Dendritic cell vaccines in acute leukaemia

Duncan, Colin; Roddie, Huw

doi:10.1016/j.beha.2008.07.010

Cited by 16 publications

(13 citation statements)

References 92 publications

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“…Furthermore, the ability of therapeutic DCs to migrate to the lymph nodes is influenced by the DC maturation stage and is considered to be important (5,29). A previous study regarding melanoma demonstrated that mature DCs loaded with melanoma antigens were superior to immature DCs loaded with melanoma antigens in the induction of immunological and clinical responses (30).…”

Section: Discussionmentioning

confidence: 99%

“…Following chemotherapy and hematopoietic stem cell transplantation, novel therapeutic strategies have been developed to improve the complete remission (CR) rate and overall survival of ALL patients (3,4). However, significant toxicity, relapse due to a state of minimal residual disease (MRD) and transplant-associated mortality limit the efficacy of allogeneic stem cell transplantation (5). Therefore, the development of additional immunotherapeutic strategies that selectively recognize and destroy leukaemia cells is required, with the aim of reducing relapse rates.…”

Section: Introductionmentioning

confidence: 99%

“…However, the primary obstacles to the introduction of this therapeutic strategy in clinical practice include insufficient numbers of DCs and insufficient production of cytokines. Therefore, DC vaccine therapy relies on either the generation of sufficient numbers of DCs, to prime CTLs, or administration of immunomodulatory agents to overcome deficiencies in DC and CTL function (5). Previous studies that focused on an in vitro methodology have revealed that it is possible to derive DCs from peripheral blood mononuclear cells (PBMCs) using cytokines, which can be used to harvest sufficient numbers of DCs for use in vaccine therapy (13,14).…”

Section: Introductionmentioning

confidence: 99%

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Effect of thymosin α1 on the phenotypic and functional maturation of dendritic cells from children with acute lymphoblastic leukemia

Liu

Zhao

et al. 2015

Molecular Medicine Reports

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Abstract.To determine the effect of thymosin α 1 (Tα1) on the phenotypic and functional maturation of HL-60 cells, freeze-thaw antigen-loaded dendritic cells (DCs) were derived from peripheral blood mononuclear cells (PBMCs) of children with acute lymphoblastic leukemia (ALL). The DCs were generated from the PBMC samples that were collected from the PB of 10 consecutive ALL children. On day 3 of culturing, the cells in the antigen + no Tα1 (AN) and antigen + Tα1 (AT) groups were incubated with 100 µl lysates obtained from freeze-thaw cycling. After 5 days of incubation, the AT group was administered with 100 ng/ml Tα1. On day 8, the DCs were stained with fluorescein isothiocyanate-conjugated cluster of differentiation (CD)1a, CD83 and HLA-DR antibodies and analyzed by flow cytometry. In addition, the killing activity of cytotoxic T lymphocytes (CTLs) from the different groups on wild-type leukemia cells was measured. The DCs in the AT group exhibited more apparent, characteristic dendritic morphologies than the control and AN group DCs. Furthermore, the lowest expression level of CD1a, and the highest expression of CD83 and HLA-DR were observed in the AT group when compared with the AN and control groups (P<0.05). The lactate dehydrogenase release assay demonstrated that the killing rate of CTL in the AT group was significantly higher than that in the control and AN groups (P<0.01). Thus, Tα1 may markedly promote the phenotypic and functional maturation of DCs, and may serve as a suitable immunomodulator of DC-based immunotherapy for treatment of hematological malignancies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effect of thymosin α1 on the phenotypic and functional maturation of dendritic cells from children with acute lymphoblastic leukemia

Liu

Zhao

et al. 2015

Molecular Medicine Reports

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“…For example, leukemic DCs generated from peripheral blood of CML patients were used as a vaccine and shown to elicit a tumor-reactive T cells response (9). DC fusions with leukemia cells or DCs loaded with tumor cell lysates also induced a potent tumor immune response (10). In addition, vaccination with WT1 mRNAelectroporated DCs induces molecular remission in AML patients (11).…”

Section: Vaccines For Hematological Malignanciesmentioning

confidence: 99%

Wilms tumor 1 peptide vaccination after hematopoietic stem cell transplant in leukemia patients

Hosen

Maeda

Hashii

et al. 2016

Stem Cell Investig.

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Although the prognosis of leukemia patients after allogeneic hematopoietic stem cell transplantation (HSCT) has greatly improved, relapse is still a major cause of death after HSCT. Cancer vaccines may have the potential to enhance the graft-versus-leukemia (GVL) effect. The post-allogeneic HSCT period provides a unique platform for vaccination, because (I) tumor burden is minimal, (II) lymphopenia allows for rapid expansion of cytotoxic T cells (CTLs), (III) donor-derived CTLs are not exhausted, (IV) inflammation is caused by alloreactions, and (V) the abundance of regulatory T cells is low due to their late recovery. Tumor cell lysates, dendritic cells (DCs), and peptides derived from leukemiaassociated antigens (LAAs) have been used as vaccines. Clinical trials with several types of vaccines for post-HSCT patients revealed that the vaccination induced an immunological response and might benefit patients with minimal residual disease; however, the efficacy of this approach must be examined in randomized studies. In addition, it is important to consider the combination of cancer vaccine with checkpoint antibodies, recently shown to be useful in treating leukemia relapse after HSCT. Vaccines for hematological malignanciesIn several types of cancers, allogeneic tumor cells expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) (GVAX) were tested as vaccine (3)(4)(5). For example, K562 cells expressing GM-CSF were used as vaccine for CML patients. In some patients, the abundance of CML cells decreased after immunotherapy, and this effect was associated with the induction of high-titer IgG antibodies against multiple leukemia-associated antigens (LAAs) (6). In another trial by Borrello et al., pre-auto HSCT patients were immunized with autologous leukemia cells mixed with GM-CSF-secreting K562 cells (7). A decrease in Wilms tumor 1 (WT1) transcripts in blood was noted in 69% of patients after immunotherapy, and was associated with longer 3-year relapse-free survival (61% in the immunized group vs. 0% in the nonimmunized group). For successful use of tumor cell vaccines, the usage of appropriate adjuvant is essential. Recently, Gibbins et al. reported that an intravenously administered vaccine consisting of irradiated leukemia cells loaded with the natural killer T (NKT)-cell agonist alpha-galactosylceramide (alpha-GalCer) was effective in a mouse leukemia model (8).Dendritic cell (DC)-based vaccines represent another effective strategy. For example, leukemic DCs generated from peripheral blood of CML patients were used as a vaccine and shown to elicit a tumor-reactive T cells response (9). DC fusions with leukemia cells or DCs loaded with tumor cell lysates also induced a potent tumor immune response (10). In addition, vaccination with WT1 mRNAelectroporated DCs induces molecular remission in AML patients (11).Several kinds of peptide vaccines have been developed. For example, LAA-derived peptides (12) and DNA (13) have been used as vaccines in combination with adjuvants. BCR-ABL for Phil...

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“…[1][2][3][4][5][6][7] Tumorassociated antigens-specific T cells can be detected in patients, and, albeit unable to properly function in the tumoral microenvironment, are capable to lyse tumor cells in vitro. [8][9][10] Adoptive cell therapy, by ex-vivo stimulated tumor infiltrating lymphocytes is already efficient in some patients, 11 and its combination with DCs vaccine could be a promising new approach to cancer treatment.…”

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confidence: 99%

Dendritic Cells Generated in Clinical Grade Bags Strongly Differ in Immune Functionality When Compared With Classical DCs Generated in Plates

Rouas

Akl²,

Fayyad‐Kazan³

et al. 2010

Journal of Immunotherapy

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Mature dendritic cells (DCs) represent, by far, the most potent antigen-presenting cells. The development of clinical grade techniques to produce them in large numbers has rendered possible their use in clinical trials. It is therefore crucial to assess the DCs characteristics according to the methodology used to generate them, to improve the comparison and standardization of these trials. We thus compared DCs generated and matured in culture plates (pla-DCs) or in clinical grade bags (bag-DCs) by analyzing, their secretion of bioactive interleukin (IL)-12 and their capacity to induce in-vitro primary responses. We also used several molecular techniques to better characterize the functional differences between the 2 type of DCs. Mature bag-DCs displayed a mature phenotype, but did not secrete significant amounts of IL-12 and failed to initiate primary immune responses. Molecular analyses performed on immature bag-DCs showed them already engaged in a particular maturation process (early activation of nuclear factor kappa B and beta-catenin). Using microarrays, we found underexpression of receptors for the maturation cocktail in bag-DCs. In mature bag-DCs, we found crucial genes (IL-12, chemokines, and costimulatory and adhesion molecules) down-regulated. Electrophoertic mobility shift assay and Western blots showed a normal activation profile in mature pla-DCs, but not in bag-DCs where the Mek/Erk pathway was still activated. Our results strongly suggest that differentiation of monocytes into DCs in bags generates immature DCs already engaged in an inefficient type of activation, with down-regulation of genes involved in response to the maturation cocktail. This results in mature DCs unable to induce T(H)1-type responses.

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Dendritic cell vaccines in acute leukaemia

Cited by 16 publications

References 92 publications

Effect of thymosin α1 on the phenotypic and functional maturation of dendritic cells from children with acute lymphoblastic leukemia

Effect of thymosin α1 on the phenotypic and functional maturation of dendritic cells from children with acute lymphoblastic leukemia

Wilms tumor 1 peptide vaccination after hematopoietic stem cell transplant in leukemia patients

Dendritic Cells Generated in Clinical Grade Bags Strongly Differ in Immune Functionality When Compared With Classical DCs Generated in Plates

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