les capacités de suppression variables entre les produits et le nombre de Treg. L’ingénierie des récepteur antigénique chimérique (CAR) donne maintenant la possibilité de rediriger les cellules T et d’augmenter leur fonction. Ici, nous avons testé le Treg CAR 4-1BB ciblant le CD19 humain (hCD19) pour supprimer la GVHD. Nous avons constaté que le CD19SFv-CAR Treg est spécifiquement activé via leur CAR. Cette hyperactivation confère des capacités métaboliques et suppressives plus élevées. Après l’activation du CAR, le CD19SFv-CAR Treg affiche des capacités de migration accrues vers l’intestin, principal organe cible de la GVHD. Les CD19SFv-CAR Treg préservent la réponse du greffon contre la leucémie (GvL) et présente une activité anti-tumorale. Dans un modele de cGVHD les CD19SFv-CAR Treg éliminent les cellules B du centre germinatif (cellules B de GC) et améliore la fonction pulmonaire des receveurs. Cette étude identifie les CAR-hCD19 Treg comme un moyen d’améliorer l’efficacité de l’immunothérapie par Treg en augmentant les capacités de suppression du Treg, leur migration et leur métabolisme sans modifier la réponse GvL du greffon.Allo-hematopoietic stem cell transplantation is a curative option for many malignant and benign hematologic disorders. However, its beneficial effect is counterbalanced by the development of acute and chronic graft versus host disease (GVHD). The therapeutic options to reduce GVHD incidence and severity mostly rely on pan immunosuppressive drugs that expose the recipient to opportunistic infections and relapse of the original disease. Regulatory T cell (Treg) therapies have proven efficient but are limited by inter product variable suppressive capacities and number of Treg. The chimeric antigen receptor (CAR) engineering now give the opportunity to redirect Tcell and increase their function. Here, we tested CAR 4-1BB Treg targeting the human CD19 (hCD19) to suppress GVHD. In aGVHD we found that CD19SFv-CAR Treg are specifically activated through their CAR. This hyperactivation confers higher metabolic and suppressive capacities. After CAR activation, CD19SFv-CAR Treg display increased homing abilities to the gut which is the main target organ in aGVHD. CD19SFv-CAR Treg preserve the Graft versus leukemia (GvL) response and display anti-tumor activity. In cGVHD CD19SFv-CAR Treg eliminate Germinal center B-cells (GC B-cells) and improve the pulmonary function of the recipients. This study identifies the CAR-hCD19 Treg as a way to improve Treg immunotherapy efficiency by increasing Treg suppressive capacities, homing, and metabolism without altering the GvL response of the graft

How I Treat TP53-Mutated Acute Myeloid Leukemia and Myelodysplastic Syndromes

TP53-mutated acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are among the myeloid malignancies with the poorest prognosis. In this review, we analyze the prognosis of these two diseases, focussing particularly on the extent of the mono or biallelic mutation status of TP53 mutation, which is largely correlated with cytogenetic complexity. We discuss the possible/potential improvement in outcome based on recent results obtained with new drugs (especially eprenetapopt and magrolimab). We also focus on the impact of allogeneic hematopoietic stem cell transplantation (aHSCT) including post aHSCT treatment

Effects of MicroRNA on Regulatory T Cells and Implications for Adoptive Cellular Therapy to Ameliorate Graft-versus-Host Disease

Regulatory T cells (Tregs) are key mediators of the immune system. MicroRNAs (miRNAs) are a family of ~22 nucleotide non-coding RNAs that are processed from longer precursors by the RNases Drosha and Dicer. miRNA regulates protein expression posttranscriptionally through mRNA destabilization or translational silencing. A critical role for miRNA in Treg function was initially discovered when both Dicer and Drosha knockout (KO) mice were found to develop a fatal autoimmune disease phenotypically similar to Foxp3 KO mice

Real‐life challenges using personalized prognostic scoring systems in acute myeloid leukemia

Abstract Personalized medicine is a challenge for patients with acute myeloid leukemia (AML). The identification of several genetic mutations in several AML trials led to the creation of a personalized prognostic scoring algorithm known as the Knowledge Bank (KB). In this study, we assessed the prognostic value of this algorithm on a cohort of 167 real life AML patients. We compared KB predicted outcomes to real‐life outcomes. For patients younger than 60‐year‐old, OS was similar in favorable and intermediate ELN risk category. However, KB algorithm failed to predict OS for younger patients in the adverse ELN risk category and for patients older than 60 years old in the favorable ELN risk category. These discrepancies may be explained by the emergence of several new therapeutic options as well as the improvement of allogeneic stem cell transplantation (aHSCT) outcomes and supportive cares. Personalized medicine is a major challenge and predictions models are powerful tools to predict patient's outcome. However, the addition of new therapeutic options in the field of AML requires a prospective validation of these scoring systems to include recent therapeutic innovations

Long-term outcomes of adults with first-relapsed/refractory systemic anaplastic large-cell lymphoma in the pre-brentuximab vedotin era: A LYSA/SFGM-TC study

International audienc

Real-Word Experience of CAR T-Cells in Patients with Relapsed/Refractory Follicular Lymphoma : A Descart Registry Analysis from the Lysa

International audienc