Heat labile enterotoxin of E. coli: a potential adjuvant for transcutaneous cancer immunotherapy

Pitcovski, Jacob; Bazak, Z.; Wasserman, Elena; Elias, Orit; Levy, Adva; Peretz, Tamar; Fingerut, E.; Frankenburg, Shoshana

doi:10.1016/j.vaccine.2005.08.052

Cited by 21 publications

(13 citation statements)

References 31 publications

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“…The approach of inserting AAY spacers between the epitopes and the use of ubiquitin as a protein-targeting sequence was previously tested in the context of minigenes containing CTL epitopes derived from MPT64 and 38 kDa proteins of Mycobacterium tubercolosis 32 . Pitcovski et al (2006) assayed a melanoma DNA immunotherapy encoding a multi-epitope polypeptide having 3 repeats of 4 modified melanoma antigens linked by 5 spacer elements that signal proteasomal cleavage and fused to the E.coli LTB enterotoxin as adjuvant 50 . In a separate study, 51 an oral DNA minigene vaccine was also evaluated containing the HIV tat translocation peptide and a spacer (AAA) followed by an HLA-A2-restricted CEA T cell epitope, all inserted into a pCMV vector including an ER signal peptide 51 .…”

Section: Discussionmentioning

confidence: 99%

A novel minigene scaffold for therapeutic cancer vaccines

Aurisicchio¹,

Fridman

Bagchi

et al. 2014

OncoImmunology

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Genetic vaccines are emerging as a powerful modality to induce T-cell responses to target tumor associated antigens (TAA). Viral or plasmid DNA or RNA vectors harbor an expression cassette encoding the antigen of choice delivered in vivo by vaccination. In this context, immunizations with minigenes containing selected, highly antigenic, T-cell epitopes of TAAs may have several advantages relative to full-length proteins. The objective of this study was to identify an optimal scaffold for minigene construction. We generated a number of minigenes containing epitopes from the carcinoembryonic antigen (CEA) model TAA and utilized muscle DNA electro-gene-transfer (DNA-EGT) to vaccinate HLA-A*0201 (HHD) and CEA/HHD double transgenic mice. The components utilized to construct the minigenes included CD8+ T cell epitopes and (or) anchor modified analogs that were selected on the basis of their predicted binding to HLA-*A0201, their uniqueness in the human proteome, and the likelihood of cancer cell natural processing and presentation via MHC-I. Other candidate components comparatively tested included: helper CD4+ T-cell epitopes, flanking regions for optimal epitope processing (including both proteasome-dependent and furin-dependent polypeptide processing mechanisms), and immunoenhancing moieties. Through a series of comparative studies and iterations we have identified an optimal minigene scaffold comprising the following elements: human tissue plasminogen activator (TPA) signal peptide, T-cell epitopes connected by furin sensitive linkers, and the E. Coli enterotoxin B subunit. The selected epitope modified minigenes (EMM) delivered by DNA-EGT were able to break immune tolerance in CEA/HHD mice and induce a strong immune response against all epitopes tested, independently of their relative positions within the scaffold. Furthermore, the optimized EMMs delivered via DNA-EGT were more immunogenic and exerted more powerful antitumor effects in a B16-CEA/HHD metastatic melanoma model than a DNA vector encoding the full-length protein or a mixture of the same peptides injected subcutaneously. Our data may shed light on the optimal design of a universal vehicle for epitope-targeted, genetic cancer vaccines.

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Section: Discussionmentioning

confidence: 99%

A novel minigene scaffold for therapeutic cancer vaccines

Aurisicchio¹,

Fridman

Bagchi

et al. 2014

OncoImmunology

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“…Conversely, by SC route, the increase of the anti-SuHV-1 humoral response occurred proportionally to the increase of the rLTB concentration in the vaccine, reaching its maximum only when the highest dose of rLTB (40 lg/dose) was used. Subcutaneous inoculation of the vaccine has probably allowed processing of the antigen by dendritic cells (Langerhans cells) which are the main APC's (Rossi and Young 2005), once maturation and activation of these cells constitute the basis of the LTB immunostimulatory effect (Pitcovski et al 2006). This way, the higher the rLTB concentration in the vaccine, the higher the activation of these dendritic cells, reflecting in the increase of anti-SuHV-1 humoral response.…”

Section: Discussionmentioning

confidence: 99%

Recombinant Escherichia coli heat-labile enterotoxin B subunit humoral adjuvant effect depends on dose and administration route

Fischer

Conceição

Moraes

et al. 2009

World J Microbiol Biotechnol

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Information on the use of Escherichia coli heatlabile enterotoxin B subunit (LTB) as a parenteral adjuvant is scarce. We evaluate the adjuvant effect of different concentrations of recombinant LTB (rLTB), as well as the influence of administration route (intramuscular and subcutaneous) on mice immune response. The use of 10 lg/ dose of rLTB as adjuvant of an inactivated vaccine composed by Suid herpesvirus type 1 (SuHV-1), used to immunize mice intramuscularly, induced the highest average titers of anti-SuHV-1 antibodies (P \ 0.05). The same vaccines used subcutaneously induced lower titers of antibodies. The lower the anti-rLTB humoral response determined by ELISA, the higher was its adjuvant activity. In the challenge experiment with SuHV-1, 56% (14/25) (P \ 0.05) of the animals inoculated intramuscularly and 32% (8/25) inoculated subcutaneously survived, highlighting the influence of the concentration and the route of administration of rLTB on its performance as an adjuvant. Therefore, rLTB can significantly help in the induction of immunity against SuHV-1 in mice, especially if used intramuscularly in the concentration of 10 lg/dose, representing the best cost-benefit ratio.

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“…The use of these substances requires their prior detoxification, which is usually accomplished genetically, either by disrupting the enzymatic activity of the A subunit or by removing it altogether. Accumulating data obtained from diverse experimental tumor systems (including mouse mastocytoma and thymoma and human and mouse melanoma) underscore the CTL-inducing capacity of this family of toxins, applied either as mixtures with the antigens [131,132] or as genetic or chemical fusion products [132][133][134][135][136].…”

Section: Intracellular Delivery Of Immunogenic Proteins Fused With Bamentioning

confidence: 99%

Targeting Tumor-Associated Antigens to the MHC Class I Presentation Pathway

Gross

Margalit²

2007

EMIDDT

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There is little doubt that cytotoxic T lymphocytes (CTLs) can kill tumor cells in-vivo. However, most CTL-inducing immunization protocols examined so far in cancer patients have yielded only limited clinical benefits, underscoring the urge to improve current approaches for the effective induction of tumor-reactive CTLs. The tumor side of the immunological frontline is armed with large masses, high mutability and an arsenal of immune evasion and suppression mechanisms. Accordingly, the confronting CTLs should come in large numbers, recognize an assortment of MHC class I (MHC-I) bound tumor-associated peptides and be brought into action under effective immunostimulatory conditions. Naïve CTLs are activated to become effector cells in secondary lymphoid organs, following their productive encounter with MHC-I-bound peptides at the surface of dendritic cells (DCs). Therefore, many cancer vaccines under development focus on the optimization of peptide presentation by DCs at this critical stage. The elucidation of discrete steps and the subsequent identification of inherent bottlenecks in the MHC-I antigen presentation pathway have fueled elaborate efforts to enhance vaccine efficacy by the rational targeting of proteins or peptides, formulated into these vaccines, to this pathway. Protein- and gene-based strategies are accordingly devised to deliver tumor-associated peptides to selected cellular compartments, which are essential for the generation of functional CTL ligands. Many of these strategies target the conventional, endogenous route, while others harness the unique pathways that enable DCs to present exogenous antigens, known as cross-presentation. Here we dissect the intricate machinery that produces CTL ligands and examine how knowledge-based cancer vaccines can target the sequence of workstations, biochemical utensils and molecular intermediates comprising this production line.

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Heat labile enterotoxin of E. coli: a potential adjuvant for transcutaneous cancer immunotherapy

Cited by 21 publications

References 31 publications

A novel minigene scaffold for therapeutic cancer vaccines

A novel minigene scaffold for therapeutic cancer vaccines

Recombinant Escherichia coli heat-labile enterotoxin B subunit humoral adjuvant effect depends on dose and administration route

Targeting Tumor-Associated Antigens to the MHC Class I Presentation Pathway

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