The Use of Filamentous Bacteriophage<i>fd</i>to Deliver MAGE-A10 or MAGE-A3 HLA-A2-Restricted Peptides and to Induce Strong Antitumor CTL Responses

Sartorius, Rossella; Pisu, Paola; D’Apice, Luciana; Pizzella, Luciano; Romano, Chiara; Cortese, Giancarlo; Giorgini, Angela; Santoni, Angela; Velotti, Francesca; Berardinis, Piergiuseppe De

doi:10.4049/jimmunol.180.6.3719

Cited by 52 publications

(49 citation statements)

References 41 publications

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“…MAGE expression is not the exclusive property of melanoma cells; among other tumors, colon carcinoma cells naturally express MAGE. CEA-, MUC1-, and MAGE-expressor allogeneic colon carcinoma cells used as vaccines presented these antigens in an immunogenic manner and elicited anti-tumor CTL reactions [212,325,342]. It probably will be first in the colon where phages will prove themselves to be oncosuppresssive.…”

Section: Concluding Discussionmentioning

confidence: 99%

Natural and genetically engineered viral agents for oncolysis and gene therapy of human cancers

Sinkovics

Horváth

2008

Arch. Immunol. Ther. Exp.

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Based on personal acquaintances and experience dating back to the early 1950s, the senior author reviews the history of viral therapy of cancer. He points out the difficulties encountered in the treatment of human cancers, as opposed by the highly successful viral therapy of experimentally maintained tumors in laboratory animals, especially that of ascites carcinomas in mice. A detailed account of viral therapy of human tumors with naturally oncolytic viruses follows, emphasizing the first clinical trials with viral oncolysates. The discrepancy between the high success rates, culminating in cures, in the treatment of tumors of laboratory animals, and the moderate results, such as stabilizations of disease, partial responses, very rare complete remissions, and frequent relapses with virally treated human tumors is recognized. The preclinical laboratory testing against established human tumor cell lines that were maintained in tissue cultures for decades, and against human tumors extricated from their natural habitat and grown in xenografts, may not yield valid results predictive of the viral therapy applied against human tumors growing in their natural environment, the human host. Since the recent discovery of the oncosuppressive efficacy of bacteriophages, the colon could be regarded as the battlefield, where incipient tumor cells and bacteriophages vie for dominance. The inner environment of the colon will be the teaching ground providing new knowledge on the value of the anti-tumor efficacy of phage-induced innate anti-tumor immune reactions. Genetically engineered oncolytic viruses are reviewed next. The molecular biology of viral oncolysis is explained in details. Elaborate efforts are presented to elucidate how gene product proteins of oncolytic viruses switch off the oncogenic cascades of cancer cells. The facts strongly support the conclusion that viral therapy of human cancers will remain in the front lines of modern cancer therapeutics. It may be a combination of naturally oncolytic viruses and wild-type viruses rendered oncolytic and harmless by genetic engineering, that will induce complete remissions of human tumors. It may be necessary to co-administer certain chemotherapeutic agents, advanced cancer vaccines, or even immune lymphocytes, and targeted therapeuticals, to ascertain, that remissions induced by the viral agents will remain complete and durable; will co-operate with anti-tumor host immune reactions, and eventually will result in cures of advanced metastatic human cancers.

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Section: Concluding Discussionmentioning

confidence: 99%

Natural and genetically engineered viral agents for oncolysis and gene therapy of human cancers

Sinkovics

Horváth

2008

Arch. Immunol. Ther. Exp.

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“…Tumor size was assessed using caliper and recorded as tumor volume (mm 3 ) according to the formula (d 2 Â D)/2 where d and D are the shortest and the longest diameters. Mice were culled once tumor size met or exceeded 1500 mm 3 , in accordance with established guidelines.…”

Section: Analysis Of Ifn-a and Il-6 Productionmentioning

confidence: 99%

“…In this context we previously demonstrated that fd phage particles have access to both MHC class I and class II compartments [1] and that the antigenic determinants displayed by fd virions on the major pVIII coat protein trigger specific CTL responses [2,3]. However, the full potential of the fd bacteriophage system for vaccine formulation is still ameliorable by exploiting simultaneous display on different phage coat proteins.…”

Section: Introductionmentioning

confidence: 99%

Vaccination with filamentous bacteriophages targeting DEC‐205 induces DC maturation and potent anti‐tumor T‐cell responses in the absence of adjuvants

et al. 2011

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The efficacy of a new vaccine-delivery vector, based on the filamentous bacteriophage fd displaying a single-chain antibody fragment known to bind the mouse DC surface molecule DEC-205, is reported. We demonstrate both in vitro and in vivo an enhanced receptormediated uptake of phage particles expressing the anti-DEC-205 fragment by DCs. We also report that DCs targeted by fd virions in the absence of other stimuli produce IFN-a and IL-6, and acquire a mature phenotype. Moreover, DC-targeting with fd particles double-displaying the anti-DEC-205 fragment on the pIII protein and the OVA [257][258][259][260][261][262][263][264] antigenic determinant on the pVIII protein induced potent inhibition of the growth of the B16-OVA tumor in vivo. This protection was much stronger than other immunization strategies and similar to that induced by adoptively transferred DCs. Since targeting DEC-205 in the absence of DC activation/maturation agents has previously been described to result in tolerance, the ability of fd bacteriophages to induce a strong tumor-specific immune response by targeting DCs through DEC-205 is unexpected, and further validates the potential employment of this safe, versatile and inexpensive delivery system for vaccine formulation.

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“…15 Briefly, 2 ml of the FliTrx library was induced in the presence of IMC medium containing ampicillin and 100 lg/ml tryptophan at 25 C. Bacteria were then ''panned'' on 60-mm tissue culture plates (Becton Dickinson, Franklin Lakes, NJ) pretreated with the mAb under investigation (50 lg/ml in sterile water). After the removal of unbound cells, bacteria were amplified o/n in IMC medium at 25 C. After five rounds of panning and culture, E. coli were streaked onto RMG medium plates containing 100 lg/ml ampicillin and incubated overnight at 30 C. Individual clones tested positive in Western blot 7 were selected and amplified o/n at 30 C in RM medium containing ampicillin. DNA was isolated using the NucleoSpin kit (Macherey-Nagel, Oensingen, Switzerland), and plasmids were sequenced by using the FliTrx forward or Rsr reverse sequencing primers.…”

Section: Epitope Mappingmentioning

confidence: 99%

“…On the other hand, only a limited number of reagents are available to detect the corresponding proteins. 3 MAGE-A10 is probably the most immunogenic antigen of the MAGE-A family, [4][5][6][7][8] and, therefore, it represents a potentially highly attractive target of active specific immunotherapies. This antigen, expressed in the form of a 72-kDa nuclear protein, has been identified thanks to broadly reactive monoclonal antibodies (mAbs) recognizing it together with other members of the MAGE-A family.…”

mentioning

confidence: 99%

MAGE‐A10 is a nuclear protein frequently expressed in high percentages of tumor cells in lung, skin and urothelial malignancies

Schultz‐Thater

Piscuoglio

Iezzi

et al. 2011

Intl Journal of Cancer

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MAGE‐A10 is a highly immunogenic member of the MAGE‐A family of cancer/testis tumor‐associated antigens (C/T TAAs). Studies performed with broadly reactive antibodies have helped to initially characterize this TAA. However, no specific reagents have been developed so far, thus preventing a thorough analysis of its expression in healthy and tumoral tissues. We have produced MAGE‐A10 gene product in soluble recombinant form, and we have used it to generate specific monoclonal antibodies (mAbs). One of these reagents, recognizing an epitope located at the COOH terminus of the MAGE‐A10 gene product, was used to stain a multitumor tissue microarray comprising more than 2,500 paraffin‐embedded specimens including healthy tissues, benign tumors and malignancies of different histological origin. MAGE‐A10 protein was identified as an intranuclear protein of an apparent molecular weight of 70 kDa, expressed in normal spermatogonia and spermatocytes but in no other healthy tissue. Most importantly, this C/T TAA appears to be expressed in high (>50%) percentages of cancer cells from a number of malignancies, including lung, skin and urothelial tumors. Unexpectedly, high expression of MAGE‐A10 TAA at the protein level was also detectable in gynecological malignancies and stomach and gall bladder cancers. The characterization of MAGE‐A10‐specific reagents might set the stage for the development of targeted active immunotherapy by clarifying potential indications and by allowing the selection of patients eligible for treatment and the monitoring of its effectiveness.

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The Use of Filamentous Bacteriophagefdto Deliver MAGE-A10 or MAGE-A3 HLA-A2-Restricted Peptides and to Induce Strong Antitumor CTL Responses

Cited by 52 publications

References 41 publications

Natural and genetically engineered viral agents for oncolysis and gene therapy of human cancers

Natural and genetically engineered viral agents for oncolysis and gene therapy of human cancers

Vaccination with filamentous bacteriophages targeting DEC‐205 induces DC maturation and potent anti‐tumor T‐cell responses in the absence of adjuvants

MAGE‐A10 is a nuclear protein frequently expressed in high percentages of tumor cells in lung, skin and urothelial malignancies

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