Chimeric antigen receptor T (CAR-T) cell therapy is regarded as an effective solution for relapsed or refractory tumors, particularly for hematological malignancies. Although the initially approved anti-CD19 CART therapy has produced impressive outcomes, setbacks such as high relapse rates and resistance were experienced, driving the need to discover engineered CART cells that are more effective for therapeutic use. Innovations in the structure and manufacturing of CART cells have resulted in significant improvements in efficacy and persistence, particularly with the development of fourth-generation CART cells. Paired with an immune modifier, the use of fourthgeneration and next-generation CART cells will not be limited because of cytotoxic effects and will be an efficient tool for overcoming the tumor microenvironment. In this review, we summarize the recent transformations in the ectodomain, transmembrane domain, and endodomain of the CAR structure, which, together with innovative manufacturing technology and improved cell sources, improve the prospects for the future development of CART cell therapy.

Our findings suggest that the repeated infusion of MSCs might inhibit cGVHD symptoms in patients after HLA-haplo HSCT, accompanied by changes in the numbers and subtypes of T, B, and NK cells, leading to the acquisition of immune tolerance.

The incidence and mortality of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) are still very high, but stem cells show some promise for its treatment. Here we found that intratracheal administration of human umbilical cord-mesenchymal stem cells (UC-MSCs) significantly improved survival and attenuated the lung inflammation in lipopolysaccharide (LPS)-induced ALI mice. We also used the proteins-chip and bioinformatics to analyze interactions between UC-MSCs treatment and immune-response alternations of ALI mice. Then we demonstrated that UC-MSCs could inhibit the inflammatory response of mouse macrophage in ALI mice, as well as enhance its IL-10 expression. We provide data to support the concept that the therapeutic capacity of UC-MSCs for ALI was primarily through paracrine secretion, particularly of prostaglandin-E2 (PGE2). Furthermore, we showed that UC-MSCs might secrete a panel of factors including GM-CSF, IL-6 and IL-13 to ameliorate ALI. Our study suggested that UC-MSCs could protect LPS-induced ALI model by immune regulation and paracrine factors, indicating that UC-MSCs should be a promising strategy for ALI/ARDS.

PURPOSE Relapse is a major cause of treatment failure after allogeneic hematopoietic stem-cell transplantation (allo-HSCT) for high-risk acute myeloid leukemia (HR-AML). The aim of this study was to explore the effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) combined with minimal-dose decitabine (Dec) on the prevention of HR-AML relapse after allo-HSCT. PATIENTS AND METHODS We conducted a phase II, open-label, multicenter, randomized controlled trial. Two hundred four patients with HR-AML who had received allo-HSCT 60-100 days before randomization and who were minimal residual disease negative were randomly assigned 1:1 to either rhG-CSF combined with minimal-dose Dec (G-Dec group: 100 µg/m2 of rhG-CSF on days 0-5 and 5 mg/m2 of Dec on days 1-5) or no intervention (non–G-Dec group). The primary outcome was relapse after transplantation, and the secondary outcomes were chronic graft-versus-host disease (cGVHD), safety of the treatment, and survival. RESULTS The estimated 2-year cumulative incidence of relapse in the G-Dec group was 15.0% (95% CI, 8.0% to 22.1%), compared with 38.3% (95% CI, 28.8% to 47.9%) in the non–G-Dec group ( P < .01), with a hazard ratio (HR) of 0.32 (95% CI, 0.18 to 0.57; P < .01). There was no statistically significant difference between the G-Dec and non–G-Dec groups in the 2-year cumulative incidence of cGVHD without relapse (23.0% [95% CI, 14.7% to 31.3%] and 21.7% [95% CI, 13.6% to 29.7%], respectively; P = .82), with an HR of 1.07 (95% CI, 0.60 to 1.92; P = .81). After rhG-CSF combined with minimal-dose Dec maintenance, increasing numbers of natural killer, CD8+ T, and regulatory T cells were observed. CONCLUSION Our findings suggest that rhG-CSF combined with minimal-dose Dec maintenance after allo-HSCT can reduce the incidence of relapse, accompanied by changes in the number of lymphocyte subtypes.

HLA-haploidentical hematopoietic SCT (HSCT) is an option for severe aplastic anemia (SAA) patients. Here, we evaluated the outcomes of 26 adult-SAA patients who received HLA-haploidentical HSCT in five transplant centers in southwestern China. Most of the patients in this study failed prior therapy and were transfused heavily before the transplantation. The patients received fludarabine þ cyclophosphamide þ antithymocyte globulin as conditioning regimens and then unmanipulated peripheral blood plus marrow transplantation. Micafungin, i.v. Ig and recombinant human TPO were used for post-grafting infection prevention and supportive care. Of 26 patients, 25 achieved engraftment at a median of 13 days (range, 11-19 days) after HSCT. One of 25 patients experienced graft rejection and did not achieve sustained engraftment after second HSCT. Therefore, the final engraftment rate was 92.3%. Three of 25 (12%) patients developed acute GVHD, 10 of 25 (40%) patients developed chronic GVHD (9 with limited whereas the other with extensive). The OS rate was 84.6% and the average follow-up time was 1313.2 (738-2005) days for surviving patients. This encouraging result suggests that HLA-haploidentical HSCT is an effective therapeutic option for adults with acquired SAA if an HLA-identical donor is not available.

The T‐cell immunoglobulin‐ and mucin‐domain‐containing molecules (TIMs) comprise a new family of cell surface molecules expressed on T cells. TIM‐3 is expressed on T helper type 1 (Th1) cells and implicated in the pathogenesis of Th1‐driven auto‐ and allo‐immune diseases. TIM‐1 is suggested to act as a co‐stimulatory molecule for all T cells, but with potentially stronger effects on Th2 than Th1 cells and is associated with Th2‐related immune diseases. However, the TIM molecules have not been investigated in the systemic lupus erythematosus (SLE). In this study, we examined the expression of TIM‐1 and TIM‐3 on peripheral blood mononuclear cells from SLE patients using quantitative real‐time RT‐PCR. An increased TIM‐1 expression was detected in SLE patients, which correlates with interleukin‐10 expression. We also found that there was a significant increase in the expression of TIM‐1 in SLE patients with quite active disease (SLE disease activity index > 6), indicating that TIM‐1 expression might be related to active clinical phases. In contrast, TIM‐3 expression remained normal in SLE patients with low statistical power (34.89%). However, the expression of TIM‐3 ligand, galectin‐9 increased in SLE patients indicating an enhanced engagement of TIM‐3 with its ligand in SLE, which may result in a decreased regulatory T‐cell function as shown by the decreased expression of FoxP3 and TGF‐β1 in SLE. These data suggest that TIM‐1 and TIM‐3/TIM‐3L are involved in the pathogenesis of SLE.

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Hypoxia inducible factor-1 alpha (HIF-1 alpha) is a key determinant of oxygen-dependent gene regulation in angiogenesis. HIF-1 alpha overexpression may be beneficial in cell therapy of hypoxia-induced pathophysiological processes, such as ischemic heart disease. To address this issue, human peripheral blood mononuclear cells (PBMNCs) were induced to differentiate into endothelial progenitor cells (EPCs), and then were transfected with either an HIF-1 alpha-expressing or a control vector and cultured under normoxia or hypoxia. Hypoxia-induced HIF-1 alpha mRNA and protein expression was increased after HIF-1 alpha transfection. This was accompanied by VEGF mRNA induction and increased VEGF secretion. Hypoxia-stimulated VEGF mRNA induction was significantly abrogated by HIF-1 alpha-specific siRNA. Functional studies showed that HIF-1 alpha overexpression further promoted hypoxia-induced EPC differentiation, proliferation and migration. The expressions of endothelial cell markers CD31, VEGFR2 (Flk-1) and eNOS as well as VEGF and NO secretions were also increased. Furthermore, in an in vivo model of hindlimb ischemia, HIF-1 alpha-transfected EPCs homed to the site of ischemia. A higher revascularization potential was also demonstrated by increased capillary density at the injury site. Our results revealed that endothelial progenitor cells ex vivo modification by hypoxia inducible factor-1 alpha gene transfection is feasible and may offer significant advantages in terms of EPC expansion and treatment efficacy.