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Background: Immunotherapies, including chimeric antigen receptor (CAR) T cells and bispecific antibodies (BsAbs), encounter several challenges in the management of acute myeloid leukemia (AML), including limited persistence of these treatments, antigen loss and resistance of leukemia stem cells (LSCs) to therapy. Methods: Here, we proposed a novel dual-targeting approach utilizing engineered anti-IL10R CAR-T cells to secrete bispecific antibodies targeting CD33. This innovative strategy, rooted in our previous research which established a connection between IL-10 and the stemness of AML cells, designed to improve targeting efficiency and eradicate both LSCs and AML blasts. Results: We first demonstrated the superior efficacy of this synergistic approach in eliminating AML cell lines and primary cells expressing different levels of the target antigens, even in cases of low CD33 or IL10R expression. Furthermore, the IL10R CAR-T cells that secret anti-CD33 bsAbs (CAR.BsAb-T), exhibited an enhanced activation and induction of cytotoxicity not only in IL10R CAR-T cells but also in bystander T cells, thereby more effectively targeting CD33-positive tumor cells. Our in vivo experiments provided additional evidence that CAR.BsAb-T cells could efficiently redirect T cells, reduce tumor burden, and demonstrate no significant toxicity. Additionally, delivering bsAbs locally to the tumor sites through this strategy helps mitigate the pharmacokinetic challenges typically associated with the rapid clearance of prototypical bsAbs. Conclusions: Overall, the engineering of a single-vector targeting IL10R CAR, which subsequently secretes CD33-targeted bsAb, addresses the issue of immune escape due to the heterogeneous expression of IL10R and CD33, and represents a promising progress in AML therapy aimed at improving treatment outcomes. [ABSTRACT FROM AUTHOR]

Chronic myeloid leukemia (CML) results from hematopoietic stem cell transformation by the BCR-ABL kinase. Despite the success of BCR-ABL tyrosine kinase inhibitors (TKIs) in treating CML patients, leukemia stem cells (LSCs) resist elimination and persist as a major barrier to cure. Previous studies suggest that overexpression of the sirtuin 1 (SIRT1) deacetylase may contribute to LSC maintenance in CML. Here, by genetically deleting SIRT1 in transgenic CML mice, we definitively demonstrated an important role for SIRT1 in leukemia development. We identified a previously unrecognized role for SIRT1 in mediating increased mitochondrial oxidative phosphorylation in CML LSCs. We showed that mitochondrial alterations were kinase independent and that TKI treatment enhanced inhibition of CML hematopoiesis in SIRT1-deleted mice. We further showed that the SIRT1 substrate PGC-1[alpha] contributed to increased oxidative phosphorylation and TKI resistance in CML LSCs. These results reveal an important role for SIRT1 and downstream signaling mechanisms in altered mitochondrial respiration in CML LSCs., Introduction Chronic myeloid leukemia (CML) is a lethal hematological malignancy that results from hematopoietic stem cell (HSC) transformation by the BCR-ABL tyrosine kinase. BCR-ABL expression bestows hematopoietic cells with malignant [...]

Hematopoietic recovery is considered to be associated with the number of multipotent hematopoietic stem cells in the bone marrow, as observed in functional assays involving stem cell transplantation. However, there is little evidence related to hematopoietic recovery in non-transplantation settings, which is accomplished by endogenous hematopoietic cells. A recent study suggested that progenitors are the main contributors during this steady-state hematopoiesis, which differs from exogenous transplantation. We hypothesized that endogenous progenitor support post-chemotherapy hematopoietic recovery. To investigate the potential impact of these progenitor cell percentage on hematopoietic recovery, we retrospectively analyzed the percentage of CD34+CD38+CD117+HLA-DR+CD13+CD33+ cells (P cells) and hematopoietic recovery in 223 newly diagnosed acute myeloid leukemia patients during two courses of consolidation chemotherapy after complete remission. We found that a lower P cell percentage was significantly associated with prolonged neutropenia recovery time after the first and second courses of consolidation chemotherapy (p = 0.001; p = 0.045, respectively). We also observed similar results with regard to platelet recovery time after the first course of consolidation chemotherapy (p = 0.000). Univariate analysis showed that P cell percentage and consolidation chemotherapy regimens, and not gender, age, induction chemotherapy regimens, infection grade, WHO classification and NCCN risk category, were associated with neutrophil recovery after chemotherapy. Multivariate analysis demonstrated that P cell percentage is an independent factor affecting neutrophil recovery capacity for both the first and second courses (p = 0.008; p = 0.032, respectively). Our results indicate that CD34+CD38+CD117+HLA-DR+CD13+CD33+ cells before each course of chemotherapy is independently associated with chemotherapy-related hematopoietic reconstitution capacity. These findings may help modify future chemotherapy regimens based on progenitor cell percentages. [ABSTRACT FROM AUTHOR]

Abstract: Emerging studies suggest that the population of malignant cells found in human acute myelogenous leukemia (AML) arises from a rare population of leukemic stem cells (LSCs). A lot of investigators have reported the identification of cell surface markers, such as CD123. Here, we report the identification of N-cadherin and Tie2 as LSCs markers. Inoculation of CD34+CD38−CD123+ N-cadherin+ and CD34+CD38−CD123+ Tie2+ population can induce leukemia in NOD/SCID mice. The leukemic blast cells from the primary leukemic mice could also induce leukemia in the secondary transplantation. These findings suggested that N-cadherin and Tie2 were the important markers that can assist in leukemia development. [Copyright &y& Elsevier]