Abstract

Comprising only 1-10% of the circulating T cell population, γδT cells play a pivotal role in cancer immunotherapy due to their unique amalgamation of innate and adaptive immune features. These cells can secrete cytokines, including interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α), and can directly eliminate tumor cells through mechanisms like Fas/FasL and antibody-dependent cell-mediated cytotoxicity (ADCC). Unlike conventional αβT cells, γδT cells can target a wide variety of cancer cells independently of major histocompatibility complex (MHC) presentation and function as antigen-presenting cells (APCs). Their ability of recognizing antigens in a non-MHC restricted manner makes them an ideal candidate for allogeneic immunotherapy. Additionally, γδT cells exhibit specific tissue tropism, and rapid responsiveness upon reaching cellular targets, indicating a high level of cellular precision and adaptability. Despite these capabilities, the therapeutic potential of γδT cells has been hindered by some limitations, including their restricted abundance, unsatisfactory expansion, limited persistence, and complex biology and plasticity. To address these issues, gene-engineering strategies like the use of chimeric antigen receptor (CAR) T therapy, T cell receptor (TCR) gene transfer, and the combination with γδT cell engagers are being explored. This review will outline the progress in various engineering strategies, discuss their implications and challenges that lie ahead, and the future directions for engineered γδT cells in both monotherapy and combination immunotherapy.

View details for DOI 10.3389/fimmu.2024.1360237

View details for PubMedID 38576617

View details for PubMedCentralID PMC10991697

Abstract

Immunocompromised individuals are at increased risk for severe disease and complications from viral infections, highlighting the importance of vaccination. However, in extremely rare situations, vaccine associated viral infections can be associated with disseminated disease and complications in immunocompromised hosts.Herein, we present a case of a 1-year-old child diagnosed with acute myeloid leukemia less than 2 weeks after receiving live viral vaccines who developed acute vaccine-strain measles virus disease, later complicated by central nervous system involvement following hematopoietic stem cell transplantation. A brain biopsy specimen was positive for vaccine-strain measles virus detected by reverse transcriptase polymerase chain reaction.She was treated with intravenous ribavirin, inosine pranobex, intrathecal interferon-alpha and donor lymphocyte infusion following measles-mumps-rubella vaccine boost. Despite these measures, the patient suffered neurologic decline and dysautonomia, expiring after compassionate extubation. Management and ideal risk mitigation strategies are discussed within the context of existing literature for this rare complication.

View details for DOI 10.1097/INF.0000000000004299

View details for PubMedID 38380931

Abstract

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.

View details for DOI 10.1016/j.jcyt.2024.02.005

View details for PubMedID 38483362

Abstract

Studies of the monogenic autoimmune disease immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) have elucidated the essential function of the transcription factor FOXP3 and thymic-derived regulatory T cells (Tregs) in controlling peripheral tolerance. However, the presence and the source of autoreactive T cells in IPEX remain undetermined. Here, we investigated how FOXP3 deficiency affects the T cell receptor (TCR) repertoire and Treg stability in vivo and compared T cell abnormalities in patients with IPEX with those in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED). To study Tregs independently of their phenotype and to analyze T cell autoreactivity, we combined Treg-specific demethylation region analyses, single-cell multiomic profiling, and bulk TCR sequencing. We found that patients with IPEX, unlike patients with APECED, have expanded autoreactive T cells originating from both autoreactive effector T cells (Teffs) and Tregs. In addition, a fraction of the expanded Tregs from patients with IPEX lost their phenotypic and functional markers, including CD25 and FOXP3. Functional experiments with CRISPR-Cas9-mediated FOXP3 knockout Tregs and Tregs from patients with IPEX indicated that the patients' Tregs gain a TH2-skewed Teff-like function, which is consistent with immune dysregulation observed in these patients. Analyses of FOXP3 mutation-carrier mothers and a patient with IPEX after hematopoietic stem cell transplantation indicated that Tregs expressing nonmutated FOXP3 prevent the accumulation of autoreactive Teffs and unstable Tregs. These findings could be directly used for diagnostic and prognostic purposes and for monitoring the effects of immunomodulatory treatments.

View details for DOI 10.1126/scitranslmed.adg6822

View details for PubMedID 38117899

Abstract

Hematopoietic stem cell transplantation (HSCT) represents a consolidated therapeutic strategy for high-risk pediatric acute lymphoblastic leukemia (ALL), offering the potential for curative treatment. This manuscript delves into the debate around the more universal application of HSCT for pediatric ALL in the modern era, considering the ubiquitous availability of suitable donors. In fact, despite significant advancements in chemotherapy, targeted therapy, and immunotherapy, a subset of pediatric patients with ALL with high-risk features or relapse continue to encounter poor prognostic outcomes. For this subgroup of patients, HSCT often remains the only potentially curative measure, leveraging the graft-versus- leukemia effect for long-term disease control. Nevertheless, the procedure's complexity and associated risks have traditionally curtailed its widespread use. However, the scenario is shifting with improvements in HLA matching, availability of alternative donor sources, less toxic conditioning regimens, and improved supportive care protocols. Concurrently, emerging therapies like CD19+ CAR T cells present new considerations for definitive therapy selection in relapsed/ refractory ALL. This article reviews critical current evidence and debates the potential of HSCT as a more universal treatment for ALL, reevaluating traditional treatment stratification in light of the constant availability of stem cell donors.

View details for DOI 10.1182/hematology.2023000423

View details for PubMedID 38066901

Abstract

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.

View details for DOI 10.1016/j.jcyt.2023.11.004

View details for PubMedID 38054912

Abstract

Serial prognostic evaluation of patients after allogeneic hematopoietic cell transplantation (alloHCT) might help identify patients at high risk of developing potentially lethal organ dysfunction. Current prediction algorithms are based on models that do not incorporate changes to the patients' clinical condition that occur after alloHCT in the model development, which limits their predictive ability. We developed and validated a robust risk-prediction algorithm to predict short-term and long-term survival after alloHCT in pediatric patients that includes baseline biological variables, as well as changes in the patients' clinical status after alloHCT. The model was developed using clinical data from children and young adults treated at a single academic quaternary-care referral center. The model was created using a randomly split training dataset (70% of the cohort), internally validated (remaining 30% of the cohort from the same center), and then externally validated on patient data from another tertiary-care referral center. Repeated clinical measurements performed from 30 days before alloHCT to 30 days afterwards were extracted from the electronic medical record and incorporated into the model to predict survival at 100 days, 1-year, and 2-years after alloHCT. Of the 738 patients who underwent their first alloHCT at our institution between 2000 and 2020, 517 (70%) were randomly included in the training dataset and 221 (30%) constituted the validation dataset. When compared with models constructed from baseline variables alone, the naïve-Bayes machine learning models incorporating longitudinal data were significantly better at predicting whether patients would be alive or deceased at the given timepoints. This proof-of-concept study demonstrates that unlike traditional prognostic tools that use fixed variables for risk assessment, incorporating dynamic variability using clinical and laboratory data improves the prediction of mortality in patients undergoing alloHCT.

View details for DOI 10.1182/bloodadvances.2023011752

View details for PubMedID 37991991

View details for DOI 10.1182/blood-2023-178400

View details for Web of Science ID 001159306700230

View details for DOI 10.1182/blood-2023-190968

View details for Web of Science ID 001159900807106

View details for DOI 10.1182/blood-2023-179456

View details for Web of Science ID 001159306708024