Fusion of Dendritic Cells and CD34+CD38− Acute Myeloid Leukemia (AML) Cells Potentiates Targeting AML-initiating Cells by Specific CTL Induction

Abstract

Distinct leukemia-initiating cells (L-ICs) represent a critical target for therapeutic intervention of acute myeloid leukemia (AML). A potential strategy to eradicate L-ICs is to generate L-IC-specific cytotoxic T lymphocytes (CTLs). However, owing to rarity and immortality of L-ICs, it is difficult for antigen-presenting cells to capture L-ICs for specific antigen presentation. Here, we report a novel approach by fusing allogeneic dendritic cells (DCs) and CD34CD38 AML progenitor cells, through which specific CTLs were effectively induced, leading to the cytolysis to AML-initiating cells. Fusion of either DC/CD34CD38 AML cell or DC/CD34 AML cell could effectively induce the proliferation and activation of CTLs. However, only the former CTLs could effectively attack AML progenitor cells, and result in the unkilled progenitor/initiating cells losing the abilities of active proliferation in vitro and engraftment in NOD-SCID mice. These findings suggest that AML progenitor/initiating cell-specific CTLs may be generated based on allogeneic DC/progenitor cell fusion strategy; the induced CTLs may potentially eradicate AML by targeting L-ICs directly or indirectly.

Immunotherapy prospects for acute myeloid leukaemia

“…However, only two of these patients were long‐term survivors [82]. Alternatively, DC have been generated from AML patients in remission and made more antigenic by fusion with AML blasts [83], exposure to AML lysates or peptide antigens or transfection with RNA [84]. A clinical trial with a monocyte‐derived DC loaded with mRNA for Wilms tumour‐1 (WT1) antigen is under way [85].…”

Autologous Dendritic Cells Combined with Cytokine-Induced Killer Cells Synergize Low-Dose Chemotherapy in Elderly Patients with Acute Myeloid Leukaemia

“…Dendritic cells (DCs) are major antigen-presenting cells (APCs) that recognize and present antigens to T cells, inducing an antitumour T cell effect. 5 Cytokine-induced killer (CIK) cells are immune effector cells that play a potential role in adoptive cell immunotherapy and exhibit potent cytotoxicity against a variety of autologous and allogeneic AML cells. 6 Thus, DCs present antigens to T cells initiating an antitumour response by activating cytotoxic T cells and CIK cells, which can kill tumour cells by acting on autologous cytotoxicity and secreting cytokines.…”

“…6 Thus, DCs present antigens to T cells initiating an antitumour response by activating cytotoxic T cells and CIK cells, which can kill tumour cells by acting on autologous cytotoxicity and secreting cytokines. 5,7 Some in vivo and in vitro animal studies have reported that the combination of CIK cells with relevant chemotherapy enhanced antitumour effectiveness in human drug-resistant cancer cell lines and that this was not influenced by the multipledrug resistance of the tumour. 8,9 In previous studies, venous transfusion of DCs and CIK cells was performed after complete haematological remission had occurred in order to mitigate the negative impact of chemotherapy and immunosuppression on the body's immune system response to DC and CIK cell therapy.…”

Immunologic Monitoring of Cellular Responses by Dendritic/Tumor Cell Fusion Vaccines

“…The efficacy of antitumor immunity induced by DC/tumor fusion vaccines has been demonstrated in murine models using melanoma [24–32], colorectal [17, 30, 31, 33–41], breast [42–47], esophageal [48], pancreatic [49, 50], hepatocellular [51–55], lung [22, 41, 56–59], renal cell [60] carcinoma, sarcoma [61–66], myeloma [67–74], mastocytoma [75], lymphoma [76], and neuroblastoma [77]. The fusion cells generated with human DC and tumor cell also have the ability to present multiple tumor antigens, thus increasing the frequency of responding T cells and maximizing antitumor immunity capable of killing tumor targets such as colon [78–84], gastric [85, 86], pancreatic [87], breast [47, 88–93], laryngeal [94], ovarian [95–97], lung [85, 98], prostate [99, 100], renal cell [101, 102], hepatocellular [103–105] carcinoma, leukemia [106–111], myeloma [112, 113], sarcoma [114, 115], melanoma [116–119], glioma [120], and plasmacytoma [121]. …”