Acute Respiratory Distress Syndrome Phenotypes After Stem Cell Transplantation: A Latent Class Analysis.

Objective: To identify distinct phenotypes of acute respiratory distress syndrome (ARDS) developing after hematopoietic cell transplantation (HCT), using routinely available clinical data at ICU admission.

Design: Multicenter retrospective cohort study using latent class analysis.

Setting: ICUs across three Mayo Clinic campuses (Minnesota, Florida, and Arizona).

Inflammasome-resistant IPSC-derived myeloid-derived suppressor cells ameliorate xenogeneic graft-versus-host disease.

Front-line pharmaceutical treatment for treatment of acute graft-versus-host disease (aGVHD) is not uniformly effective and has toxic side effects. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells with potent in vitro and in vivo immunosuppressive functions. Clinical translation of in vitro generated MDSCs has been limited by the need for high MDSC:T cell ratios, multiple infusions to reduce inflammation and a relatively low peripheral blood-derived MDSC (PB-MDSCs) yield.

Characteristics of patients with newly diagnosed acute myeloid leukemia not receiving treatment.

Not available.

Differential susceptibility and role for senescence in CART cells based on costimulatory domains.

Despite the success of chimeric antigen receptor T (CART) cell therapy in hematological malignancies, durable remissions remain low. Here, we report CART senescence as a potential resistance mechanism in 41BB-costimulated CART cell therapy. To mimic cancer relapse, we utilized an in vitro model with repeated CART cell activation cycles followed by rest periods.

Intrinsic immunosuppressive features of monocytes suppress CAR-T19 through IL-1 pathway modulation in mantle cell lymphoma.

CD19-targeted chimeric antigen receptor T cells (CAR-T19) have shown remarkable success in B cell malignancies, but most patients relapse within 1-2 years. Here, we identified interleukin-1 (IL-1) receptor antagonist (IL-1ra) as a mediator of M2-like macrophage-derived inhibition of CAR-T19 in mantle cell lymphoma (MCL), as well as a potential target to enhance CAR-T19 efficacy. In preclinical models that recapitulated interactions between tumor, macrophages, and T cells, we demonstrated that M2-derived IL-1ra impairs IL-1 signaling and functions of CAR-T19.

Comparison of Chimerism Kinetics and Associated Outcomes in Patients Receiving Post-Transplant Cyclophosphamide Versus Methotrexate based GVHD Prophylaxis Following Allogeneic Hematopoietic Cell Transplant.

Post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis is now being used beyond haploidentical (HID) allogeneic hematopoietic cell transplant (alloHCT). However, the kinetics of chimerism in patients receiving PTCy and its impact on post-transplant relapse is unknown. In this study we describe the kinetics of donor chimerism in patients receiving PTCy, factors predisposing to mixed donor chimerism, and the associated survival outcomes.

Validation of the 5th edition of the World Health Organization and International Consensus Classification guidelines for TP53-mutated myeloid neoplasm in an independent international cohort.

The World Health Organization (WHO-5) and International Consensus Classification (ICC) acknowledge the poor prognosis of TP53-mutated (TP53) myeloid neoplasm (MN). However, there are substantial differences between the two classifications that may lead to under- or overestimation of the prognostic risk. We retrospectively applied WHO-5 and ICC to 603 MN cases harboring TP53 (variant allele frequency, VAF ≥ 2%).

Factors associated with survival after allogeneic transplantation for myeloid neoplasms harboring TP53 mutations.

Allogeneic hematopoietic stem cell transplant (alloHCT) is considered for all patients with myeloid neoplasms (MNs) harboring TP53 mutations (TP53mut). The aim of this international study across 7 transplant centers in the United States and Australia was to identify factors associated with improved post-alloHCT survival. Of 134 TP53mut MN cases who underwent alloHCT, 80% harbored complex karyotype; 94% of TP53 variants were localized to the DNA-binding domain (DBD).

Clinical Outcomes and Treatment Strategies of Adult Transplant-Associated Thrombotic Microangiopathy: External Validation of Harmonizing Definitions and High-Risk Criteria.

Transplant-associated thrombotic microangiopathy (TA-TMA) is an endothelial dysfunction syndrome observed after allogeneic hematopoietic cell transplant (alloHCT). Our aim was to externally validate the impact of high-risk features on the clinical outcomes of adult patients meeting the updated TA-TMA harmonizing criteria. Between 2005 and 2022, 99 patients were diagnosed with TA-TMA at Mayo Clinic Rochester (incidence 6.

Mesenchymal stromal cells with chimaeric antigen receptors for enhanced immunosuppression.

Allogeneic mesenchymal stromal cells (MSCs) are a safe treatment option for many disorders of the immune system. However, clinical trials using MSCs have shown inconsistent therapeutic efficacy, mostly owing to MSCs providing insufficient immunosuppression in target tissues. Here we show that antigen-specific immunosuppression can be enhanced by genetically modifying MSCs with chimaeric antigen receptors (CARs), as we show for E-cadherin-targeted CAR-MSCs for the treatment of graft-versus-host disease in mice.

CD19 occupancy with tafasitamab increases therapeutic index of CART19 cell therapy and diminishes severity of CRS.

In the development of various strategies of anti-CD19 immunotherapy for the treatment of B-cell malignancies, it remains unclear whether CD19 monoclonal antibody therapy impairs subsequent CD19-targeted chimeric antigen receptor T-cell (CART19) therapy. We evaluated the potential interference between the CD19-targeting monoclonal antibody tafasitamab and CART19 treatment in preclinical models. Concomitant treatment with tafasitamab and CART19 showed major CD19 binding competition, which led to CART19 functional impairment.

AXL Inhibition Improves the Antitumor Activity of Chimeric Antigen Receptor T Cells.

The receptor tyrosine kinase AXL is a member of the TYRO3, AXL, and proto-oncogene tyrosine-protein kinase MER family and plays pleiotropic roles in cancer progression. AXL is expressed in immunosuppressive cells, which contributes to decreased efficacy of immunotherapy. Therefore, we hypothesized that AXL inhibition could serve as a strategy to overcome resistance to chimeric antigen receptor T (CAR T)-cell therapy.

Emerging translational strategies and challenges for enhancing regulatory T cell therapy for graft-versus-host disease.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapy for many types of cancer. Genetic disparities between donor and host can result in immune-mediated attack of host tissues, known as graft versus host disease (GVHD), a major cause of morbidity and mortality following HSCT. Regulatory CD4+ T cells (Tregs) are a rare cell type crucial for immune system homeostasis, limiting the activation and differentiation of effector T cells (Teff) that are self-reactive or stimulated by foreign antigen exposure.

Murine CAR19 Tregs suppress acute graft-versus-host disease and maintain graft-versus-tumor responses.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) efficacy is complicated by graft-versus-host disease (GVHD), a leading cause of morbidity and mortality. Regulatory T cells (Tregs) have shown efficacy in preventing GVHD. However, high Treg doses are often required, necessitating substantial ex vivo or in vivo expansion that may diminish suppressor function.

GM-CSF disruption in CART cells modulates T cell activation and enhances CART cell anti-tumor activity.

Inhibitory myeloid cells and their cytokines play critical roles in limiting chimeric antigen receptor T (CART) cell therapy by contributing to the development of toxicities and resistance following infusion. We have previously shown that neutralization of granulocyte-macrophage colony-stimulating factor (GM-CSF) prevents these toxicities and enhances CART cell functions by inhibiting myeloid cell activation. In this report, we study the direct impact of GM-CSF disruption during the production of CD19-directed CART cells on their effector functions, independent of GM-CSF modulation of myeloid cells.

Dynamic Imaging of Chimeric Antigen Receptor T Cells with [18F]Tetrafluoroborate Positron Emission Tomography/Computed Tomography.

T cells genetically engineered to express chimeric antigen receptors (CAR) have shown unprecedented results in pivotal clinical trials for patients with B cell malignancies or multiple myeloma (MM). However, numerous obstacles limit the efficacy and prohibit the widespread use of CAR T cell therapies due to poor trafficking and infiltration into tumor sites as well as lack of persistence in vivo. Moreover, life-threatening toxicities, such as cytokine release syndrome or neurotoxicity, are major concerns.

Targeting cancer-associated fibroblasts in the bone marrow prevents resistance to CART-cell therapy in multiple myeloma.

Pivotal clinical trials of B-cell maturation antigen-targeted chimeric antigen receptor T (CART)-cell therapy in patients with relapsed/refractory multiple myeloma (MM) resulted in remarkable initial responses, which led to a recent US Food and Drug Administration approval. Despite the success of this therapy, durable remissions continue to be low, and the predominant mechanism of resistance is loss of CART cells and inhibition by the tumor microenvironment (TME). MM is characterized by an immunosuppressive TME with an abundance of cancer-associated fibroblasts (CAFs).

A novel Iowa-Mayo validated composite risk assessment tool for allogeneic stem cell transplantation survival outcome prediction.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative option for many hematologic conditions and is associated with considerable morbidity and mortality. Therefore, prognostic tools are essential to navigate the complex patient, disease, donor, and transplant characteristics that differentially influence outcomes. We developed a novel, comprehensive composite prognostic tool.

Emerging approaches to improve allogeneic hematopoietic cell transplantation outcomes for nonmalignant diseases.

Many congenital or acquired nonmalignant diseases (NMDs) of the hematopoietic system can be potentially cured by allogeneic hematopoietic cell transplantation (HCT) with varying types of donor grafts, degrees of HLA matching, and intensity of conditioning regimens. Unique features that distinguish the use of allogeneic HCT in this population include higher rates of graft failure, immune-mediated cytopenias, and the potential to achieve long-term disease-free survival in a mixed chimerism state. Additionally, in contrast to patients with hematologic malignancies, a priority is to completely avoid graft-versus-host disease in patients with NMD because there is no theoretical beneficial graft-versus-leukemia effect that can accompany graft-versus-host responses.

Regulatory T Cell Therapy of Graft-versus-Host Disease: Advances and Challenges.

Graft-versus-host disease (GVHD) is the leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Immunomodulation using regulatory T cells (Tregs) offers an exciting option to prevent and/or treat GVHD as these cells naturally function to maintain immune homeostasis, can induce tolerance following HSCT, and have a tissue reparative function. Studies to date have established a clinical safety profile for polyclonal Tregs.