B and T lymphocyte attenuator (BTLA) is an inhibitory immune checkpoint, which typically interacts with herpesvirus entry mediator (HVEM) and plays a crucial role in regulating immune balance. BTLA interacts with its ligand HVEM in a cis manner on the surface of the same immune cell to maintain immune tolerance, while trans interactions on the surface of different immune cells mediate immunosuppressive effects. Dysregulation of the BTLA/HVEM axis can impair the functions of immune cells, particularly T lymphocytes, promoting immune escape of tumor cells and ultimately leading to tumor progression. Researchers have found that BTLA and HVEM are abnormally expressed in various tumors and are associated with prognosis, suggesting that they may be potential targets for tumor immunotherapy. This review summarizes the molecular structures of BTLA and HVEM, immunomodulatory mechanisms, recent advances in hematologic malignancies, potential inhibitors of BTLA/HVEM interaction, and their applications in immunotherapy for hematologic malignancies.
Humans ; Receptors, Tumor Necrosis Factor, Member 14/chemistry* ; Receptors, Immunologic/immunology* ; Hematologic Neoplasms/genetics* ; Immunotherapy/methods* ; Animals

T cell exhaustion plays an immunosuppressive role in malignant tumors. Continuous tumor antigen stimulation, the presence of suppressive immune cells and cytokines in the tumor microenvironment, the up regulation of inhibitory receptor expression on the surface of T cells, changes in T cell related transcription factors, and metabolites in the tumor microenvironment may lead to T cell exhaustion. Reversing the exhaustion of T cells in tumor patients is a promising strategy for tumor immunotherapy. This article will review the latest research progress on T cell exhaustion status, pathogenesis, reversal methods, and clinical applications in hematological tumors.
Humans ; Hematologic Neoplasms/immunology* ; T-Lymphocytes/immunology* ; Tumor Microenvironment ; Immunotherapy ; T-Cell Exhaustion

Human leukocyte antigen (HLA)-matched donors for hematopoietic stem cell transplantation (HSCT) have long been scarce in China. Haploidentical (haplo) donors are available for the vast majority of patients, but toxicity has limited this approach. Three new approaches for haplo-HSCT originated from Italy, China, and USA in 1990 and have been developed to world-renowned system up to now. The Chinese approach have been greatly improved by implementing new individualized conditioning regimens, donor selection based on non-HLA systems, risk-directed strategies for graft-versus-host disease and relapse, and infection management. Haplo-HSCT has exhibited similar efficacy to HLA-matched HSCT and has gradually become the predominant donor source and the first alternative donor choice for allo-HSCT in China. Registry-based analyses and multicenter studies adhering to international standards facilitated the transformation of the unique Chinese experience into an inspiration for the refinement of global practice. This review will focus on how the new era in which "everyone has a donor" will become a reality in China.
China ; Donor Selection ; Graft vs Host Disease ; immunology ; HLA Antigens ; immunology ; Hematologic Neoplasms ; immunology ; surgery ; Hematopoietic Stem Cell Transplantation ; Histocompatibility ; Histocompatibility Testing ; Humans ; Randomized Controlled Trials as Topic ; Transplantation Conditioning

BACKGROUNDDespite substantial progress toward measles control are making in China, measles outbreaks in immunocompromised population still pose a challenge to interrupt endemic transmission. This study aimed to investigate the features of measles in pediatric hematology and oncology patients and explore the reasons behind the outbreak.

METHODSWe collected demographic, epidemiological, and clinical data of immunocompromised measles children. All suspected measles cases were laboratory-confirmed based on the presence of measles IgM and/or identification of measles RNA. The clinical data were statistically analyzed by t-test for continuous variables and Fisher's exact test for categorical variables.

RESULTSFrom March 9 to July 25 in 2015, a total of 23 children with malignancies and post hematopoietic stem cell transplantation (post-HSCT) were notified to develop measles in Shanghai. Of these 23 patients with the median age of 5.5 years (range: 11 months-14 years), 20 (87.0%) had received 1-3 doses of measles vaccine previously; all patients had fever with the median fever duration of 8 days; 21 (91.3%) had cough; 18 (78.3%) had rash; 13 (56.5%) had Koplik's spot; 13 (56.5%) had complications including pneumonia and acute liver failure; and five (21.7%) vaccinated patients died from severe pneumonia or acute liver failure. Except the first patient, all patients had hospital visits within 7-21 days before measles onset and 20 patients were likely to be exposed to each other.

CONCLUSIONSThe outcome of measles outbreak in previously vaccinated oncology and post-HSCT pediatric patients during chemotherapy and immunosuppressant medication was severe. Complete loss of protective immunity induced by measles vaccine during chemotherapy was the potential reason. Improved infection control practice was critical for the prevention of measles in malignancy patients and transplant recipients.

Adolescent ; Child ; Child, Preschool ; China ; Disease Outbreaks ; statistics & numerical data ; Female ; Hematologic Diseases ; epidemiology ; Humans ; Immunocompromised Host ; immunology ; Infant ; Male ; Measles ; epidemiology ; Neoplasms ; epidemiology

Hematologic Neoplasms ; therapy ; Humans ; Immunotherapy, Adoptive ; Receptors, Antigen, T-Cell ; Receptors, IgG ; immunology ; T-Lymphocytes

BACKGROUND/AIMS: In this study, the sensitivity-specificity of galactomannan-enzyme immunoassay (GM-EIA) with a cut-off value of 0.5 for a single, two, or three consecutive positivity in the diagnosis of invasive pulmonary aspergillosis (IPA) in neutropenic patients with hematological malignancy was investigated. METHODS: IPA was classified as "proven," "probable," or "possible" as described in the guidelines prepared by the European Organization for Research and Treatment of Cancer and Mycoses Study Group." Serum samples were collected from the patients twice a week throughout their hospitalization. A total of 1,385 serum samples, with an average of 8.3 samples per episode, were examined. RESULTS: Based on the 165 febrile episodes in 106 patients, 80 (48.5%) were classified as IPA (4 proven, 11 probable, 65 possible) and 85 (51.5%) as non-IPA. The sensitivity/ specificity was 100%/27.1% for a single proven/probable IPA with the cut of value of GM-EIA > or = 0.5, 86.7%/71.8% for two consecutive positive results, and 73.3%/85.9% for three consecutive positive results. CONCLUSIONS: With the galactomannan levels measured twice a week, consecutive sensitivity decreased and specificity increased. Therefore, an increase may be obtained in sensitivity-specificity by more frequent monitoring of GM-EIA starting from the first day of positivity is detected.
Adult ; Aged ; Antineoplastic Agents/*adverse effects ; Biomarkers/blood ; Enzyme-Linked Immunosorbent Assay ; Female ; Hematologic Neoplasms/diagnosis/*therapy ; Hematopoietic Stem Cell Transplantation/*adverse effects ; Humans ; Immunocompromised Host ; Immunosuppressive Agents/*adverse effects ; Invasive Pulmonary Aspergillosis/*blood/diagnosis/immunology/microbiology ; Male ; Mannans/*blood ; Middle Aged ; Opportunistic Infections/*blood/diagnosis/immunology/microbiology ; Predictive Value of Tests ; Reproducibility of Results ; Time Factors

Dendritic cells (DCs) comprise two functionally distinct subsets: plasmacytoid DCs (pDCs) and myeloid DCs (mDCs). pDCs are specialized in rapid and massive secretion of type I interferon (IFN-I) in response to nucleic acids through Toll like receptor (TLR)-7 or TLR-9. In this report, we characterized a CD56(+) DC population that express typical pDC markers including CD123 and BDCA2 but produce much less IFN-I comparing with pDCs. In addition, CD56(+) DCs cluster together with mDCs but not pDCs by genome-wide transcriptional profiling. Accordingly, CD56(+) DCs functionally resemble mDCs by producing IL-12 upon TLR4 stimulation and priming naïve T cells without prior activation. These data suggest that the CD56(+) DCs represent a novel mDC subset mixed with some pDC features. A CD4(+)CD56(+) hematological malignancy was classified as blastic plasmacytoid dendritic cell neoplasm (BPDCN) due to its expression of characteristic molecules of pDCs. However, we demonstrated that BPDCN is closer to CD56(+) DCs than pDCs by global gene-expression profiling. Thus, we propose that the CD4(+)CD56(+) neoplasm may be a tumor counterpart of CD56(+) mDCs but not pDCs.
Biomarkers ; metabolism ; CD56 Antigen ; genetics ; immunology ; Cell Lineage ; genetics ; immunology ; Dendritic Cells ; immunology ; metabolism ; pathology ; Gene Expression ; Hematologic Neoplasms ; genetics ; immunology ; pathology ; Humans ; Immunophenotyping ; Interferon Type I ; biosynthesis ; metabolism ; Interleukin-12 ; biosynthesis ; metabolism ; Interleukin-3 Receptor alpha Subunit ; genetics ; immunology ; Lectins, C-Type ; genetics ; immunology ; Membrane Glycoproteins ; genetics ; immunology ; Myeloid Cells ; immunology ; metabolism ; pathology ; Receptors, Immunologic ; genetics ; immunology ; Terminology as Topic ; Toll-Like Receptor 4 ; genetics ; immunology ; Toll-Like Receptor 7 ; genetics ; immunology ; Toll-Like Receptor 9 ; genetics ; immunology

OBJECTIVETo compare the clinical efficacy of HLA- mismatched related donor (MRD) and HLA-matched unrelated donor (MUD) hematopoietic stem cell transplantation (HSCT) for hematopoietic malignancies.

METHODS174 patients with hematopoietic malignancies undergoing allogeneic HSCT (allo-HSCT) (82 from MRD and 92 from MUD) between June 2002 and December 2012 were enrolled in this retrospective study. Hematopoietic engraftment, graft versus host disease (GVHD), relapse, overall survival (OS) and disease-free survival (DFS) were compared between MRD and MUD group.

RESULTSThere was no significant difference between MRD and MUD group in terms of age, gender, disease type and disease status before transplantation (all P>0.05). The incidence of Ⅰ-IV acute GVHD (aGVHD) was 62.2% and 54.3% in MRD and MUD group (P=0.295); the incidence of III-IV aGVHD between the two groups was 15.9% and 9.8% (P=0.229). The incidence of chronic GVHD (cGVHD) was 28.4% and 45.1% in MRD and MUD group (P=0.036), but there was no significant difference in the incidence of extensive cGVHD between the two groups (9.0% vs 12.2%, P=0.525). The mortality of GVHD was 8.5% and 10.9% in MRD and MUD group (P=0.605). The 10-year OS and DFS were (50.1±6.1)% and (48.8±6.1)% in MRD group, compared with (50.5±6.7)% and (46.3±6.2)% in MUD group (P=0.501, P=0.873, respectively). The 10-year cumulative relapse rate was (21.5±5.7)% and (37.6±7.3)% in MRD and MUD group (P=0.194).

CONCLUSIONMRD is equivalent to MUD in efficacy and safety. Without HLA- matched related donors, MRD is superior to MUD because donor source is unlimited and transplantation could be made promptly according to disease status.

Adolescent ; Disease-Free Survival ; Graft vs Host Disease ; Hematologic Neoplasms ; therapy ; Hematopoietic Stem Cell Transplantation ; Histocompatibility Antigens Class I ; immunology ; Humans ; Neoplasm Recurrence, Local ; Retrospective Studies ; Transplantation, Homologous ; Treatment Outcome ; Unrelated Donors

OBJECTIVETo retrospectively study the impact of human leukocyte antigen (HLA) mtyping mismatching between donor and recipient on outcome of single unit unrelated cord blood transplantation (sUCBT).

METHODS139 patients with hematological malignancies received sUCBT in single center from May 2008 to August 2012 were analyzed. Of 139 patients at enrollment, 22 were 0 mismatched (mm), 69 1 mm, 48 2 mm by low-resolution HLA-A, -B, and high-resolution (HR) DRB1. All patients'conditioning regimen was myeloablative, and a combination of cyclosporine A (CsA) and mycophenolate mofetil (MMF) was given for graft-versus-host disease (GVHD) prophylaxis for all patients. The cohort of patients were followed-up until December 15, 2013.

RESULTSPatients of 0 mm had a statistically significant higher cumulative incidence of neutrophil engraftment by day 42 than those of 1 and 2 mm (P=0.042 and 0.002, respectively), patients of 0 mm with either a higher prefreeze total nucleated cell (TNC) dose (>5 × 10⁷/kg) or lower dose (<5 × 10⁷/kg) had a statistically significant higher cumulative incidence of neutrophil engraftment by day 42 than those of 2 mm (P=0.01 and 0.02, respectively). Patients of 0 mm had a statistically significant lower cumulative incidence of acute GVHD by day 100 than those of 1 and 2 mm (P=0.006 and 0.001, respectively). The difference of 1-year transplant-related mortality (TRM) between 0 and 2 mm patients was statistically significant (P=0.03). Patients of 2 mm received UCB units with a TNC dose less than 5 × 10⁷/kg had a higher 1-year TRM than of 0 mm patients (P=0.03). Patients of 0 mm had a statistically significant higher 3-year disease free survival (DFS) than those of 2 mm (P=0.03), compared with patients of 2 mm given CB units with a TNC dose less than 5 × 10⁷/kg, 0 mm patients and 1mm patients received UCB units with a TNC dose greater than 4 × 10⁷/kg had higher DFS rates (P=0.02 and 0.02, respectively).

CONCLUSIONThe HLA typing mismatching between donor and recipient had a great impact on neutrophil engraftment and long term DFS after sUCBT, 2mm cord blood unit with less TNC (<5 × 10⁷/kg) was not an optimum UCB graft.

Adolescent ; Adult ; Child ; Child, Preschool ; Cord Blood Stem Cell Transplantation ; Female ; Follow-Up Studies ; HLA Antigens ; immunology ; Hematologic Neoplasms ; therapy ; Histocompatibility Testing ; Humans ; Male ; Middle Aged ; Retrospective Studies ; Treatment Outcome ; Young Adult

Chimeric antigen receptors (CAR) are fusion proteins between single-chain variable fragments (scFv) from monoclonal antibodies and signaling domains of T-cells, which allow T-cells recognize specific cell-surface targets in an MHC-unrestricted fashion. The structure of CAR has changed over time, from first generation CAR (scFv + signaling moiety) to 2 and 3 generation CAR (combined with one or multiple costimulatory endodomains, such as CD28, 4-1BB and OX40), which enhance persistence, expansion and cytotoxicity of CAR. Many clinical trials treating hematological malignancies using the CAR-modified T-cells targeting CD19 and CD20 are under evaluation or even finished. These clinical trials indicated that CAR-based immunotherapy prolonged the survival of patients with relapsed/refractory B-cell malignancies. Furthermore, CAR have being studied to translate to other fields like adoptive therapy after hematopoietic stem cell transplantation. As to the treatment toxicity, CAR modified T-cell infusion is tolerant and safe in most patients. However, insertional mutagenesis, off-target effect and inflammatory response are safety issues surrounding CAR-modified T-cell therapy. In this review, the use of CAR technique in treatment of hematologic malignancies and evaluation of CAR safety are summarized.
Cell- and Tissue-Based Therapy ; Hematologic Neoplasms ; therapy ; Humans ; Immunotherapy ; Receptors, Antigen ; immunology ; Recombinant Fusion Proteins ; immunology ; T-Lymphocytes ; immunology