Allogeneic haematopoietic stem cell transplantation (allo-HSCT) was the first successful therapy for patients with haematological malignancies, predominantly owing to graft-versus-tumour (GvT) ...effects. Dramatic methodological changes, designed to expand eligibility for allo-HSCT to older patients and/or those with comorbidities, have led to the use of reduced-intensity conditioning regimens, in parallel with more aggressive immunosuppression to better control graft-versus-host disease (GvHD). Consequently, disease relapse has become the major cause of death following allo-HSCT. Hence, the prevention and treatment of relapse has come to the forefront and remains an unmet medical need. Despite >60 years of preclinical and clinical studies, the immunological requirements necessary to achieve GvT effects without promoting GvHD have not been fully established. Herein, we review learnings from preclinical modelling and clinical studies relating to the GvT effect, focusing on mechanisms of relapse and on immunomodulatory strategies that are being developed to overcome disease recurrence after both allo-HSCT and autologous HSCT. Emphasis is placed on discussing current knowledge and approaches predicated on the use of cell therapies, cytokines to augment immune responses and dual-purpose antibody therapies or other pharmacological agents that can control GvHD whilst simultaneously targeting cancer cells.
With the increasing use of mismatched, unrelated, and granulocyte colony-stimulating factor–mobilized peripheral blood stem cell donor grafts and successful treatment of older recipients, chronic ...graft-versus-host disease (cGVHD) has emerged as the major cause of nonrelapse mortality and morbidity. cGVHD is characterized by lichenoid changes and fibrosis that affects a multitude of tissues, compromising organ function. Beyond steroids, effective treatment options are limited. Thus, new strategies to both prevent and treat disease are urgently required. Over the last 5 years, our understanding of cGVHD pathogenesis and basic biology, born out of a combination of mouse models and correlative clinical studies, has radically improved. We now understand that cGVHD is initiated by naive T cells, differentiating predominantly within highly inflammatory T-helper 17/T-cytotoxic 17 and T-follicular helper paradigms with consequent thymic damage and impaired donor antigen presentation in the periphery. This leads to aberrant T- and B-cell activation and differentiation, which cooperate to generate antibody-secreting cells that cause the deposition of antibodies to polymorphic recipient antigens (ie, alloantibody) or nonpolymorphic antigens common to both recipient and donor (ie, autoantibody). It is now clear that alloantibody can, in concert with colony-stimulating factor 1 (CSF-1)-dependent donor macrophages, induce a transforming growth factor β–high environment locally within target tissue that results in scleroderma and bronchiolitis obliterans, diagnostic features of cGVHD. These findings have yielded a raft of potential new therapeutics, centered on naive T-cell depletion, interleukin-17/21 inhibition, kinase inhibition, regulatory T-cell restoration, and CSF-1 inhibition. This new understanding of cGVHD finally gives hope that effective therapies are imminent for this devastating transplant complication.
Clinical application of umbilical cord blood (UCB) as a source of hematopoietic stem cells for transplantation is limited by low CD34+ cell dose, increased risk of graft failure, and slow ...hematopoietic recovery. While the cell dose limitation is partially mitigated by using two UCB units, larger-dosed single units would be preferable. We have evaluated the feasibility and safety of StemRegenin-1 (SR-1), an aryl hydrocarbon receptor antagonist that expands CD34+ cells, by placing one of the two units in expansion culture. SR-1 produced a 330-fold increase in CD34+ cells and led to engraftment in 17/17 patients at a median of 15 days for neutrophils and 49 days for platelets, significantly faster than in patients treated with unmanipulated UCB. Taken together, the marked expansion, absence of graft failure, and enhanced hematopoietic recovery support testing of SR-1 expansion as a stand-alone graft and suggest it may ameliorate a limitation of UCB transplant.
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•SR-1 led to significant expansion of CD34+ HSPCs in culture•Seventeen patients with hematological malignancy received SR-1 expanded UCB•SR-1 expanded cells were co-infused with a second unexpanded UCB unit•SR-1 expansion improved neutrophil and platelet recovery compared to controls
Clinical testing of the aryl hydrocarbon antagonist StemRegenin-1 showed robust expansion of hematopoietic stem and progenitor cells and an adequate safety profile in the setting of double UCB transplant, supporting its further testing for safety and efficacy as a stand-alone graft after myeloablative conditioning.
Current approaches to prevent and treat graft-versus-host disease (GVHD) after stem cell transplantation rely principally on pharmacological immune suppression. Such approaches are limited by drug ...toxicity, nonspecific immune suppression, and a requirement for long-term therapy. Our increased understanding of the regulatory cells and molecular pathways involved in limiting pathogenic immune responses opens the opportunity for the use of these cell subsets to prevent and/or GVHD. The theoretical advantages of this approach is permanency of effect, potential for facilitating tissue repair, and induction of tolerance that obviates a need for ongoing drug therapy. To date, a number of potential cell subsets have been identified, including FoxP3+ regulatory T (Treg) and FoxP3negIL-10+ (FoxP3-negative) regulatory T (Tr1), natural killer (NK) and natural killer T (NKT) cells, innate lymphoid cells, and various myeloid suppressor populations of hematopoietic (eg, myeloid derived suppressor cells) and stromal origin (eg, mesenchymal stem cells). Despite initial technical challenges relating to large-scale selection and expansion, these regulatory lineages are now undergoing early phase clinical testing. To date, Treg therapies have shown promising results in preventing clinical GVHD when infused early after transplant. Results from ongoing studies over the next 5 years will delineate the most appropriate cell lineage, source (donor, host, third party), timing, and potential exogenous cytokine support needed to achieve the goal of clinical transplant tolerance.
During the past decade, progress in basic immunology has been impressive. In parallel, whereas our understanding of the pathophysiology of acute graft-versus-host disease (GVHD) has greatly improved, ...so has our knowledge of the complexities of the immune system. Much of the immunobiology of acute GVHD has been gleaned from preclinical models and far less from correlations with clinical observations or therapeutic interventions. In this review, we summarize some of the major advances in GVHD pathophysiology, including the translation of these from the bench to the bedside, and discuss preclinical approaches that warrant further exploration in the clinic.
The success of allogeneic hematopoietic cell transplantation (HCT) is typically assessed as individual complications, including graft-versus-host disease (GVHD), relapse, or death, yet no one factor ...can completely characterize cure without ongoing morbidity. We examined a novel composite end point of GVHD-free/relapse-free survival (GRFS) in which events include grade 3-4 acute GVHD, systemic therapy-requiring chronic GVHD, relapse, or death in the first post-HCT year. In 907 consecutive University of Minnesota allogeneic HCT recipients (2000-2012), 1-year GRFS was 31% (95% confidence interval CI 28-34). Regression analyses showed age, disease risk, and donor type significantly influencing GRFS. Adults age 21+ had 2-fold worse GRFS vs children; GRFS did not differ beyond age 21. Adjusted for conditioning intensity, stem cell source, disease risk, age, and transplant year, HLA-matched sibling donor marrow resulted in the best GRFS (51%, 95% CI 46-66), whereas HLA-matched sibling donor peripheral blood stem cells were significantly worse (25%, 95% CI 20-30, P = .01). GRFS after umbilical cord blood transplants and marrow from matched unrelated donors were similar (31%, 95% CI 27-35 and 32%, 95% CI 22-42, respectively). Because GRFS measures freedom from ongoing morbidity and represents ideal HCT recovery, GRFS has value as a novel end point for benchmarking new therapies.
•GRFS is a new composite end point useful for comparing HCT techniques and represents ideal post-HCT recovery.•In our cohort of 907 allogeneic HCT recipients, 1-year GRFS was 31%, with best outcomes in recipients of marrow from matched sibling donors.
Allogeneic haematopoietic stem cell transplantation is used to treat a variety of disorders, but its efficacy is limited by the occurrence of graft-versus-host disease (GVHD). The past decade has ...brought impressive advances in our understanding of the role of stimulatory and suppressive elements of the adaptive and innate immune systems from both the donor and the host in GVHD pathogenesis. New insights from basic immunology, preclinical models and clinical studies have led to novel approaches for prevention and treatment. This Review highlights the recent advances in understanding the pathophysiology of GVHD and its treatment, with a focus on manipulations of the immune system that are amenable to clinical application.
Over the last decade, our understanding of the pathophysiology of chronic graft-versus-host disease (cGVHD) has improved considerably. In this spotlight, we discuss emerging insights into the ...pathophysiology of cGVHD with a focus on B cells. First, we summarize supporting evidence derived from mouse and human studies. Next, novel cGVHD therapy approaches that target B cells will be covered to provide treating physicians with an overview of the rationale behind the emerging armamentarium against cGVHD.
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