Acute myeloid leukemia (AML) is a hematological malignancy derived from neoplastic myeloid progenitor cells characterized by abnormal clonal proliferation and differentiation. Although novel therapeutic strategies have recently been introduced, the prognosis of AML is still unsatisfactory. So far, the efficacy of chimeric antigen receptor (CAR)-T-cell therapy in AML has been hampered by several factors, including the poor accumulation of the blood-injected cells in the leukemia bone marrow (BM) niche in which chemotherapy-resistant leukemic stem cells reside. Thus, we hypothesized that overexpression of CXCR4, whose ligand CXCL12 is highly expressed by BM stromal cells within this niche, could improve T-cell homing to the BM and consequently enhance their intimate contact with BM-resident AML cells, facilitating disease eradication. Specifically, we engineered conventional CD33.CAR-cytokine-induced killer cells (CIKs) with the wild-type (wt) CXCR4 and the variant CXCR4R334X, responsible for leukocyte sequestration in the BM of patients with warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis syndrome. Overexpression of both CXCR4wt and CXCR4mut in CD33.CAR-CIKs resulted in significant improvement of chemotaxis toward recombinant CXCL12 or BM stromal cell-conditioned medium, with no observed impairment of cytotoxic potential in vitro. Moreover, CXCR4-overexpressing CD33.CAR-CIKs showed enhanced in vivo BM homing, associated with a prolonged retention for the CXCR4R334X variant. However, only CD33.CAR-CIKs coexpressing CXCR4wt but not CXCR4mut exerted a more sustained in vivo antileukemic activity and extended animal survival, suggesting a noncanonical role for CXCR4 in modulating CAR-CIK functions independent of BM homing. Taken together, these data suggest that arming CAR-CIKs with CXCR4 may represent a promising strategy for increasing their therapeutic potential for AML.
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http://dx.doi.org/10.1182/blood.2022018330 | DOI Listing |
Nat Commun
December 2024
Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, China.
Although acute myeloid leukemia (AML) affects hematopoietic stem cell (HSC)-supportive microenvironment, it is largely unknown whether leukemia-modified bone marrow (BM) microenvironment can be remodeled to support normal hematopoiesis after complete remission (CR). As a key element of BM microenvironment, endothelial progenitor cells (EPCs) provide a feasible way to investigate BM microenvironment remodeling. Here, we find reduced and dysfunctional BM EPCs in AML patients, characterized by impaired angiogenesis and high ROS levels, could be partially remodeled after CR and improved by N-acetyl-L-cysteine (NAC).
View Article and Find Full Text PDFHaemophilia
December 2024
Advanced Center for Oncology, Hematology and Rare Disorders (ACOHRD), K.J. Somaiya Super Speciality Hospital & Research Center, Somaiya Ayurvihar, Sion East, Mumbai, Maharashtra, India.
Introduction: Mortality and morbidity in persons with haemophilia (PWH) have decreased due to improved diagnosis and treatment along with comprehensive population outreach efforts, but the impact is not uniform in different countries.
Aim: The study aims to assess all-cause and intracranial haemorrhage (ICH)-specific mortality of PWH in India.
Methods: This is a retrospective, observational, multi-centric cohort study of 1020 haemophilia patients from three centres in India.
Elife
December 2024
Department of Dermatology, Course of Integrated Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan.
Psoriasis is a multifactorial disorder mediated by IL-17-producing T cells, involving immune cells and skin-constituting cells. Semaphorin 4A (Sema4A), an immune semaphorin, is known to take part in T helper type 1/17 differentiation and activation. However, Sema4A is also crucial for maintaining peripheral tissue homeostasis and its involvement in skin remains unknown.
View Article and Find Full Text PDFCancer Med
January 2025
Lymphoma and Cell Therapy Research Center, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Background: The prognostic significance of extranodal sites in stage IV diffuse large B-cell lymphoma (DLBCL) remains uncertain, making it challenging to select appropriate treatment strategies for individual patients. In this study, we aimed to evaluate the influence of different extranodal sites on prognosis in young patients with stage IV DLBCL who achieved complete remission (CR) following initial chemo-immunotherapy and to explore the potential of autologous hematopoietic stem cell transplantation (ASCT) as a consolidation treatment for specific patient subgroups.
Methods: We retrospectively reviewed data from 119 patients with DLBCL aged < 60 years who achieved CR after chemo-immunotherapy between 2008 and 2020.
J Pediatr Hematol Oncol
January 2025
Pediatric Bone Marrow Transplantation Unit, Istanbul Medipol University, Bagcilar, Istanbul, Turkey.
Introduction: Thrombocytopenia is a common clinical problem in cancer patients undergoing high-dose chemotherapy and autologous hematopoietic stem cell transplantation (HSCT). It can occur as prolonged isolated thrombocytopenia (PIT) or secondary failure of platelet recovery (SFPR) and may cause potentially fatal bleeding. However, data on the treatment of post-transplant thrombocytopenia is still lacking.
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