Anti-CD30 CAR T cells as consolidation after autologous haematopoietic stem-cell transplantation in patients with high-risk CD30 lymphoma: a phase 1 study.

Background: Chimeric antigen receptor (CAR) T cells targeting CD30 are safe and have promising activity when preceded by lymphodepleting chemotherapy. We aimed to determine the safety of anti-CD30 CAR T cells as consolidation after autologous haematopoietic stem-cell transplantation (HSCT) in patients with CD30 lymphoma at high risk of relapse.

Methods: This phase 1 dose-escalation study was performed at two sites in the USA.

Third-party type 2 innate lymphoid cells prevent and treat GI tract GvHD.

Acute graft-versus-host disease (aGVHD), mediated by the recognition of host major histocompatibility complex/peptide polymorphisms by donor T cells, remains a significant complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). aGVHD most commonly involves the gastrointestinal tract, liver, and skin; symptomatic aGVHD is treated with corticosteroids. Steroid-nonresponsive aGVHD is a significant problem for patients undergoing allo-HSCT, with <15% of these patients alive 1 year after diagnosis.

Influence of Germline Genetics on Tacrolimus Pharmacokinetics and Pharmacodynamics in Allogeneic Hematopoietic Stem Cell Transplant Patients.

Tacrolimus exhibits high inter-patient pharmacokinetics (PK) variability, as well as a narrow therapeutic index, and therefore requires therapeutic drug monitoring. Germline mutations in cytochrome P450 isoforms 4 and 5 genes () and the ATP-binding cassette B1 gene () may contribute to interindividual tacrolimus PK variability, which may impact clinical outcomes among allogeneic hematopoietic stem cell transplantation (HSCT) patients. In this study, 252 adult patients who received tacrolimus for acute graft versus host disease (aGVHD) prophylaxis after allogeneic HSCT were genotyped to evaluate if germline genetic variants associated with tacrolimus PK and pharmacodynamic (PD) variability.

R707, a fully human antibody directed against CC-chemokine receptor 7, attenuates xenogeneic acute graft-versus-host disease.

Acute graft-versus-host disease (aGVHD) remains a barrier to the success of allogeneic hematopoietic stem cell transplantation (HSCT). Previously, we demonstrated that CC-chemokine receptor 7 (CCR7) is critical for aGVHD pathogenesis but dispensable for beneficial graft-versus-leukemia responses. As a result, we evaluated a fully human anti-CCR7-blocking antibody as a new approach to prevent aGVHD in preclinical models.

The Ex Vivo Treatment of Donor T Cells with Cosalane, an HIV Therapeutic and Small-Molecule Antagonist of CC-Chemokine Receptor 7, Separates Acute Graft-versus-Host Disease from Graft-versus-Leukemia Responses in Murine Hematopoietic Stem Cell Transplantation Models.

Despite recent advances in therapy, allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative option for a range of high-risk hematologic malignancies. However, acute graft-versus-host disease (aGVHD) continues to limit the long-term success of HSCT, and new therapies are still needed. We previously demonstrated that aGVHD depends on the ability of donor conventional T cells (T) to express the lymph node trafficking receptor, CC-Chemokine Receptor 7 (CCR7).

Evaluation of a Test Dose Strategy for Pharmacokinetically-Guided Busulfan Dosing for Hematopoietic Stem Cell Transplantation.

Targeted busulfan dosing helps limit chemotherapy-related toxicity and optimize disease outcomes in hematopoietic stem cell transplantation (HCT). The objective of this study was to evaluate busulfan exposure from a pharmacokinetic (PK)-guided dosing strategy using a test dose. This retrospective evaluation included adult patients who underwent HCT at our institution with busulfan-based myeloablative (>9 mg/kg) conditioning between January 2014 and October 2015.

Impaired bone marrow B-cell development in mice with a bronchiolitis obliterans model of cGVHD.

Chronic graft-versus-host disease (cGVHD) causes significant morbidity and mortality in patients after allogeneic bone marrow (BM) or stem cell transplantation (allo-SCT). Recent work has indicated that both T and B lymphocytes play an important role in the pathophysiology of cGVHD. Previously, our group showed a critical role for the germinal center response in the function of B cells using a bronchiolitis obliterans (BO) model of cGVHD.

18F-3'-Deoxy-3'-Fluorothymidine Positron Emission Tomography Imaging for the Prediction of Acute Graft-Versus-Host Disease in Mouse Hematopoietic Stem Cell Transplant Models.

Acute graft-versus-host disease (aGVHD) remains a barrier to the success of allogeneic hematopoietic stem cell transplantation. In mice, studies have demonstrated that donor conventional T cells traffic into host secondary lymphoid tissues early after transplant, and that this process is critical for the development of disease. As a result, the measurement of cellular proliferation within lymphoid sites early after transplant might be a useful approach for predicting aGVHD in humans.

Identification of Cosalane as an Inhibitor of Human and Murine CC-Chemokine Receptor 7 Signaling via a High-Throughput Screen.

CC-chemokine receptor 7 (CCR7) is a G protein-coupled receptor expressed on a variety of immune cells. CCR7 plays a critical role in the migration of lymphocytes into secondary lymphoid tissues. CCR7 expression, however, has been linked to numerous disease states.

T-cell expression of AhR inhibits the maintenance of pT cells in the gastrointestinal tract in acute GVHD.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that affects the function and development of immune cells. Here, we show that recipient mice receiving AhR T cells have improved survival and decreased acute graft-versus-host disease (aGVHD) in 2 different murine allogeneic bone marrow transplant (BMT) models. We also show that CD4 T cells lacking AhR demonstrate reduced accumulation in secondary lymphoid tissue because of low levels of proliferation 4 days after BMT.

Type 2 innate lymphoid cells treat and prevent acute gastrointestinal graft-versus-host disease.

Acute graft-versus-host disease (aGVHD) is the most common complication for patients undergoing allogeneic stem cell transplantation. Despite extremely aggressive therapy targeting donor T cells, patients with grade III or greater aGVHD of the lower GI tract, who do not respond to therapy with corticosteroids, have a dismal prognosis. Thus, efforts to improve understanding of the function of local immune and non-immune cells in regulating the inflammatory process in the GI tract during aGVHD are needed.

Targeting the Canonical Nuclear Factor-κB Pathway with a High-Potency IKK2 Inhibitor Improves Outcomes in a Mouse Model of Idiopathic Pneumonia Syndrome.

Idiopathic pneumonia syndrome (IPS) is a noninfectious inflammatory disorder of the lungs that occurs most often after fully myeloablative allogeneic hematopoietic stem cell transplantation (HSCT). IPS can be severe and is associated with high 1-year mortality rates despite existing therapies. The canonical nuclear factor-(NF) κB signaling pathway has previously been linked to several inflammatory disorders of the lung, including asthma and lung allograft rejection.

Peptide/MHC tetramer-based sorting of CD8⁺ T cells to a leukemia antigen yields clonotypes drawn nonspecifically from an underlying restricted repertoire.

Testing of T cell-based cancer therapeutics often involves measuring cancer antigen-specific T-cell populations with the assumption that they arise from in vivo clonal expansion. This analysis, using peptide/MHC tetramers, is often ambiguous. From a leukemia cell line, we identified a CDK4-derived peptide epitope, UNC-CDK4-1 (ALTPVVVTL), that bound HLA-A*02:01 with high affinity and could induce CD8⁺ T-cell responses in vitro.

Altered T-cell entry and egress in the absence of Coronin 1A attenuates murine acute graft versus host disease.

Acute graft-versus-host disease (aGvHD) is a major limitation to the use of allogeneic stem cell transplantation for the treatment of patients with relapsed malignant disease. Previous work using animals lacking secondary lymphoid tissue (SLT) suggested that activation of donor T cells in SLT is critically important for the pathogenesis of aGvHD. However, these studies did not determine if impaired migration into, and more importantly, out of SLT, would ameliorate aGvHD.

Intravital imaging of donor allogeneic effector and regulatory T cells with host dendritic cells during GVHD.

Graft-versus-host disease (GVHD) is a systemic inflammatory response due to the recognition of major histocompatibility complex disparity between donor and recipient after hematopoietic stem cell transplantation (HSCT). T-cell activation is critical to the induction of GVHD, and data from our group and others have shown that regulatory T cells (Tregs) prevent GVHD when given at the time of HSCT. Using multiphoton laser scanning microscopy, we examined the single cell dynamics of donor T cells and dendritic cells (DCs) with or without Tregs postallogeneic transplantation.

CC chemokine receptor 8 potentiates donor Treg survival and is critical for the prevention of murine graft-versus-host disease.

The infusion of donor regulatory T cells (Tregs) has been used to prevent acute graft-versus-host disease (GVHD) in mice and has shown promise in phase 1 clinical trials. Previous work suggested that early Treg migration into lymphoid tissue was important for GVHD prevention. However, it is unclear how and where Tregs function longitudinally to affect GVHD.

Attenuation of acute graft-versus-host disease in the absence of the transcription factor RORγt.

Graft-versus-host disease (GVHD) remains the most significant complication after allogeneic stem cell transplantation. Previously, acute GVHD had been considered to be mediated predominantly by Th1-polarized T cells. Recently, investigators have identified a second proinflammatory lineage of T cells termed Th17 that is critically dependent on the transcription factor retinoic acid-related orphan receptor (ROR)γt.

Effector CD4+ T cells, the cytokines they generate, and GVHD: something old and something new.

GVHD is a syndrome that results from minor and major histocompatibility complex incompatibilities between the donor and recipient. More than 50 years after its initial description, the pathophysiology of GVHD remains poorly understood. Nonetheless, donor T cells have been shown to be critical to the pathophysiology of acute and chronic GVHD, yet precisely how they function remains unclear.

Separation of graft-versus-host disease from graft-versus-leukemia responses by targeting CC-chemokine receptor 7 on donor T cells.

CC-chemokine receptor 7 (CCR7) is expressed on the surface of naive T cells, and plays a critical role in their movement into secondary lymphoid tissue. Here, we show that murine T cells lacking CCR7 (CCR7(-/-)) generate attenuated graft-versus-host disease (GVHD) responses compared with wild-type (WT) cells, with the difference varying inversely with the degree of major histocompatibility complex (MHC) disparity between the donor and recipient. CCR7(-/-) T cells exhibited an impaired ability to traffic to recipient lymph nodes, with an increased capacity to home to the spleen.

In vitro-differentiated TH17 cells mediate lethal acute graft-versus-host disease with severe cutaneous and pulmonary pathologic manifestations.

The morbidity and mortality associated with graft-host-disease (GVHD) is a significant obstacle to the greater use of allogeneic stem cell transplantation. Donor T cells that predominantly differentiate into TH1/Tc1 T cells and generate pro-inflammatory cytokines such as interferon-gamma (IFN-gamma) mediate GVHD. Although numerous studies have described a pathogenic role for IFN-gamma, multiple reports have demonstrated that the lack of IFN-gamma paradoxically exacerbated GVHD lethality.

The biology and therapeutic potential of natural regulatory T-cells in the bone marrow transplant setting.

Graft-versus-host disease (GVHD) remains a major barrier to the long-term success of allogeneic hematopoietic stem-cell transplantation for hematologic malignancies. This has prompted a great deal of interest in the development of alternative GVHD management strategies such as the adoptive transfer of lymphocytes with immunosuppressant activity. This review will focus on the biology of thymically derived regulatory T-cells (Tregs) and their potential therapeutic role in human bone marrow transplantation.