Immunologic and Clinical Responses after Vaccinations with Peptide-Pulsed Dendritic Cells in Metastatic Renal Cancer Patients

Wierecky, Jan; Müller, Martin; Wirths, Stefan; Halder-Oehler, Edith; Dörfel, Daniela; Schmidt, Susanne; Häntschel, Maik; Brugger, Wolfram; Schröder, Stephen; Horger, Marius; Kanz, Lothar; Brossart, Peter

doi:10.1158/0008-5472.can-05-3905

Cited by 206 publications

(145 citation statements)

References 35 publications

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“…Dendritic cell vaccines have been evaluated in phase I-III clinical trials for patients with various solid tumors such as melanoma, [18][19][20] prostate cancer, 21,22 renal cell carcinoma [23][24][25] and lymphoma. 26,27 Immunological and also clinical responses observed in these patients prompted researchers in the field to extend the concept of DC vaccination also to leukemia patients.…”

Section: Discussionmentioning

confidence: 99%

Vaccination of B-CLL patients with autologous dendritic cells can change the frequency of leukemia antigen-specific CD8+ T cells as well as CD4+CD25+FoxP3+ regulatory T cells toward an antileukemia response

et al. 2008

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Recently, we described that vaccination with allogeneic dendritic cells (DCs) pulsed with tumor cell lysate generated specific CD8 þ T cell response in patients with B-cell chronic lymphocytic leukemia (B-CLL). In the present study, the potential of autologous DCs pulsed ex vivo with tumor cell lysates to stimulate antitumor immunity in patients with B-CLL in early stages was evaluated. Twelve patients at clinical stage 0-2 as per Rai were vaccinated intradermally up to eight times with a mean number of 7.4 Â 10 6 DCs pulsed with B-CLL cell lysate. We observed a decrease of peripheral blood leukocytes and CD19 þ /CD5 þ leukemic cells in five patients, three patients showed a stable disease and four patients progressed despite DC vaccination. A significant increase of specific cytotoxic CD8 þ T lymphocytes against the leukemia-associated antigens RHAMM or fibromodulin was detected in four patients after DC vaccination. In patients with a clinical response, an increase of interleukin 12 (IL-12) serum levels and a decrease of the frequency of CD4 þ CD25 þ FOXP3 þ T regulatory cells were observed. Taken together, the study demonstrated that vaccination with autologous DC in CLL patients is feasible and safe. Immunological and to some extend hematological responses could be noted, justifying further investigation on this immunotherapeutical approach.

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Section: Discussionmentioning

confidence: 99%

Vaccination of B-CLL patients with autologous dendritic cells can change the frequency of leukemia antigen-specific CD8+ T cells as well as CD4+CD25+FoxP3+ regulatory T cells toward an antileukemia response

et al. 2008

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“…Importantly, there have been several reports of two HLA-A2 binding peptides derived from the MUC1 protein [25][26][27]. MUC1-specific CTLs have also been induced in vivo after vaccination of breast, ovarian, and metastatic renal cancer patients with peptide-pulsed dendritic cells (DCs) [16,28,29]. However, these approaches have generated only modest and infrequent clinical responses.…”

Section: Introductionmentioning

confidence: 99%

MUC1-specific immune therapy generates a strong anti-tumor response in a MUC1-tolerant colon cancer model

Mukherjee

Pathangey

Bradley

et al. 2007

Vaccine

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A MUC1-based vaccine was used in a preclinical model of colon cancer. The trial was conducted in a MUC1-tolerant immune competent host injected with MC38 colon cancer cells expressing MUC1. The vaccine included: MHC class I-restricted MUC1 peptides, MHC class II-restricted pan helper peptide, unmethylated CpG oligodeoxynucleotide, and granulocyte macrophage-colony stimulating factor. Immunization was successful in breaking MUC1 self-tolerance, and in eliciting a robust antitumor response. The vaccine stimulated IFN-γ-producing CD4 + helper and CD8 + cytotoxic T cells against MUC1 and other undefined MC38 tumor antigens. In the prophylactic setting, immunization caused complete rejection of tumor cells, while in the therapeutic regimen, tumor burden was significantly reduced.

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“…17,18 Clinical trials revealed promising immunologic and anti-tumor responses of antigenloaded DCs administered as a vaccine against cancer. [19][20][21][22] In the context of myeloma, DC-based immunotherapy alone or in combination with other strategies may also represent an interesting treatment modality. 23,24 Thus, recent studies investigated the potential of bortezomib to enhance DC-mediated anti-tumor immunity.…”

Section: Introductionmentioning

confidence: 99%

Bortezomib significantly impairs the immunostimulatory capacity of human myeloid blood dendritic cells

et al. 2007

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Bortezomib is a potent drug for the treatment of multiple myeloma. Its anti-tumor activity is mediated by proteasome inhibition leading to decreased cell proliferation and induction of apoptosis. However, an unimpaired proteasomal function plays a crucial role for the induction of anti-tumor immunity by dendritic cells (DCs), which are currently used for therapeutic vaccination against various tumors including myeloma. In the present study, we investigated the impact of bortezomib on the immunostimulatory capacity of 6-sulfo LacNAc (slan) DCs, which represent a major subset of human blood DCs. We demonstrated that this proteasome inhibitor efficiently impairs the spontaneous in vitro maturation of slanDCs and the release of tumor necrosis factor (TNF)-a as well as interleukin (IL)-12 upon lipopolysaccharide (LPS) stimulation. Functional data revealed that bortezomib profoundly inhibits slanDC-induced proliferation and differentiation of CD4 þ T cells. In addition, the capacity of slanDCs to promote interferon-c secretion and tumor-directed cytotoxicity of natural killer (NK) cells is markedly impaired by bortezomib. These results provide evidence that bortezomib significantly reduces the ability of native human blood DCs to regulate innate and adaptive antitumor immunity and may have implications for the design of therapeutic strategies combining DC vaccination and bortezomib treatment.

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Immunologic and Clinical Responses after Vaccinations with Peptide-Pulsed Dendritic Cells in Metastatic Renal Cancer Patients

Abstract: A phase I trial was conducted to evaluate the feasibility, safety, and efficacy of a dendritic cell-based vaccination in patients with metastatic renal cell carcinoma (RCC). Autologous mature dendritic cells derived from peripheral blood monocytes were pulsed with the HLA-

Cited by 206 publications

References 35 publications

Vaccination of B-CLL patients with autologous dendritic cells can change the frequency of leukemia antigen-specific CD8+ T cells as well as CD4+CD25+FoxP3+ regulatory T cells toward an antileukemia response

Vaccination of B-CLL patients with autologous dendritic cells can change the frequency of leukemia antigen-specific CD8+ T cells as well as CD4+CD25+FoxP3+ regulatory T cells toward an antileukemia response

MUC1-specific immune therapy generates a strong anti-tumor response in a MUC1-tolerant colon cancer model

Bortezomib significantly impairs the immunostimulatory capacity of human myeloid blood dendritic cells

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