Is it possible to separate the graft-versus-leukemia (GVL) effect against B cell acute lymphoblastic leukemia from graft-versus-host disease (GVHD) after hematopoietic cell transplant?

Hematopoietic cell transplant is a curative therapy for many pediatric patients with high risk acute lymphoblastic leukemia. Its therapeutic mechanism is primarily based on the generation of an alloreactive graft-versus-leukemia effect that can eliminate residual leukemia cells thus preventing relapse. However its efficacy is diminished by the concurrent emergence of harmful graft-versus-host disease disease which affects healthly tissue leading to significant morbidity and mortality. The purpose of this review is to describe the interventions that have been trialed in order to augment the beneficial graft-versus leukemia effect post-hematopoietic cell transplant while limiting the harmful consequences of graft-versus-host disease. This includes many emerging and promising strategies such a

Immunometabolic Therapeutic Targets of Graft-versus-Host Disease (GvHD)

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative option in the treatment of aggressive malignant and non-malignant blood disorders. However, the benefits of allo-HSCT can be compromised by graft-versus-host disease (GvHD), a prevalent and morbid complication of allo-HSCT. GvHD occurs when donor immune cells mount an alloreactive response against host antigens due to histocompatibility differences between the donor and host, which may result in extensive tissue injury. The reprogramming of cellular metabolism is a feature of GvHD that is associated with the differentiation of donor CD4+ cells into the pathogenic Th1 and Th17 subsets along with the dysfunction of the immune-suppressive protective T regulatory cells (Tregs). The activation of glycolysis and glutaminolysis with concomitant changes in fatty acid oxidation metabolism fuel the anabolic activities of the proliferative alloreactive microenvironment characteristic of GvHD. Thus, metabolic therapies such as glycolytic enzyme inhibitors and fatty acid metabolism modulators are a promising therapeutic strategy for GvHD. We comprehensively review the role of cellular metabolism in GvHD pathogenesis, identify candidate therapeutic targets, and describe potential strategies for augmenting immunometabolism to ameliorate GvHD

Targeting of chimeric antigen receptor T cell metabolism to improve therapeutic outcomes

Genetically engineered chimeric antigen receptor (CAR) T cells can cure patients with cancers that are refractory to standard therapeutic approaches. To date, adoptive cell therapies have been less effective against solid tumors, largely due to impaired homing and function of immune cells within the immunosuppressive tumor microenvironment (TME). Cellular metabolism plays a key role in T cell function and survival and is amenable to manipulation. This manuscript provides an overview of known aspects of CAR T metabolism and describes potential approaches to manipulate metabolic features of CAR T to yield better anti-tumor responses. Distinct T cell phenotypes that are linked to cellular metabolism profiles are associated with improved anti-tumor responses. Several steps within the CAR T manufacture process are amenable to interventions that can generate and maintain favorable intracellular metabolism phenotypes. For example, co-stimulatory signaling is executed through metabolic rewiring. Use of metabolic regulators during CAR T expansion or systemically in the patient following adoptive transfer are described as potential approaches to generate and maintain metabolic states that can confer improved in vivo T cell function and persistence. Cytokine and nutrient selection during the expansion process can be tailored to yield CAR T products with more favorable metabolic features. In summary, improved understanding of CAR T cellular metabolism and its manipulations have the potential to guide the development of more effective adoptive cell therapies

Impaired Bone Mineral Density in Pediatric Patients with Chronic Graft-Versus-Host Disease

Pediatric allogeneic hematopoietic stem cell transplantation (AHSCT) recipients with chronic graft-versus-host disease (cGVHD) are at high risk for endocrinopathies, particularly impaired bone mineral density (BMD). However, rates of BMD impairment in pediatric AHSCT recipients with cGVHD have not been well documented. We report 33 patients with cGVHD who were referred to the National Institutes of Health (NIH) for the Natural History of Clinical and Biological Factors Determining Outcomes in Chronic Graft-versus-Host Disease Study (NCT 0092235) and underwent formal BMD assessment via dual-energy X-ray absorptiometry (DEXA). Not surprisingly, we found much higher rates of BMD impairment than previously reported for pediatric AHSCT recipients who were not stratified by the presence or absence of cGVHD. Most of these patients (73%) had a z-score ≤-2 in at least 1 anatomic site. Although we expected the rate to be higher than that observed for pediatric AHSCT recipients in studies that did not analyze patients with cGVHD separately, this rate is nonetheless extremely high. Furthermore, the overall rate of occult vertebral compression fractures (VCFs) in our cohort was 17%, and the rate was 23% in patients with at least 1 z-score of ≤-2. The rates of BMD impairment and VCF in our pediatric cohort were significantly higher than those seen in the adult AHSCT recipients who were concurrently enrolled on the same study at the NIH and had similar cGVHD severity. We found that older age at cGVHD diagnosis and a greater number of systemic therapies were associated with occult VCF. Moreover, the intensity of current immunosuppression negatively impacted lumbar spine and total hip BMD in this cohort. Our study, although limited by small patient numbers and lack of a control AHSCT recipient group without cGVHD, indicates that children with cGVHD are at a greater risk for BMD impairment than previously appreciated. Given the rising incidence of cGVHD in AHSCT recipients and our findings, we recommend that pre-AHSCT DEXA be incorporated into routine pediatric pretransplantation screening studies. A baseline DEXA study could facilitate longitudinal monitoring of BMD in children, who may be more susceptible than adults to the negative effects of AHSCT on BMD. In addition, given the high risk of BMD impairment in pediatric AHSCT recipients with cGVHD, such patients should undergo BMD evaluation upon developing cGVHD, with continued monitoring thereafter to allow intervention before progression of the BMD impairment to its severe manifestation, VCF