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T-cell acute lymphoblastic leukemia (T-ALL) is a highly heterogeneous and aggressive subtype of hematologic malignancy, with limited therapeutic options due to the complexity of its pathogenesis. Although high-dose chemotherapy and allogeneic hematopoietic stem cell transplantation have improved outcomes for T-ALL patients, there remains an urgent need for novel treatments in cases of refractory or relapsed disease. Recent research has demonstrated the potential of targeted therapies aimed at specific molecular pathways to improve patient outcomes. Chemokine-related signals, both upstream and downstream, modulate the composition of distinct tumor microenvironments, thereby regulating a multitude of intricate cellular processes such as proliferation, migration, invasion and homing. Furthermore, the progress in research has made significant contributions to precision medicine by targeting chemokine-related pathways. This review article summarizes the crucial roles of chemokines and their receptors in T-ALL pathogenesis. Moreover, it explores the advantages and disadvantages of current and potential therapeutic options that target chemokine axes, including small molecule antagonists, monoclonal antibodies, and chimeric antigen receptor T-cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Opinion Statement: Chimeric antigen receptor (CAR) cell therapy offers patients with hematological malignancies a new therapeutic option. Traditionally, autologous T cells are used to generate CAR designed T cells for each patient. However, this method has several drawbacks, the development of allogeneic CAR cell therapy would be a promising breakthrough that could address several of these limitations. From the clinical trials that have published data, the efficacy of allogeneic CAR cell therapy did not meet the expectations. Because of the host-versus-graft (HvG) effect, allogeneic CAR cells are eliminated by the host, resulting in short-term persistence of allogeneic CAR cells and poor efficacy. It is critical to solve the HvG effect of allogeneic CAR cells. The current commonly used methods are suppressing the host's immune system, using HLA-matched homozygous donors, reducing the expression of HLA, targeting alloreactive lymphocytes and eliminating anti-CAR activities. In this review, we will focus on the HvG effect of the "off-the-shelf" allogeneic CAR cell therapy, especially its mechanism and current methods to solve this problem and summarize relevant clinical trial data., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Trial Registration: Effect of co-infusion third party umbilical cord blood stem cells on haploidentical hematopoietic stem cell transplantation https://www.chictr.org.cn Reg. No. ChiCTR-OIN-17011426.

Pretreatment before transplantation initiates an inflammatory response. Inflammasomes are key regulators of immune and inflammatory responses, but their role in regulating hematopoiesis is unclear. Our study intended to assess the role and mechanism of nucleotide-binding domain and leucine-rich repeat pyrin-domain containing protein 1 (NLRP1) in the bone marrow microenvironment on hematopoiesis regulation. To explore the effects of an absence of NLRP1 on hematopoietic reconstitution, we established a hematopoietic cell transplantation model by infusing bone marrow mononuclear cells of wild-type C57BL/6 mice into either NLRP1 knockout (NLRP1-KO) or wild-type C57BL/6 mice. Using the transplantation model, the role of NLRP1 in the bone marrow microenvironment was determined by flow cytometry, hemacytometry, and hematoxylin and eosin staining. As the major component of the bone marrow microenvironment, mesenchymal stem cells (MSCs) were isolated to analyze the effects of NLRP1 on them by osteogenic and adipogenic induction. Endothelial cells (ECs) were isolated and sorted by magnetic beads. The expression of adhesion molecules and their relationship with nuclear factor kappa B (NF-κB) were measured by immunofluorescence, enzyme-linked immunosorbent assay, and western blot. Finally, the effect of NLRP1-deleted MSCs or ECs on hematopoietic stem and progenitor cells (HSPCs) was examined by establishing co-culture models. Compared with C57BL/6 recipients, reduced inflammatory cell infiltration, decreased levels of proinflammatory cytokines interleukin (IL)-18, IL-1β, IL-6, tumor necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ), together with reduced pathological injury of bone marrow, were observed in NLRP1-KO recipients after transplantation. However, increased HSPC engraftment and hematopoietic reconstitution were detected in NLRP1-KO recipients after transplantation. Furthermore, MSCs isolated from NLRP1-KO mice had decreased osteogenic and adipogenic differentiation and increased proliferation and differentiation of HSPCs. The expression of adhesion molecules in ECs from NLRP1-KO mice was increased due to the promotion of nuclear translocation of NF-κB; these adhesion molecules are critical for hematopoietic stem cell homing. Knockout of NLRP1 in the bone marrow microenvironment could significantly relieve bone marrow inflammatory response and promote hematopoietic reconstitution, perhaps by regulating MSCs and ECs, indicating that NLRP1 might be a target for the treatment of delayed hematopoietic and immune recovery in patients after hematopoietic stem cell transplantation., (Copyright © 2021. Published by Elsevier Inc.)

Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are usually associated with poor outcomes, especially in high-risk AML/MDS. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative option for patients suffering from high-risk AML/MDS. However, many patients relapse after allo-HSCT. Novel therapy to prevent relapse is urgently needed. Both the BCL-2 inhibitor venetoclax (VEN) and the hypomethylating agent decitabine (DEC) possess significant antitumor activity effects against AML/MDS. Administration of DEC has been shown to ameliorate graft-versus-host disease (GVHD) and boost the graft-versus-leukemia (GVL) effect post-transplantation. We therefore conducted a prospective study (ChiCTR1900025374) to examine the tolerability and efficacy of a maintenance therapy of low-dose decitabine (LDEC) plus VEN to prevent relapse after allo-HSCT for high-risk AML/MDS patients. Twenty patients with high-risk AML (n = 17) or high-risk MDS (n = 3) post-transplantation were recruited. Approximately day 100 post-transplantation, all patients received LDEC (15 mg/m 2 for 3 d) followed by VEN (200 mg) on d 1-21. The cycle interval was 2 mo, and there was 10 cycles. The primary end points of this study were rates of overall survival (OS) and event-free survival (EFS). The secondary endpoints included adverse events (AEs), cumulative incidence of relapse (CIR), nonrelapse mortality (NRM), incidences of acute GVHD (aGVHD) and chronic GVHD (cGVHD), and incidences of viral infection after allo-HSCT. Survival outcomes were assessed using Kaplan-Meier analysis. The median follow-up was 598 (149-1072) d. Two patients relapsed, 1 died, and 1 is still alive after the second transplant. The 2-y OS and EFS rates were 85.2% and 84.7%, respectively. The median 2-y EFS time was 525 (149-1072) d, and 17 patients still had EFS and were alive at the time of this writing. The most common AEs were neutropenia, anemia, thrombocytopenia, neutropenic fever, and fatigue. Grade 2 or 3 AEs were observed in 35% (7/20) and 20% (4/20) of the patients, respectively. No grade >3 AEs were observed. aGVHD (any grade) and cGVHD (limited or extensive) occurred in 55% and 20% of patients, respectively. We conclude that LDEC + VEN can be administered safely after allo-HSCT with no evidence of an increased incidence of GVHD, and this combination decreases the relapse rate in high-risk AML/MDS patients. This novel maintenance therapy may be a promising way to prevent relapse in high-risk AML/MDS patients., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background Aims: Mesenchymal stem cells (MSCs) use multiple mechanisms to constrain both innate and adaptive immune responses to prevent graft-versus-host disease (GVHD). Myeloid-derived suppressor cells (MDSCs), as a heterogeneous population of early myeloid progenitor cells originating from bone marrow, are a naturally occurring immune regulatory population associated with inhibition of ongoing inflammatory responses, indicating their potential for GVHD therapy. There is accumulating evidence that MSCs and MDSCs do not act independently, but rather establish crosstalk. However, the role of MSCs in MDSC expansion and activation in GVHD remains unexplored., Methods: In vitro experiments included 2 groups: peripheral blood mononuclear cells (PBMCs) after mobilization and human umbilical cord blood-derived MSCs (UCB-MSCs) co-cultured with PBMCs. The number and functional difference of MDSCs in PBMCs were determined by flow cytometry. The culture supernatants of co-cultured cells were analyzed to identify cytokines involved in MDSC proliferation. The relationship between MSCs and MDSCs was clarified in GVHD and graft-versus-leukemia (GVL) animal models., Results: In vitro experiments confirmed that UCB-MSCs secreted HLA-G protein to promote and maintain the proliferation of MDSCs in peripheral blood after granulocyte colony-stimulating factor mobilization, and UCB-MSCs mediated the function of MDSCs to inhibit the proliferation of T cells and promote the proliferation of regulatory T cells. UCB-MSCs overexpressing HLA-G induced MDSC production in recipient mice, improved the ability of MDSCs to suppress T cells and further reduced acute GVHD (aGVHD) symptoms and survival time without influencing GVL effects., Conclusions: UCB-MSCs expanded MDSCs via HLA-G/Ig-like transcript 4, reducing the severity of aGVHD without affecting GVL. The immunosuppressive potential of MSCs for the treatment of aGVHD significantly affects the development of MDSCs, thereby consolidating the position of MSCs in the prevention and treatment of aGVHD., (Copyright © 2020 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Preconditioning before bone marrow transplantation such as irradiation causes vascular endothelial cells damage and promoting the repair of damaged endothelial cells is beneficial for hematopoietic reconstitution. Pigment epithelium-derived factor (PEDF) regulates vascular permeability. However, PEDF's role in the repair of damaged endothelial cells during preconditioning remains unclear. The purpose of our study is to investigate PEDF's effect on preconditioning-induced damage of endothelial cells and hematopoietic reconstitution., Methods: Damaged endothelial cells induced by irradiation was co-cultured with hematopoietic stem cells (HSC) in the absence or presence of PEDF followed by analysis of HSC number, cell cycle, colony formation and differentiation. In addition, PEDF was injected into mice model of bone marrow transplantation followed by analysis of bone marrow injury, HSC number and peripheral hematopoietic reconstitution as well as the secretion of cytokines (SCF, TGF-β, IL-6 and TNF-α). Comparisons between two groups were performed by student t-test and multiple groups by one-way or two-way ANOVA., Results: Damaged endothelial cells reduced HSC expansion and colony formation, induced HSC cell cycle arrest and apoptosis and promoted HSC differentiation as well as decreased PEDF expression. Addition of PEDF increased CD144 expression in damaged endothelial cells and inhibited the increase of endothelial permeability, which were abolished after addition of PEDF receptor inhibitor Atglistatin. Additionally, PEDF ameliorated the inhibitory effect of damaged endothelial cells on HSC expansion in vitro. Finally, PEDF accelerated hematopoietic reconstitution after bone marrow transplantation in mice and promoted the secretion of SCF, TGF-β and IL-6., Conclusions: PEDF inhibits the increased endothelial permeability induced by irradiation and reverse the inhibitory effect of injured endothelial cells on hematopoietic stem cells and promote hematopoietic reconstruction.

Previous study indicated that co-infusion of cord blood cells may potentially improve the outcome of haploidentical donor (HID) transplantation. In this study, we analyzed the outcomes of patients who underwent HID transplantation supported by cord blood when compared with HLA-matched unrelated donor (URD) transplantation. Starting in 2015, 40 patients with hematopoietic malignancies underwent HID transplantation and 26 patients underwent URD transplantation. Hematopoietic recovery, the incidences of grade II-IV acute graft-versus-host disease (GVHD) and chronic GVHD was comparable in the two groups. At two year, the relapse risk in HID group was significantly lower than in URD group (RR 4.630; 95%CI, 1.081-19.839; p  = .039). Moreover, HID group have prolonged PFS (RR 2.642; 95%CI, 1.046-6.672; p  = .040). In conclusion, HID transplantation supported by cord blood results in better outcomes compared with URD transplantation and it might be a favorable alternative to a HLA-matched URD transplantation.

Background: Metagenomic next-generation sequencing (mNGS) is a fast, sensitive and accurate diagnostic method for pathogens detection. However, reports on the application of mNGS in mucormycosis remain scarce. Methods: From January 2019 to December 2021, we recruited 13 patients with hematological malignancies who were suspected of mucormycosis and completed mNGS in D20. Then we retrospectively analyze the clinical data, diagnosis, therapeutic process, and outcomes. In order to evaluate the diagnostic value of mNGS in hematological malignancies patients with suspected mucormycosis. Results: All patients had high risk factors of Invasive Fungal Disease, including hematopoietic stem cell transplantation, immunosuppression, glucocorticoids, etc. The clinical presentations were pulmonary (n=9), rhino-orbito-cerebral (n=4). But the manifestations were nonspecific. All enrolled patients completed mNGS. And most (8/13, 61.54%) of the samples were from blood. Fungi can be detected in all specimens, including Rhizopus (n=7), Rhizomucor (n=4) and Mucor (n=2). In addition, 7/13 (53.85%) specimens were detected bacteria at the same time and virus were detected in 5/13 (38.46%). Histopathological examination was completed in 5 patients, 3 of which were completely consistent with the results of mNGS. After treatment, 6 patients were cured, while the other 7 patients died. Conclusion: mNGS may be a complementary method for early diagnosis, especially for patients who are not suitable for histopathology examination or unable to obtain culture specimen. mNGS can also help detect bacteria and viruses simultaneously, allowing for appropriate and timely antibiotic administration and thus improving patient outcomes. [ABSTRACT FROM AUTHOR]

Relapsed or refractory (R/R) acute myeloid leukemia (AML) has a poor prognosis. In this study, we evaluated chimeric antigen receptor (CAR) T cell therapy targeting CLL-1 in adults with R/R AML patients. Patients received conditioning chemotherapy with cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) for 3 days and an infusion of a dose of 1–2 × 106 CAR-T cells/kg. The incidence of dose-limiting toxicity was the primary endpoint. Ten patients were treated, and all developed cytokine release syndrome (CRS); 4 cases were low-grade, while the remaining 6 were considered high-grade CRS. No patient developed CAR-T cell-related encephalopathy syndrome (CRES). Severe pancytopenia occurred in all patients. Two patients died of severe infection due to chronic agranulocytosis. The complete response (CR)/CR with incomplete hematologic recovery (CRi) rate was 70% (n = 7/10). The median follow-up time was 173 days (15–488), and 6 patients were alive at the end of the last follow-up. CAR-T cells showed peak expansion within 2 weeks. Notably, CLL-1 is also highly expressed in normal granulocytes, so bridging hematopoietic stem cell transplantation (HSCT) may be a viable strategy to rescue long-term agranulocytosis due to off-target toxicity. In conclusion, this study is the first to demonstrate the positive efficacy and tolerable safety of CLL-1 CAR-T cell therapy in adult R/R AML. [ABSTRACT FROM AUTHOR]