Mesenchymal stromal cells (MSCs), also known as mesenchymal stem cells, have been intensely investigated for clinical applications within the last decades. However, the majority of registered clinical trials applying MSC therapy for diverse human diseases have fallen short of expectations, despite the encouraging pre-clinical outcomes in varied animal disease models. This can be attributable to inconsistent criteria for MSCs identity across studies and their inherited heterogeneity. Nowadays, with the emergence of advanced biological techniques and substantial improvements in bio-engineered materials, strategies have been developed to overcome clinical challenges in MSC application. Here in this review, we will discuss the major challenges of MSC therapies in clinical application, the factors impacting the diversity of MSCs, the potential approaches that modify MSC products with the highest therapeutic potential, and finally the usage of MSCs for COVID-19 pandemic disease.
Abstract The Phase 3 single‐arm COMMODORE 3 study ( ClinicalTrials.gov , NCT04654468) evaluated efficacy and safety of crovalimab (novel C5 inhibitor) in complement inhibitor‐naive patients with paroxysmal nocturnal hemoglobinuria (PNH). COMMODORE 3 enrolled patients from five China centers. Eligible complement inhibitor‐naive patients with PNH were ≥12 years old, had lactate dehydrogenase (LDH) ≥2 × upper limit of normal (ULN), and had ≥4 transfusions of packed red blood cells within the prior 12 months. Patients received crovalimab loading doses (one intravenous, four subcutaneous) and subsequent every‐4‐weeks subcutaneous maintenance doses per weight‐based tiered‐dosing schedule. Co‐primary efficacy endpoints were mean proportion of patients with hemolysis control (LDH ≤1.5 × ULN) from Week (W)5 through W25 and difference in proportion of patients with transfusion avoidance from baseline through W25 versus within 24 weeks of prescreening in patients who had ≥1 crovalimab dose and ≥1 central LDH assessment after first dose. Between March 17 and August 24, 2021, 51 patients (15–58 years old) were enrolled; all received treatment. At primary analysis, both co‐primary efficacy endpoints were met. Estimated mean proportion of patients with hemolysis control was 78.7% (95% CI: 67.8–86.6). Difference between proportion of patients with transfusion avoidance from baseline through W25 (51.0%; n = 26) versus within 24 weeks of prescreening (0%) was statistically significant ( p < .0001). No adverse events led to treatment discontinuation. One treatment‐unrelated death (subdural hematoma following a fall) occurred. In conclusion, crovalimab, with every‐4‐weeks subcutaneous dosing is efficacious and well tolerated in complement inhibitor‐naive patients with PNH.
Abstract Background Selinexor 80 mg combined with low-dose dexamethasone (Sd) demonstrated significant clinical benefit in patients with relapsed/refractory multiple myeloma (RRMM) who had disease refractory to a proteasome inhibitor (PI), an immunomodulator (IMiD), and an anti-CD38 monoclonal antibody based on a global phase II STORM study. The present study, MARCH, addresses China regulatory needs to further validate the data from STORM in Chinese patients with RRMM. Methods The MARCH study was conducted at 17 sites in China, where eligible Chinese RRMM patients who had disease refractory to PI and IMiD were enrolled. Selinexor 80 mg combined with dexamethasone 20 mg was administered orally on day 1 and day 3 of each week in 4-week cycles. The primary endpoint was the overall response rate (ORR) per an independent review committee, with the null hypothesis of ≤15%. Patients who received at least 1 dose of study treatment were included in the safety population. The pharmacokinetic (PK) profile was characterized by parameter and ethnicity sensitivity analyses. Results A total of 82 patients with RRMM were enrolled in the study, with a median age of 60 years. Of the 82 patients, 55 patients (67.1%) had high-risk cytogenetic abnormalities, defined as one or more of del 17p13, t(4;14), t(14;16), or 1q amplification identified by fluorescence in situ hybridization (FISH); 18 patients (22.0%) had abnormal renal function. Enrolled patients were heavily pre-treated with a median prior regimen number of 5. All 82 patients (100%) were refractory to both PI and IMiD, including 20 patients (24.4%) categorized as triple-class refractory population (refractory to PI, IMiD, and daratumumab). Ten patients (12.2%) had undergone CAR-T therapy. ORR was 29.3% (95% CI 19.7, 40.4) with a median DOR of 4.7 months. The median PFS and OS were 3.7 and 13.2 months, respectively. ORR was 25.0% (95% CI 8.7, 49.1) in the triple-class refractory population. Efficacy was consistent across various subgroups. The most frequent grade 3/4 adverse events (AEs) included anemia (57.3%), thrombocytopenia (51.2%), lymphopenia (42.7%), neutropenia (40.2%), hyponatremia (29.3%), and lung infection (26.8%). Serious AEs were reported in 54.9% of patients. No significant drug accumulation was shown following multiple administrations. No human PK ethnicity difference was identified between Chinese and western patients. Conclusions With an encouraging ORR, the MARCH study has demonstrated that selinexor combined with low-dose dexamethasone (Sd) delivers meaningful clinical benefit to Chinese patients with RRMM, including triple-class refractory patients. AEs were expected and manageable with supportive care and dose modification. Trial registration ClinicalTrials.gov, NCT03944057 (May 09, 2019); Chinadrugtrials.org.cn , CTR20190858 (June 05, 2019)
Early molecular response is associated with improved probability of deep molecular response and superior survival in patients with CML-CP. However, ~1 in 3 patients on first-line imatinib do not achieve this threshold. The phase 2b DASCERN trial (NCT01593254) assessed the outcome of early switch to dasatinib in patients with suboptimal response to first-line imatinib. Adult patients with CML-CP were randomized (2:1) to receive 100 mg dasatinib (n = 174) or continue imatinib at ≥400 mg (n = 86). The primary endpoint was the rate of major molecular response (MMR) at 12 months, which was 29% (dasatinib) and 13% (imatinib; P = 0.005). After ≥2 years of follow-up, 45 patients (52%) randomized to continue imatinib had crossed over to dasatinib. Considering treatment crossover, the 2-year cumulative MMR rate was 64% with dasatinib and 41% with imatinib (66% and 67%, respectively by intent-to-treat). Adverse events were consistent with the established safety profiles of both drugs. The results of this first prospective study support early monitoring of patients treated with first-line imatinib, and suggest that switching to dasatinib in cases of suboptimal response may offer clinical benefit. Further follow-up is needed to assess the long-term clinical benefit of early switching.
Immune suppression based on alternative regulation of immune checkpoint proteins, for example, programmed cell death receptor-1 (PD-1) and cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), which results in T-cell exhaustion, contributes to cancer development and progression. In this study, we sought to characterize the distribution of CTLA-4 and T-cell lymphocyte activation gene-3 (LAG-3) expression on exhausted T cells in different T-cell subsets from patients with acute myeloid leukemia (AML).The coexpression of CTLA-4 and LAG-3 on exhausted CD244+ and CD57+ T cells from the CD3+ , CD4+ , and CD8+ T-cell subsets in peripheral blood from 12 patients with newly diagnosed AML was analyzed by multicolor flow cytometry assay.A significantly higher percentage of CTLA-4+ CD3+ , CD4+ and CD8+ T cells was found in patients with AML. In addition, higher numbers of both CTLA-4+ CD244+ and CTLA-4+ CD57+ CD3+ T cells were detected. Interestingly, the increased CTLA-4+ CD244+ T cells were predominantly CD4+ T cells. In contrast, the increased CTLA-4+ CD57+ T cells primarily consisted of the CD8+ T-cell subset. A high proportion of LAG-3+ T cells was found in only a few cases with AML; however, a significantly higher proportion of coexpression of CTLA-4 and LAG-3 in the CD3+ and CD8+ T-cell subsets was detected.We for the first time observed higher CTLA-4+ CD244+ CD4+ , CTLA-4+ CD57+ CD8+ , CTLA-4+ LAG-3+ CD3+ and CTLA-4+ LAG-3+ CD8+ T cells in patients with AML, whereas the upregulated expression of LAG-3 on T cells was only found in a subset of the cases. These data may provide further information by complementing the heterogeneity of immune checkpoints expression in AML.
von Willebrand factor is a useful predictor and prognostic measure for TA-TMA, which may help clinicians identify and manage this life-threatening disease earlier.
Cell therapy is a promising approach for the treatment of refractory ocular disease. This study investigated the efficacy of mesenchymal stromal cells (MSCs) for the treatment of dry eye associated with chronic graft-versus-host disease (cGVHD) and assessed the immunomodulatory effects of MSCs on regulatory CD8(+)CD28(-) T lymphocytes. A total of 22 patients with refractory dry eye secondary to cGVHD were enrolled. The symptoms of 12 out of 22 patients abated after MSCs transplantation by intravenous injection, improving in the dry eye scores, ocular surface disease index scores and the Schirmer test results. The clinical improvements were accompanied by increasing level of CD8(+)CD28(-) T cells, but not CD4(+)CD25(+) T cells, in the 12 patients who were treated effectively. They had significantly higher levels of Th1 cytokines (interleukin (IL)-2 and interferon-γ) and lower levels of Th2 cytokines (IL-10 and IL-4). In addition, CD8(+) T cells were prone to differentiation into CD8(+)CD28(-) T cells after co-culture with MSCs in vitro. In conclusion, transfusion of MSCs improved the clinical symptoms in patients (54.55%) with refractory dry eye secondary to cGVHD. MSCs appear to exert their effects by triggering the generation of CD8(+)CD28(-) T cells, which may regulate the balance between Th1 and Th2.
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