Strategic infection prevention after genetically modified hematopoietic stem cell therapies: recommendations from the International Society for Cell & Gene Therapy Stem Cell Engineering Committee.

There is lack of guidance for immune monitoring and infection prevention after administration of ex vivo genetically modified hematopoietic stem cell therapies (GMHSCT). We reviewed current infection prevention practices as reported by providers experienced with GMHSCTs across North America and Europe, and assessed potential immunologic compromise associated with the therapeutic process of GMHSCTs described to date. Based on these assessments, and with consensus from members of the International Society for Cell & Gene Therapy (ISCT) Stem Cell Engineering Committee, we propose risk-adapted recommendations for immune monitoring, infection surveillance and prophylaxis, and revaccination after receipt of GMHSCTs. Disease-specific and GMHSCT-specific considerations should guide decision making for each therapy.

Engineering the best transplant outcome for high-risk acute myeloid leukemia: the donor, the graft and beyond.

Allogeneic hemopoietic cell transplantation remains the goal of therapy for high-risk acute myeloid leukemia (AML). However, treatment failure in the form of leukemia relapse or severe graft-versus-host disease remains a critical area of unmet need. Recently, significant progress has been made in the cell therapy-based interventions both before and after transplant. In this review, the Stem Cell Engineering Committee of the International Society for Cell and Gene Therapy summarizes the literature regarding the identification of high risk in AML, treatment approaches before transplant, optimal transplant platforms and measures that may be taken after transplant to ideally prevent, or, if need be, treat AML relapse. Although some strategies remain in the early phases of clinical investigation, they are built on progress in pre-clinical research and cellular engineering techniques that are already improving outcomes for children and adults with high-risk malignancies.

Prospective assessment of risk biomarkers of sinusoidal obstruction syndrome after hematopoietic cell transplantation.

BACKGROUNDCurrently, no laboratory tests exist to stratify for the risk of developing sinusoidal obstruction syndrome (SOS), an early endothelial complication after hematopoietic cell transplantation (HCT). Risk biomarkers of SOS have not been verified in a prospective cohort accounting for differences between practices across institutions. Herein, we aimed to define risk groups for SOS occurrence using 3 proteins: L-ficolin, hyaluronic acid (HA), and stimulation 2 (ST2). METHODSBetween 2017 and 2021, we prospectively accrued 80 pediatric patients across 4 US centers. Biomarkers were tested by ELISA blind to patient groupings and associated with SOS incidence on day 35 after HCT, and overall survival (OS) on day 100 after HCT. Cutpoints were identified using retrospective cohorts and applied to the prospective cohort.RESULTSCombination of the 3 biomarkers measured on day 3 after HCT in the prospective cohort provided 80% (95% CI 55%-100%) sensitivity and 73% (95% CI 62%-83%) specificity for risk of SOS occurrence. Patients with low L-ficolin were 9 times (95% CI 3-32) more likely to develop SOS, while patients with high HA and ST2 were 6.5 (95% CI 1.9-22.0) and 5.5 (95% CI 2.3-13.1) times more likely to develop SOS. These 3 markers also predicted worse day 100 OS - L-ficolin: HR, 10.0 (95% CI 2.2-45.1), P = 0.0002; HA: HR, 4.1 (95% CI 1.0-16.4), P = 0.031; and ST2: HR, 3.9 (95% CI 0.9-16.4), P = 0.04.CONCLUSIONL-ficolin, HA, and ST2 levels measured as early as 3 days after HCT improved risk stratification for SOS occurrence and OS and may guide risk-adapted preemptive therapy.TRIAL REGISTRATIONClinicalTrials.gov NCT03132337.FUNDINGNIH.

Current Definitions and Clinical Implications of Biomarkers in Graft-versus-Host Disease.

Hematopoietic cell transplantation (HCT) is a potentially curative treatment for many hematologic and nonhematologic disorders. Graft-versus-host-disease (GVHD) in its acute or chronic form remains the most important nonrelapse post-HCT complication. Biomarkers offer objective, unbiased information on systemic disorders, and significant attention has focused on identifying biomarkers for GVHD. Ideally, a GVHD biomarker is actionable, with the results of biomarker testing used to guide clinical management of disease and clinical trial design. Although many GVHD biomarkers have been identified, none have been properly qualified for clinical use. The National Institutes of Health (NIH) and Food and Drug Administration (FDA) have provided biomarker subtype definitions; however, confusion remains about the proper definition and application of these subtypes in the HCT field. The 2014 NIH consensus development project provided a framework for the development of biomarkers for clinical practice. This review aims to clarify the biomarker subtype definitions and reemphasize the developmental framework. Armed with this knowledge, clinicians can properly translate GVHD biomarkers for clinical use.

Regenerating islet-derived protein 3-α is a prognostic biomarker for gastrointestinal chronic graft-versus-host disease.

Prognostic biomarkers used to identify likelihood of disease progression have not been identified for chronic graft-versus-host disease (cGVHD), the leading cause of late nonrelapse mortality (NRM) in survivors of allogeneic hematopoietic cell transplantation. Gastrointestinal cGVHD (GI-cGVHD) has been particularly challenging to classify. Here, we analyzed 3 proteomics markers (Regenerating islet-derived protein 3-α [Reg3α], C-X-C motif ligand 9 [CXCL9], and Stimulation-2 [ST2]) in 2 independent cohorts of patients with cGVHD totaling 289 patients. Plasma concentrations of Reg3α were significantly increased in patients with GI-cGVHD (P = .0012) compared with those without (P = .01), but plasma concentrations of CXCL9 and ST2 were not. Patients with high Reg3α (≥72 ng/mL) vs low Reg3α had higher NRM (23% vs 11%; P = .015). Because Reg3α has been identified as a lower GI tract marker in acute GVHD, we correlated Reg3α with lower acute-like GI-cGVHD vs classical fibrotic-like esophageal manifestations and found that Reg3α did not differ between the subtypes. No difference was observed between upper GI tract and lower GI tract subtypes. Patients with extremely high Reg3α (≥180 ng/mL) had higher GI scores but not higher scores for the lower GI tract. In a multivariable Cox regression model, patients with high Reg3α were 1.9 times more likely to die without relapse. Our findings demonstrate the utility of Reg3α as a prognostic marker for GI-cGVHD. These data warrant prospective biomarker validation studies.

T Cell Subsets in Graft Versus Host Disease and Graft Versus Tumor.

Allogeneic hematopoietic cell transplantation (allo-HCT) is an essential therapeutic modality for patients with hematological malignancies and other blood disorders. Unfortunately, acute graft-versus-host disease (aGVHD) remains a major source of morbidity and mortality following allo-HCT, which limits its use in a broader spectrum of patients. Chronic graft-versus-host disease (cGVHD) also remains the most common long-term complication of allo-HCT, occurring in reportedly 30-70% of patients surviving more than 100 days. Chronic GVHD is also the leading cause of non-relapse mortality (NRM) occurring more than 2 years after HCT for malignant disease. Graft versus tumor (GVT) is a major component of the overall beneficial effects of allogeneic HCT in the treatment of hematological malignancies. Better understanding of GVHD pathogenesis is important to identify new therapeutic targets for GVHD prevention and therapy. Emerging data suggest opposing roles for different T cell subsets, e.g., IFN-γ producing CD4+ and CD8+ T cells (Th1 and Tc1), IL-4 producing T cells (Th2 and Tc2), IL-17 producing T cells (Th17 and Tc17), IL-9 producing T cells (Th9 and Tc9), IL-22 producing T cells (Th22), T follicular helper cells (Tfh), regulatory T-cells (Treg) and tissue resident memory T cells (Trm) in GVHD and GVT etiology. In this review, we first summarize the general description of the cytokine signals that promote the differentiation of T cell subsets and the roles of these T cell subsets in the pathogenesis of GVHD. Next, we extensively explore preclinical findings of T cell subsets in both GVHD/GVT animal models and humans. Finally, we address recent findings about the roles of T-cell subsets in clinical GVHD and current strategies to modulate T-cell differentiation for treating and preventing GVHD in patients. Further exploring and outlining the immune biology of T-cell differentiation in GVHD that will provide more therapeutic options for maintaining success of allo-HCT.

An overview of multiplexed analyses of CAR T-cell therapies: insights and potential.

INTRODUCTION: Cancer immunotherapy is a rapidly growing field with exponential advancement in engineered immune cell-based therapies. For instance, an engineered chimeric antigen receptor (CAR) can be introduced in T-cells or other immune cells and adoptively transferred to target and kill cancer cells in hematologic malignancies or solid tumors. The first CAR-T-cell (CAR-T) therapy has been developed against CD19, a B-cell marker expressed on lymphoma and lymphoblastic leukemia. To allow for personalized treatment, proteomics approaches could provide insights into biomarkers for CAR-T therapy efficacy and toxicity. AREAS COVERED: We researched the most recent technology methods of biomarker evaluation used in the laboratory and clinical setting. Publications of CAR-T biomarkers were then systematically reviewed to provide a narrative of the most validated biomarkers of CAR-T efficacy and toxicity. Examples of biomarkers include CAR-T functionality and phenotype as well as interleukin-6 and other cytokines. EXPERT COMMENTARY: Biomarkers of CAR-T efficacy and toxicity have been identified, but still need to be validated and standardized across institutions. Moreover, few are used in the clinical setting due to limitations in real-time technology. Expansion of biomarker research could provide better understanding of patient response and risk of life-threatening side effects with potential for improved precision medicine.