Linvoseltamab for Treatment of Relapsed/Refractory Multiple Myeloma.

Purpose: We present a phase I/II first-in-human trial evaluating the safety and efficacy of 50 mg and 200 mg doses of linvoseltamab, a B-cell maturation antigen × CD3 bispecific antibody in relapsed/refractory multiple myeloma (RRMM).

Methods: Phase II eligible patients had RRMM that either progressed on/after ≥three lines of therapy including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody or was triple-class (PI/IMiD/anti-CD38) refractory. Phase II treatment was once a week through week 14 and then once every 2 weeks.

Optimizing the therapeutic window of sirolimus by monitoring blood concentration for the treatment of immune thrombocytopenia.

Previous studies have demonstrated that sirolimus (SRL) is an effective agent for the treatment of refractory/relapsed (R/R) ITP. However, the therapeutic window of sirolimus in the treatment of ITP has not been established. As the toxicity of sirolimus increases with higher blood concentrations, it is crucial to determine the optimal therapeutic concentration of SRL for the treatment of ITP.

Donor T cell STAT3 deficiency enables tissue PD-L1-dependent prevention of graft-versus-host disease while preserving graft-versus-leukemia activity.

STAT3 deficiency (STAT3-/-) in donor T cells prevents graft-versus-host disease (GVHD), but the impact on graft-versus-leukemia (GVL) activity and mechanisms of GVHD prevention remains unclear. Here, using murine models of GVHD, we show that STAT3-/- donor T cells induced only mild reversible acute GVHD while preserving GVL effects against nonsusceptible acute lymphoblastic leukemia (ALL) cells in a donor T cell dose-dependent manner. GVHD prevention depended on programmed death ligand 1/programmed cell death protein 1 (PD-L1/PD-1) signaling.

Azacitidine and lenalidomide combination: a novel relapse prophylaxis regimen after allogeneic hematopoietic stem-cell transplantation in patients with acute myeloid leukemia.

Introduction: While allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be a curative regimen for acute myeloid leukemia (AML), relapse of AML remains a serious risk post-transplantation. Once relapsed, salvage options are limited and management of AML is difficult. Here we designed a prospective study to examine the efficacy and tolerability of maintenance therapy with azacytidine (AZA) plus low-dose lenalidomide (LEN) to prevent relapse after allo-HSCT for AML patients (ChiCTR2200061803).

Blockade of trans PD-L1 interaction with CD80 augments antitumor immunity.

PD-L1 has two receptors: PD-1 and CD80. Previous reports assumed that PD-L1 and CD80 interacted in trans, but recent reports showed that only cis PD-L1/CD80 interactions existed, and prevention of cis PD-L1/CD80 interactions on antigen-presenting cells (APCs) reduced antitumor immunity via augmenting PD-L1/PD-1 and CD80/CTLA4 interactions between T and APCs. Here, using tumor-bearing mice capable of cis and trans or trans only PD-L1/CD80 interactions, we show that trans PD-L1/CD80 interactions do exist between tumor and T cells, and the effects of trans PD-L1/CD80 interactions require tumor cell expression of MHC-I and T cell expression of CD28.

Progress on the efficacy and potential mechanisms of rapamycin in the treatment of immune thrombocytopenia.

Objective: The complex pathogenesis of relapsed and refractory (R/R) immune thrombocytopenia (ITP) contributes to the varied efficacy and tolerability of current treatment regimens. Rapamycin, an immunomodulatory agent, was originally used in the prevention of organ rejection after organ transplantation. Additional evidence now shows that rapamycin can successfully treat R/R ITP.

Trafficking between clonally related peripheral T-helper cells and tissue-resident T-helper cells in chronic GVHD.

Chronic graft-versus-host disease (cGVHD) is an autoimmune-like syndrome. CXCR5-PD-1hi peripheral T-helper (Tph) cells have an important pathogenic role in autoimmune diseases, but the role of Tph cells in cGVHD remains unknown. We show that in patients with cGVHD, expansion of Tph cells among blood CD4+ T cells was associated with cGVHD severity.

Clinical characteristics in immune thrombocytopenia patients after COVID-19 vaccination.

It is well documented that COVID-19 vaccines greatly reduce the severity and complications of SARS-CoV-2 infection. However, it has been reported that COVID-19 related vaccines may induce or exacerbate autoimmune hematological disorders, for example, a decrease in platelet numbers characteristic of immune thrombocytopenia (ITP). To investigate this, we retrospectively reported, for the first time, the clinical characteristics of 42 ITP patients after COVID-19 vaccination in southwest China.

microRNA-142 guards against autoimmunity by controlling Treg cell homeostasis and function.

Regulatory T (Treg) cells are critical in preventing aberrant immune responses. Posttranscriptional control of gene expression by microRNA (miRNA) has recently emerged as an essential genetic element for Treg cell function. Here, we report that mice with Treg cell-specific ablation of miR-142 (hereafter Foxp3CremiR-142fl/fl mice) developed a fatal systemic autoimmune disorder due to a breakdown in peripheral T-cell tolerance.

The Addition of Sirolimus to GVHD Prophylaxis After Allogeneic Hematopoietic Stem Cell Transplantation: A Meta-Analysis of Efficacy and Safety.

Objective: The objective of this study was to evaluate the safety and efficacy of sirolimus (SRL) in the prevention of graft--host disease (GVHD) in recipients following allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Methods: Randomized controlled trials (RCTs) evaluating the safety and efficacy of SRL-based prophylaxis regimens in patients receiving allo-HSCT were obtained from PubMed, Embase, and the Cochrane database. Following specific inclusion and exclusion criteria, studies were selected and screened by two independent reviewers who subsequently extracted the study data.

Case Report: PD-1 Blockade Combined Autologous Hematopoietic Stem Cell Transplantation With Modified BEAM Regimen Containing High-Dose Cytarabine to Treat R/R Hodgkin's Lymphoma.

The emergence of new drugs has provided additional options in the treatment of relapsed and refractory (R/R) Hodgkin's lymphoma (HL). However, the use of autologous stem cell transplantation (ASCT) has not been completely replaced in this setting. The use of anti-programmed death-1 (PD-1) antibody bridging to ASCT and as maintenance after transplantation is a novel approach in HL treatment.

The Role of mTOR Inhibitors in Hematologic Disease: From Bench to Bedside.

The mTOR pathway plays a central role in many cellular processes, such as cellular growth, protein synthesis, glucose, and lipid metabolism. Aberrant regulation of mTOR is a hallmark of many cancers, including hematological malignancies. mTOR inhibitors, such as Rapamycin and Rapamycin analogs (Rapalogs), have become a promising class of agents to treat malignant blood diseases-either alone or in combination with other treatment regimens.

Effect of rhG-CSF Combined With Decitabine Prophylaxis on Relapse of Patients With High-Risk MRD-Negative AML After HSCT: An Open-Label, Multicenter, Randomized Controlled Trial.

Purpose: Relapse is a major cause of treatment failure after allogeneic hematopoietic stem-cell transplantation (allo-HSCT) for high-risk acute myeloid leukemia (HR-AML). The aim of this study was to explore the effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) combined with minimal-dose decitabine (Dec) on the prevention of HR-AML relapse after allo-HSCT.

Patients And Methods: We conducted a phase II, open-label, multicenter, randomized controlled trial.

Sirolimus as Rescue Therapy for Refractory/Relapsed Immune Thrombocytopenia: Results of a Single-Center, Prospective, Single-Arm Study.

Immune thrombocytopenia (ITP) is an autoimmune disease which arises due to self-destruction of circulating platelets. Failure to respond or maintain a response to first-line treatment can lead to refractory/relapsed (R/R) ITP. The mechanism remains complicated and lacks a standard clinical treatment.

TET2 Function in Hematopoietic Malignancies, Immune Regulation, and DNA Repair.

Over the last decade, investigation of () gene function and mutation have become of increasing interest in the field of hematology. This heightened interest was sparked by the seminal discoveries that (1) mutation is associated with development of hematological malignancies and that (2) the TET family of proteins is critical in promoting DNA demethylation and immune homeostasis. Since then, additional studies have begun to unravel the question "Does TET2 have additional biological functions in the regulation of hematopoiesis?" Here, we present a mini-review focused on the current understanding of TET2 in hematopoiesis, hematological malignancies, and immune regulation.

Regulation of GVHD and GVL Activity via PD-L1 Interaction With PD-1 and CD80.

Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy for hematological malignancies (i.e. leukemia and lymphoma), because graft-versus-leukemia (GVL) activity mediated by alloreactive T cells can eliminate residual malignant cells and prevent relapse.

PD-L1 interacts with CD80 to regulate graft-versus-leukemia activity of donor CD8+ T cells.

Programmed death ligand-1 (PD-L1) interacts with programmed death-1 (PD-1) and the immunostimulatory molecule CD80 and functions as a checkpoint to regulate immune responses. The interaction of PD-L1 with CD80 alone has been shown to exacerbate the severity of graft-versus-host disease (GVHD), whereas costimulation of CD80 and PD-1 ameliorates GVHD. Here we have demonstrated that temporary depletion of donor CD4+ T cells early after hematopoietic cell transplantation effectively prevents GVHD while preserving strong graft-versus-leukemia (GVL) effects in allogeneic and xenogeneic murine GVHD models.

Increased Expression of System xc- in Glioblastoma Confers an Altered Metabolic State and Temozolomide Resistance.

Unlabelled: Glioblastoma multiforme is the most aggressive malignant primary brain tumor in adults. Several studies have shown that glioma cells upregulate the expression of xCT (SLC7A11), the catalytic subunit of system x, a transporter involved in cystine import, that modulates glutathione production and glioma growth. However, the role of system x in regulating the sensitivity of glioma cells to chemotherapy is currently debated.

Antibodies from donor B cells perpetuate cutaneous chronic graft-versus-host disease in mice.

Cutaneous sclerosis is one of the most common clinical manifestations of chronic graft-versus-host disease (cGVHD). Donor CD4(+) T and B cells play important roles in cGVHD pathogenesis, but the role of antibodies from donor B cells remains unclear. In the current studies, we generated immunoglobulin (Ig)H(µγ1) DBA/2 mice whose B cells have normal antigen-presentation and regulatory functions but cannot secrete antibodies.

MHC-mismatched mixed chimerism augments thymic regulatory T-cell production and prevents relapse of EAE in mice.

Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system with demyelination, axon damage, and paralysis. Induction of mixed chimerism with allogeneic donors has been shown to not cause graft-versus-host disease (GVHD) in animal models and humans. We have reported that induction of MHC-mismatched mixed chimerism can cure autoimmunity in autoimmune NOD mice, but this approach has not yet been tested in animal models of MS, such as experimental autoimmune encephalomyelitis (EAE).

B7H1/CD80 interaction augments PD-1-dependent T cell apoptosis and ameliorates graft-versus-host disease.

Interactions of B7H1 (programmed death ligand 1 [PD-L1]) with its two ligands, PD-1 and CD80, on T cells play a pivotal role in controlling T cell activation, proliferation, anergy, and apoptosis. However, the interactions between the two pathways remain unknown. Using an alloimmune response model of graft-versus-host disease (GVHD), we report in this study that: 1) Comparison of proliferation and apoptosis of wild-type (WT) and PD-1(-/-)CD4(+) conventional T (Tcon) cells in WT and B7H1(-/-) recipients revealed that B7H1/CD80 interaction per se augments T cell proliferation, and this interaction augments T cell apoptosis mediated by B7H1/PD-1 interaction.

Administration of anti-CD20 mAb is highly effective in preventing but ineffective in treating chronic graft-versus-host disease while preserving strong graft-versus-leukemia effects.

Chronic graft-versus-host disease (cGVHD) is an autoimmune-like syndrome, and donor B cells play important roles in augmenting its pathogenesis. B cell-depleting anti-CD20 mAb has been administered before or after cGVHD onset for preventing or treating cGVHD in the clinic. Although administration before onset appeared to be more effective, the effect is variable and sometimes minimal.

Depletion of host CCR7(+) dendritic cells prevented donor T cell tissue tropism in anti-CD3-conditioned recipients.

We reported previously that anti-CD3 mAb treatment before hematopoietic cell transplantation (HCT) prevented graft-versus-host disease (GVHD) and preserved graft-versus-leukemia (GVL) effects in mice. These effects were associated with downregulated donor T cell expression of tissue-specific homing and chemokine receptors, marked reduction of donor T cell migration into GVHD target tissues, and deletion of CD103(+) dendritic cells (DCs) in mesenteric lymph nodes (MLN). MLN CD103(+) DCs and peripheral lymph node (PLN) DCs include CCR7(+) and CCR7(-) subsets, but the role of these DC subsets in regulating donor T cell expression of homing and chemokine receptors remain unclear.