Cancer Vaccine Design: A Novel Bacterial Adjuvant for Peptide-Specific CTL Induction

Miconnet, Isabelle; Coste, Isabelle; Beermann, Friedrich; Haeuw, Jean‐François; Cerottini, Jean‐Charles; Bonnefoy, Jean‐Yves; Romero, Pedro; Renno, Toufic

doi:10.4049/jimmunol.166.7.4612

Cited by 45 publications

(44 citation statements)

References 37 publications

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“…Purified P40 has previously been found to stimulate the immune response against a TRP-2 peptide antigen present on B16F10 tumors and to confer protection against these tumors when administered with the peptide at the time of tumor implantation. 21 In our RenCa-MUC1 model, Ad-flagellin combined with Ad-MUC1 produced the highest survival rates when compared with Ad-P40 or Ad NDV HN. Ad-flagellin also showed the strongest effects in vitro on the maturation of human moDCs and on lymphocyte proliferation in MLR.…”

Section: Adenovirus-pamps For Cancer Immunotherapy C Tosch Et Almentioning

confidence: 77%

“…The gene encoding the P40 from K. pneumoniae was provided by the Centre d'Immunologie Pierre Fabre (CIPF, Saint Julien en Genevois, France). [18][19][20][21] The human CD40L cDNA was purchased from InvivoGen (Cayla, Toulouse, France). The gene encoding the HN of the NDV was derived from plasmid p36/7-HN.…”

Section: Adenoviral Vectorsmentioning

confidence: 99%

“…18,19 P40 binds TLR2 on the surface of antigen-presenting cells (DCs and macrophages) and induces the phenotypic maturation of DCs, [18][19][20] secretion of interleukin (IL)-12 and the inflammatory cytokines IL-6, IL-8 and tumor necrosis factor (TNF)-a. P40 mixed with a tumor antigen peptide was shown to elicit tumor-specific CTL responses and to significantly delay the growth of B16F10 melanoma tumors implanted at the time of immunization. 21 Flagellin is the main component of the bacterial flagella and induces DC maturation and chemokine secretion by activating NF-kB through their interaction with TLR5. 22,23 Recombinant flagellin from Salmonella typhimurium induces maturation of human DCs and causes secretion of chemokines.…”

Section: Introductionmentioning

confidence: 99%

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Adenovirus-mediated gene transfer of pathogen-associated molecular patterns for cancer immunotherapy

et al. 2008

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The delivery of stimulatory signals to dendritic cells (DCs) in the tumor microenvironment could be an effective means to break tumorinduced tolerance. The work presented here evaluates the immunostimulatory properties of pathogen-associated molecular patterns (PAMPs), microbial molecules which bind Toll-like receptors and deliver activating signals to immune cells, when expressed in tumor cells using adenoviral (Ad) vectors. In vitro, transduction of A549 tumor cells with Ad vectors expressing either flagellin from Listeria monocytogenes or P40 protein from Klebsiella pneumoniae induced the maturation of human monocyte-derived DCs in co-cultures. In mixed lymphocyte reactions (MLRs), Ad-flagellin and Ad-P40 transduction of tumor cells stimulated lymphocyte proliferation and the secretion of IFN-g. In vivo, these vectors were used either as stand-alone immunoadjuvants injected intratumorally or as vaccine adjuvants combined with a tumor antigen-expressing vector. When Ad-PAMPs were administered intratumorally to mice bearing subcutaneous syngeneic B16F0-CAR (cocksackie-adenovirus receptor) melanomas, tumor progression was transiently inhibited by Ad-P40. In a therapeutic vaccine setting, the combination of Ad-MUC1 and Ad-PAMP vectors injected subcutaneously delayed the growth of implanted RenCa-MUC1 tumors and improved tumor rejection when compared with vaccination with Ad-MUC1 alone. These results suggest that Ad-PAMPs could be effective immunoadjuvants for cancer immunotherapy.

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Section: Adenovirus-pamps For Cancer Immunotherapy C Tosch Et Almentioning

confidence: 77%

Section: Adenoviral Vectorsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Adenovirus-mediated gene transfer of pathogen-associated molecular patterns for cancer immunotherapy

et al. 2008

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“…5 The use of synthetic peptide analogues with increased affinity for MHC class I 6,7 or TCR molecules 8 greatly enhanced specific CTL responses that were able to control tumor cells in vivo, especially in combination with appropriate adjuvants or recombinant viral vectors, allowing efficient antigen delivery and induction of a nonspecific inflammatory response. 9,10 Another important factor that can influence the induction and maintenance of antitumor CTLs is the simultaneous activation of CD4 ϩ helper T cells. Depending on the route of antigen administration, CD4 T-cell responses become very important.…”

mentioning

confidence: 99%

Testing mouse mammary tumor virus superantigen as adjuvant in cytotoxic T‐lymphocyte responses against a melanoma tumor antigen

Wirth¹,

Bille²,

Koenig³

et al. 2002

Intl Journal of Cancer

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Cytotoxic T cells represent a powerful strategy for antitumor treatment. Depending on the route of injection, an important role for CD4 T cell-mediated help was observed in the induction of this response. For this reason, we investigated whether induction of a CTL response to the HLA-A2-restricted immunodominant peptide melanoma antigen Melan-A was improved by using rVVs expressing the CTLdefined epitope alone or in combination with an SAg. In the latter case, the few infected dendritic cells simultaneously presented an SAg and an antigen, i.e., peptide. Here, we show that the anti-Melan-A response was efficiently induced but not significantly improved by coexpression of the SAg.

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“…(5)(6)(7)(8) In peptide vaccine therapy, the T cells of the acquired immune system play an important role in recognizing and attacking tumor cells. (9) Dendritic cells play a key role in the regulation of the acquired immune system by presenting antigen and inducing a primary immune response. The identification of the Toll-like receptor (TLR) family advanced the understanding of DC function and of the role of adjuvants, because almost all microbial adjuvants work as TLR ligands and activate DCs.…”

mentioning

confidence: 99%

Adjuvant engineering for cancer immunotherapy: Development of a synthetic TLR2 ligand with increased cell adhesion

Akazawa

Inoue²,

Shime

et al. 2010

Cancer Science

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The development of effective immunoadjuvants for tumor immunotherapy is of fundamental importance. The use of Mycobacterium bovis bacillus Calmette-Gué rin cell wall skeleton (BCG-CWS) in tumor immunotherapy has been examined in various clinical applications. Because BCG-CWS is a macromolecule that cannot be chemically synthesized, the development of an alternative synthetic molecule is necessary to ensure a constant supply of adjuvant. In the present study, a new adjuvant was designed based on the structure of macrophage-activating lipopeptide (MALP)-2, which is a Toll-like receptor (TLR)-2 ligand similar to BCG-CWS. Macrophage-activating lipopeptide-2, [S-(2,3-bispalmitoyloxypropyl)Cys (P2C) -GNNDESNISFKEK], originally identified in a Mycoplasma species, is a lipopeptide that can be chemically synthesized. A MALP-2 peptide was substituted with a functional motif, RGDS, creating a novel molecule named P2C-RGDS. RGDS was selected because its sequence constitutes an integrin-binding motif and various integrins are expressed in immune cells including dendritic cells (DCs). Thus, this motif adds functionality to the ligand. P2C-RGDS activated DCs and splenocytes more efficiently than MALP-2 over short incubation times in vitro, and the RGDS motif contributed to their activation. Furthermore, P2C-RGDS showed higher activity than MALP-2 in inducing migration of DCs to draining lymph node, and in inhibiting tumor growth in vivo. This process of designing and developing synthetic adjuvants has been named ''adjuvant engineering,'' and the evaluation and improvement of P2C-RGDS constitutes a first step in the development of stronger synthetic adjuvants in the future. (Cancer Sci 2010; 101: 1596-1603 B acterial adjuvants that were used as biological response modifiers (BRM) for cancer immunotherapy in the 1970s have recently been re-evaluated.(1-3) Cancer antigens that had been identified in many laboratories were tested as peptide vaccines for clinical applications, but the peptides alone were not sufficient to fully activate the immune system.(4) These results suggested that the activation of the innate immune system, including dendritic cells (DCs), by a supporting adjuvant was important.(5-8) In peptide vaccine therapy, the T cells of the acquired immune system play an important role in recognizing and attacking tumor cells.(9) Dendritic cells play a key role in the regulation of the acquired immune system by presenting antigen and inducing a primary immune response. The identification of the Toll-like receptor (TLR) family advanced the understanding of DC function and of the role of adjuvants, because almost all microbial adjuvants work as TLR ligands and activate DCs.(10-12) These findings provide the basis for the understanding of the mechanism of adjuvant therapy.Dr Azuma developed BCG-CWS, a cell-wall skeleton preparation of Mycobacterium bovis bacillus Calmette-Guérin, (13,14) as an antitumor immunotherapeutic adjuvant. Although many BRM studies have been discontinued, basic and clinical research on BCG-CWS has...

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Cancer Vaccine Design: A Novel Bacterial Adjuvant for Peptide-Specific CTL Induction

Cited by 45 publications

References 37 publications

Adenovirus-mediated gene transfer of pathogen-associated molecular patterns for cancer immunotherapy

Adenovirus-mediated gene transfer of pathogen-associated molecular patterns for cancer immunotherapy

Testing mouse mammary tumor virus superantigen as adjuvant in cytotoxic T‐lymphocyte responses against a melanoma tumor antigen

Adjuvant engineering for cancer immunotherapy: Development of a synthetic TLR2 ligand with increased cell adhesion

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