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The success of chimeric antigen receptor (CAR) T cells in treating B cell malignancies comes at the price of eradicating normal B cells. Even though T cell malignancies are aggressive and treatment options are limited, similar strategies for T cell malignancies are constrained by the severe immune suppression arising from bystander T cell aplasia. Here, we show the selective killing of malignant T cells without affecting normal T cell-mediated immune responses in vitro and in a mouse model of disseminated leukemia. Further, we develop a CAR construct that carries the single chain variable fragment of a subtype-specific antibody against the variable TCR β-chain region. We demonstrate that these anti-Vβ8 CAR-T cells are able to recognize and kill all Vβ8+ malignant T cells that arise from clonal expansion while sparing malignant or healthy Vβ8− T cells, allowing sufficient T cell-mediated cellular immunity. In summary, we present a proof of concept for a selective CAR-T cell therapy to eradicate T cell malignancies while maintaining functional adaptive immunity, which opens the possibility for clinical development. Healthy T cells are polyclonal, while malignant T cells are developing via clonal expansion. Here authors show that T cell tumours could be eradicated by chimeric antigen receptor T cells targeting the T cell receptor (TCR) β-chain that is specific to malignant T cells, while healthy T cells using diverse TCR β-chains are spared. [ABSTRACT FROM AUTHOR]

Introduction: Anti‐CD19 chimeric antigen receptor (CAR) ‐T cells, which recognize and kill both B lymphoblasts and normal B cells, result in B cell aplasia and humoral immunodeficiency. However, there were only a few detailed reports on the profile of immune reconstitution after anti‐CD19 CAR‐T cell therapy. Methods: Thirty nine patients with relapsed or refractory (R/R) B cell acute lymphoblastic leukemia (ALL) receiving anti‐CD19 CAR‐T cell therapy were enrolled. Subjects died, relapsed, received other treatment, or lost to follow‐up within 60 days post‐infusion were excluded. 21 patients were finally selected. Laboratory and clinical data were collected for analysis of immune reconstitution. Results: CD8+ cells were the first to recover with a median time on day 21(7‐87), followed by CD16/CD56+ cells on day 28(14‐87), and finally CD4+ cells with only 5(23.81%) patients recovered within 60 days post‐infusion. CD4/CD8 ratio was inverted, sustaining for at least 1 year. B cell aplasia occurred in all patients and CD19+ cells returned to normal on a median time of day 79(41‐118). All patients developed hypogammaglobulinemia with a median onset time of 2 weeks post‐infusion. IgG recovered in 6 patients with a median time on day 184(89‐346). IgM recovered on days 212, 242, and 346 in 3 patients. IgA recovered most slowly and remained low >1 year postinfusion. A total of 9 infections occurred in 6(28.57%) patients. Conclusions: Our data showed prolonged reconstitution of immune function, especially humoral immunity, in R/R B cell ALL patients receiving anti‐CD19 CAR‐T cell therapy. [ABSTRACT FROM AUTHOR]

Acute graft-versus-host disease (aGVHD) has become the important complication post-allogeneic hematopoietic stem cell transplantation. Abnormally activated T cells might play an important role in the pathogenesis of aGVHD. But its exact mechanism remains poorly understood. T cell immune response cDNA 7 (TIRC7) has been identified to be essential in T cell activation; however, the role of TIRC7 in aGVHD remains unclear. The purpose of this study was to measure the expression of TIRC7 and T helper (Th) cells in patients with aGVHD before and after treatment. We showed that TIRC7 levels in aGVHD patients were higher than those of healthy controls and markedly declined after treatment. The levels of IFN-γ (Th1), IL-17 (Th17), and IL-22 (Th22) were in accordance with the grade of aGVHD. In addition, TIRC7 levels were also associated with the severity of aGVHD. In conclusion, TIRC7 might be involved in the pathogenesis of aGVHD and TIRC7 level might be an indicator to evaluate the response of patients with aGVHD to treatment. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to investigate the expression levels of T-cell immune response cDNA 7 (TIRC7) in immune thrombocytopenia (ITP) patients before and after high-dose dexamethasone (HD-DXM) treatment. Methods: Forty-four patients with ITP were enrolled and received dexamethasone (40 mg/day) for 4 consecutive days. Patients who had platelet counts more than 50 × 109/l or less were defined as responders or non-responders, respectively. Quantitative polymerase chain reaction and enzyme-linked immunosorbent assay were used to measure RNA level and plasma level of TIRC7, respectively. Results: TIRC7 levels (RNA and plasma level) were significantly higher in ITP than that in control (P < 0.0001). However, after treatment, TIRC7 levels were significantly decreased in responders (P < 0.0001) but not in non-responders (P > 0.05). Discussions: TIRC7 might be associated with the pathogenesis of ITP, and TIRC7 levels could be used as an indicator to evaluate patients’ response to HD-DXM treatment. [ABSTRACT FROM AUTHOR]

This randomized trial was performed to investigate the efficacy of low-dose rituximab in combination with glucocorticoids for treatment of patients with immune thrombocytopenia (ITP). Sixty-two patients were randomly separated into the glucocorticoids (control) and the experimental (glucocorticoids + rituximab) groups. Patients in both groups received dexamethasone 40 mg/day on days 1-4, followed by decrements of prednisone 60, 30, 15, 10 mg/day on days 5-7, 8-14, 15-21, 22-28, respectively. Patients in the experimental group also received rituximab 100 mg on days 7, 14, 21, 28. The overall response (OR) was similar in both groups at day 28 (experimental group vs. glucocorticoids group: 80.6 vs. 74.2%, P = .938); however, sustained response (SR) was more pronounced in the experimental group as compared to that in the glucocorticoids group (77.4 vs. 38.7%, P < .001). Both groups showed similar incidence of adverse events (experimental group vs. glucocorticoids group: 9.7 vs. 6.5%, P = .325). As expected, B cell depletion was seen in the experimental group. In addition, both groups experienced a significant up-regulation in Treg cell levels, but the up-regulation in the experimental group was maintained at an even higher level and persisted a longer time than those in the glucocorticoids group. Thus, low-dose rituximab combined with short-term glucocorticoids provides an alternative treatment for ITP prior to splenectomy. [ABSTRACT FROM AUTHOR]

Abstract: Regulatory T cells (Tregs) can prevent graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT). Here we developed a lentivirus-based strategy to ectopically express Foxp3 in mouse CD4+CD25− T cells. These cells shared similar immunophenotypes and biological features of natural Tregs. Co-injection of engineered Tregs with donor bone marrow cells and splenocytes prevented recipients from lethal GVHD. Furthermore, we showed that graft-versus-leukemia (GVL) effect against EL4/DsRed leukemic cells was maximally preserved while GVHD was minimized during exposure to engineered Tregs in a mouse leukemia model. These findings provide a novel approach to preventing GVHD while maintaining GVL effect during BMT. [ABSTRACT FROM AUTHOR]

Immune thrombocytopenia (ITP) is an acquired autoimmune disease characterized by autoantibody‐mediated platelet destruction. Multiple factors have been implicated in ITP pathogenesis, including T‐lymphocyte dysfunctions. Increasing studies have indicated that stem cell memory‐like T cell (TSCM) plays an important role in the development of multiple autoimmune diseases. This study aimed to explore the clinical correlation between the TSCM subset and ITP. The percentages of peripheral blood naïve T cells (TNs), TSCMs, central memory T cells (TCMs), effector memory T cells (TEMs) and effector T cells (TEs) among CD4+ and CD8+ T cells in 20 ITP patients before and after treatment were detected using flow cytometry. Our results showed that the percentages of peripheral blood CD4+ and CD8+ T cells in ITP patients were imbalanced. The percentage of CD8+ TSCMs in peripheral blood before treatment in ITP patients was significantly higher than that in healthy controls, whereas the percentages of the other T cell subsets did not exhibit significant differences. Our study further analysed the correlation between the change in the percentage of CD8+ TSCMs and the treatment efficacy. The results showed that the percentage of peripheral blood CD8+ TSCMs in ITP patients after glucocorticoid treatment significantly decreased and the changes of the percentages of CD8+ TSCMs before and after treatment in complete response (CR) and response (R) patients were obvious. Our finding showed that the imbalance of the percentage of CD8+ TSCMs might be involved in the development of ITP and might serve as a novel indicator of efficacy. [ABSTRACT FROM AUTHOR]

Few studies have reported the associations of granulocyte colony-stimulating factor (G-CSF) with cytokine release syndrome (CRS), neurotoxic events (NEs) and efficacy after chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory (R/R) multiple myeloma (MM). We present a retrospective study performed on 113 patients with R/R MM who received single anti-BCMA CAR T-cell, combined with anti-CD19 CAR T-cell or anti-CD138 CAR T-cell therapy. Eight patients were given G-CSF after successful management of CRS, and no CRS re-occurred thereafter. Of the remaining 105 patients that were finally analyzed, 72 (68.6%) received G-CSF (G-CSF group), and 33 (31.4%) did not (non G-CSF group). We mainly analyzed the incidence and severity of CRS or NEs in two groups of patients, as well as the associations of G-CSF timing, cumulative dose and cumulative time with CRS, NEs and efficacy of CAR T-cell therapy. Both groups of patients had similar duration of grade 3–4 neutropenia, and the incidence and severity of CRS or NEs.There were also no differences in the incidence and severity of CRS or NEs between patients with the timing of G-CSF administration ≤3 days and those >3 days after CAR T-cell infusion. The incidence of CRS was greater in patients receiving cumulative doses of G-CSF >1500 μg or cumulative time of G-CSF administration >5 days. Among patients with CRS, there was no difference in the severity of CRS between patients who used G-CSF and those who did not. The duration of CRS in anti-BCMA and anti-CD19 CAR T-cell–treated patients was prolonged after G-CSF administration. There were no significant differences in the overall response rate at 1 and 3 months between the G-CSF group and the non–G-CSF group. Our results showed that low-dose or short-time use of G-CSF was not associated with the incidence or severity of CRS or NEs, and G-CSF administration did not influence the antitumor activity of CAR T-cell therapy. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T-cell therapy is a new and effective method in relapsed or refractory (R/R) multiple myeloma (MM). This study was aimed to explore the risk factors of infection events. We retrospectively analyzed 68 patients with R/R MM who received CAR T-cell therapy at the Affiliated Hospital of Xuzhou Medical University from June 2017 to June 2021.35 patients received anti-CD19 combined with anti-BCMA CAR T-cell therapy and 33 patients received anti-BCMA CAR T-cell therapy alone. Infection events in patients who received ≥4 prior lines of treatment or with grade 3–5 cytokines released syndrome (CRS) mainly occurred within 4 months after CAR T-cell infusion(CTI). The duration of infection-free survival was positively correlated with progression-free survival of patients with R/R MM (R2 = 0.962, p < 0.001) and the first infection event was closely accompanied by the disease relapse or progression. Treatment lines (p = 0.05), duration of ANC<500 cells/mm3 after CTI (p = 0.036), CRS grade (p = 0.007) and treatment response (p < 0.001) were the independent risk factors associated with infection for a multivariable model. The infection incidence was higher in patients with dual CAR T-cell therapy than with mono CAR T-cell therapy18 months after CTI although no statistic differences were observed within 18 months. Infections after CTI were closely associated with more lines of prior treatment, longer duration of ANC<500 cells/mm3, higher grade CRS and poor treatment response. Infections tended to occur in the early stage after CTI in patients with more lines of prior treatment and higher grade CRS. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) is widely acknowledged as a severe traumatic event, and depression, anxiety, and psychological distress are common in diagnosed patients. However, the correlations of biological indicators with emotion are rarely reported. The primary objective of this study was to explore the dysfunction of immune-inflammatory characteristics in patients with depression-anxiety symptoms. We investigated the mental status of inpatients with COVID-19 in Wuhan and compared the differences in cytokines and lymphocytes between patients with and without depression-anxiety symptoms at admission. After two weeks of treatment, we evaluated the mental conditions and measured the cytokines and lymphocytes of the patients with depression and anxiety symptoms and explored the changes and their associations. Approximately half of the patients with COVID-19 had depression and anxiety symptoms, and the symptoms were related to the ratio of CD4+/CD8+ and the level of CD4+ T lymphocytes. When compared with patients without depression-anxiety symptoms, CD4+ T lymphocytes level was significantly higher in COVID-19 patients with depression-anxiety symptoms. This study provided novel evidence regarding the association between depression and anxiety symptoms and immune characteristics, especially CD4+ T lymphocyte levels, in COVID-19 patients. We emphasized the importance of paying attention to the dynamic immune process of patients diagnosed with COVID-19 with depression/anxiety. [ABSTRACT FROM AUTHOR]

Background: We conducted a survey to investigate the prevalence and factors associated with anxiety and depressive symptoms among patients hospitalized with hematological malignancies after chimeric antigen receptor T-cell (CAR-T) therapy.Methods: In total, 130 eligible patients completed the Self-Rating Anxiety Scale and Self-Rating Depression Scale at week 4 after CAR-T cell infusion. We collected sociodemographic information during the same period. We studied factors associated with anxiety and depressive symptoms using logistic regression analysis.Results: The prevalence of anxiety and depressive symptoms at week 4 after infusion were 13.8% and 40.0%, respectively. A cutoff value of 50 or above indicates significantly anxiety and depressive symptoms. Binary logistic regression analysis showed that high school education and above (OR = 0.22, 95% CI = 0.06-0.78) and middle age (OR = 0.16, 95% CI = 0.03-0.90) were associated with lower risk of anxiety symptoms, and increased odds of depressive symptoms was associated with old age (OR = 11.39, 95% CI = 2.50-51.88), non-manual occupations before illness (OR = 3.72, 95% CI = 1.20-11.58), and higher healthcare expenditure (OR = 3.93, 95% CI = 1.50-10.33), while lower risk of depressive symptoms was associated with rural household location (OR = 0.25, 95% CI = 0.08-0.76) and being cared for by spouse (OR = 0.12, 95% CI = 0.02-0.63).Conclusions: Patients receiving CAR-T therapy with lower education background, old ages, urban household location, or who used to work as non-manual workers require more attention and psychological care. Support from a spouse and medical expense deductions from the government may help patients develop positive attitudes. [ABSTRACT FROM AUTHOR]

• A high incidence of coagulation disorders was observed after chimeric antigen receptor (CAR)-T cell therapy infusion. • The changes of coagulation parameters were associated with cytokine release syndrome (CRS). • Disseminated intravascular coagulation was found in patients with severe CRS and indicated a poor prognosis. • Coagulation disorders are manageable in most patients after CAR-T cell infusion. Chimeric antigen receptor (CAR)-T cell therapy, a new immunotherapy for relapsed and refractory (R/R) hematologic malignancies, can be accompanied by adverse events, including coagulation disorders. Here, we performed a comprehensive analysis of coagulation parameters in 100 patients with R/R hematologic malignancies after receiving CAR-T cell therapy to illuminate the profiles of coagulation disorders and to facilitate the management of coagulation disorders. A high incidence of coagulation disorders was observed, including elevated D-dimer (50/100, 50%), increased fibrinogen degradation product (45/100, 45%), decreased fibrinogen (23/100, 23%), prolonged activated partial thromboplastin time (16/100, 16%), and prolonged prothrombin time (10/100, 10%). Coagulation disorders occurred mainly during day 6 to day 20 after CAR-T cell infusion. The changes in coagulation parameters were associated with high tumor burden in acute lymphoblastic leukemia, more lines of prior therapies, lower baseline platelet count, and especially cytokine release syndrome (CRS). Disseminated intravascular coagulation (DIC) was found in 7 patients with grade ≥3 CRS and indicated a poor prognosis. Our study suggests that coagulation disorders are manageable in most patients after CAR-T cell therapy. Coexistence of DIC and severe CRS is closely related to nonrelapsed deaths during the acute toxicity phase, and effective and timely treatment is the key to reduce nonrelapse mortality for patients with DIC and severe CRS. [ABSTRACT FROM AUTHOR]

Donor-derived CD4 + T lymphocytes are the major effector cells directly involved in the development of graft-versus-host disease (GVHD). As a negative regulator of immune cell differentiation and development, microRNA-150 (miR-150) induces immunological tolerance in CD4 + T cells after transplantation. However, the specific mechanisms have not been fully elucidated. In this study, we demonstrated that miR-150 is capable of not only inhibiting proliferation and activation of CD4 + T cells but also promoting apoptosis. Mechanistically, miR-150 targets v-akt murine thymoma viral oncogene homolog 3 (AKT3), and subsequently downregulates B-cell lymphoma 2 (Bcl-2) interacting mediator of cell death (BIM). We have also demonstrated that re-expression of AKT3 reversed miR-150-mediated inhibition of CD4 + T lymphocyte development. Therefore, we conclude that miR-150 negatively regulates CD4 + T cell function by inhibiting the AKT3/BIM signaling pathway. These findings also suggest that manipulating the levels of miRNA-150 could be a valuable strategy in prevention and/or treatment of acute graft-versus-host disease. [ABSTRACT FROM AUTHOR]

Numerous previous studies have suggested that cytotoxic T lymphocyte antigen-4 (CTLA-4) plays an important role in acute graft-versus-host disease (GVHD). How CTLA-4 acts in regulating acute GVHD remains unknown, however. In the present study, we found that, compared with healthy controls, CTLA-4 plasma and relative mRNA levels in patients with acute GVHD were initially decreased and then markedly elevated after 28 days of treatment. CTLA-4 levels were higher in patients with grade I-II acute GVHD compared with those with grade III-IV acute GVHD both before and after treatment. Up-regulation of CTLA-4 significantly increased the luciferase activity and degree of phosphorylation of signal transducer and activator of transcription 3 (STAT3). Meanwhile, T cell activation was significantly inhibited, and levels of IFN-γ, IL-17, and IL-22 decreased. These findings suggest that CTLA-4 might be involved in the pathogenesis of acute GVHD, and may down-regulate T helper 1 cells by increasing STAT3 expression in acute GVHD. [ABSTRACT FROM AUTHOR]

Abstract: Graft-versus-host disease (GVHD) remains the major obstacle for allogeneic bone marrow transplantation, in which many proinflammatory cytokines secreted by alloreactive donor T cells are involved. Role of IL-22 as a member of IL-10 family in GVHD is still disputed and the properties of IL-22-producing cells are unclear. We demonstrated here that CD4+ T cells but not CD8+ T cells involved in GVHD were the main cellular source of donor-derived IL-22. Th1 and Th17 cells were detected not only express classical cytokine IFN-γ or IL-17, but also contributed to IL-22 secretion in GVHD. Th22 cells characterized by the independent secretion of IL-22 were identified and occupied almost half percentage of IL-22-producing CD4+ T cells. The frequency of IL-22-producing CD4+ T cells showed dynamic changes with the development of GVHD. Finally, we observed that IL-22-producing CD4+ T cells in GVHD mouse carried CD62L−CD44high/low surface markers. In conclusion, we illuminate the characteristics of donor-derived IL-22-producing CD4+ T cells, which may have potent implication for further study of pathogenesis of GVHD. [Copyright &y& Elsevier]

• Ac-YVAD-CMK reduces the pathological damage of recipient tissues. • Ac-YVAD-CMK improves the GVHD in a murine model of aGVHD. • Ac-YVAD-CMK reduces the expression of IL-1β, IL-18, and HMGB1 in recipients. • Ac-YVAD-CMK modulates the balance of Th1/Th17/Treg subsets in recipients. Our previous studies have implicated Caspase-1 signaling in driving the proinflammatory state of acute graft versus host disease (aGVHD). Therefore, we aimed to elucidate the mechanism of Caspase-1 in in murine models of aGVHD through specific inhibition of its activity with the decoy peptide Ac-YVAD-CMK. We transplanted bone marrow from donor C57BL/6 (H-2b) mice into recipient BALB/c (H-2Kd) mice and randomized the recipients into the following treatment cohorts: (1) allogeneic hematopoietic stem cell transplantation and splenic cell infusion control (PBS group); (2) low dose Ac-YVAD-CMK (AC low group); (3) and high dose Ac-YVAD-CMK (AC high group). Indeed, we observed that Caspase-1 inhibition by Ac-YVAD-CMK ameliorated pathological damage and inflammation in the liver, lungs, and colon elicited by aGVHD. This was associated with reduced mortality secondary to aGVHD. Mechanistically, we found that Caspase-1 inhibition modulated donor T cell expansion, restored the balance of Th1/Th17/Treg subsets, and markedly decreased serum levels and aGVHD target organ mRNA expression of IL-1β, IL-18, and HMGB1. Thus, we demonstrate that inhibition of Caspase-1 by Ac-YVAD-CMK mitigates murine aGVHD by regulating Th1/Th17/Treg balance and attenuating its characteristic proinflammatory state. [ABSTRACT FROM AUTHOR]