Background: Though the efficacy of anti C‐type lectin‐like molecule‐1 (CLL1) CAR T‐cells in refractory/relapsed acute myeloid leukemia (R/R‐AML) have been occasionally reported, the influence of co‐stimulatory domain CAR T‐cells is not investigated so far.Method: Seven R/R‐AML children treated with anti‐CLL1 CAR T‐cells were enrolled onto this preliminary comparison study. Among these seven patients, four received CD28/CD27‐based CAR T‐cells therapy, and three received 4‐1BB‐based CAR T‐cells therapy.Result: The overall response rates were 75% and 66.7% in CD28/CD27 and 4‐1BB group respectively. All patients experienced grade 1 to 2 cytokine release syndrome, with only one patient experiencing grade 2 immune effector cell‐associated neurotoxicity syndrome. The maximum CAR T‐cells durations were 156 and 274 days for CD28/CD27 group and 4‐1BB group respectively. The 1‐yr overall survival rate was 57.1%.Conclusions: A preliminary similar efficacy/safety index was observed in anti‐CLL1‐based CAR T‐cells with 4‐1BB or CD28/CD27 co‐stimulatory elements in treating pediatric R/R‐AML.

Cancer immunotherapies exhibit impressive efficacy in some cancers but show only limited benefits for refractory hematological malignancies. The complex immune escape mechanisms of hematological cancers remain unclear. Here, we found that P-selectin glycoprotein ligand 1 (PSGL-1) was highly expressed by hematological cancers and negatively correlated with cancer prognosis. PSGL-1 deficiency in tumors suppressed the progression of multiple mouse models of hematological cancer by promoting infiltration of macrophages and their phagocytic activity. Tumor PSGL-1 inhibited the interaction between tumor ICAM-1 and CD11a/CD18 integrin (LFA-1) in macrophages, thereby suppressing prophagocytic signaling downstream of LFA-1. A humanized antibody targeting human PSGL-1 (αhPSGL-1) efficiently triggered macrophage phagocytosis of human hematological malignancies in vitro and slowed cancer progression in vivo. Additionally, PSGL-1 blockade potentiated the efficacy of doxorubicin chemotherapy and anti-CD47 and anti-CD38 antibody therapy. Therefore, PSGL-1 is a previously undescribed phagocytosis checkpoint, and targeting PSGL-1 could be a promising immunotherapy strategy for treating hematological malignancies.

Through the advancements in recent decades, childhood acute lymphoblastic leukemia (ALL) is gradually becoming a highly curable disease. However, the truth is there remaining relapse in ∼15% of ALL cases with dismal outcomes. RAS mutations, in particular NRAS mutations, were predominant mutations affecting relapse susceptibility. KRAS mutations targeting has been successfully exploited, while NRAS mutation targeting remains to be explored due to its complicated and compensatory mechanisms. Using targeted sequencing, we profiled RAS mutations in 333 primary and 18 relapsed ALL patients and examined their impact on ALL leukemogenesis, therapeutic potential, and treatment outcome. Cumulative analysis showed that RAS mutations were associated with a higher relapse incidence in children with ALL. In vitro cellular assays revealed that about one-third of the NRAS mutations significantly transformed Ba/F3 cells as measured by IL3-independent growth. Meanwhile, we applied a high-throughput drug screening method to characterize variable mutation-related candidate targeted agents and uncovered that leukemogenic-NRAS mutations might respond to MEK, autophagy, Akt, EGFR signaling, Polo−like Kinase, Src signaling, and TGF−β receptor inhibition depending on the mutation profile.

Background: A high ecotropic viral integration site 1 (EVI1) expression (EVI1^high) is an independent prognostic factor in adult acute myeloid leukemia (AML). However, little is known of the prognostic value of EVI1^high in pediatric AML. This study aimed to examine the biological and prognostic significance of EVI1^high in uniformly treated pediatric patients with AML from a large cohort of seven centers in China.Methods: A diagnostic assay was developed to determine the relative EVI1 expression using a single real-time quantitative polymerase chain reaction in 421 newly diagnosed pediatric AML patients younger than 14 years from seven centers in southern China. All patients were treated with a uniform protocol, but only 383 patients were evaluated for their treatment response. The survival data were included in the subsequent analysis (n = 35 for EVI1^high, n = 348 for EVI1^low).Results: EVI1^high was found in 9.0% of all 421 pediatric patients with de novo AML. EVI1^high was predominantly found in acute megakaryoblastic leukemia (FAB M7), MLL rearrangements, and unfavorable cytogenetic aberrance, whereas it was mutually exclusive with t (8; 21), inv (16)/t (16; 16), CEBPA, NPM1, or C-KIT mutations. In the univariate Cox regression analysis, EVI1^high had a significantly adverse 5-year event-free survival (EFS) and overall survival (OS) [hazard ratio (HR) = 1.821 and 2.401, p = 0.036 and 0.005, respectively]. In the multivariate Cox regression analysis, EVI1^high was an independent prognostic factor for the OS (HR = 2.447, p = 0.015) but not EFS (HR = 1.556, p = 0.174). Furthermore, EVI1^high was an independent adverse predictor of the OS and EFS of patients with MLL rearrangements (univariate analysis: HR = 9.921 and 7.253, both p < 0.001; multivariate analysis: HR = 7.186 and 7.315, p = 0.005 and 0.001, respectively). Hematopoietic stem cell transplantation (HSCT) in first complete remission (CR1) provided EVI1^high patients with a tendential survival benefit when compared with chemotherapy as a consolidation (5-year EFS: 68.4% vs. 50.8%, p = 0.26; 5-year OS: 65.9% vs. 54.8%, p = 0.45).Conclusion: It could be concluded that EVI1^high can be detected in approximately 10% of pediatric AML cases. It is predominantly present in unfavorable cytogenetic subtypes and predicts adverse outcomes. Whether pediatric patients with EVI1^high AML can benefit from HSCT in CR1 needs to be researched further.

Langerhans cell histiocytosis (LCH) is a rare disease with localized to disseminated clinical features. Thyroid involvement in LCH is rare and presenting as either a single-organ or multisystem disease, it is usually misinterpreted as another thyroid disorder. Therefore, the LCH diagnosis is often delayed. We report a pediatric case of LCH with thyroid involvement as the initial clinical manifestation progressing to respiratory failure. Clinicians should note insidious extrathyroidal laboratory abnormalities and consider infiltrative thyroid diseases, such as LCH. Systematic clinical and laboratory investigations are needed to prevent delayed diagnosis because the classic features of LCH may become evident only over time.