Rational Peptide-Based Vaccine Design for Cancer Immunotherapeutic Applications

Lazoura, Eliada; Apostolopoulos, Vasso

doi:10.2174/0929867053202188

Cited by 46 publications

(42 citation statements)

References 83 publications

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“…23 This may be important for CTL epitopes that have low binding affinity for class I MHC, which frequently is the case for tumor peptides. 29 Tumors may escape from immunosurveillance through the mutation of a single, immunodominant T-cell epitope or through the down-regulation of a specific human leukocyte antigen (HLA) allele. 30,31 By including multiple immunogenic epitopes, long-peptide vaccines may interact with many more HLA class I and class II alleles than short peptides.…”

Section: Therapeutic Vaccines Combined With Chemotherapymentioning

confidence: 99%

A new era in anticancer peptide vaccines

Perez

Hofe

Kallinteris

et al. 2010

Cancer

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The use of synthetic peptides as vaccines aimed at the induction of therapeutic CD8-positive T-cell responses against tumor cells initially experienced great enthusiasm, mostly because of advances in vaccine technology, including design, synthesis, and delivery. However, despite impressive results in animal models, the application of such vaccines in humans has met with only limited success. The therapeutic activity of vaccine-stimulated, tumor-specific, CD8-positive T cells can be hampered through the physical burden of the tumor, tolerance mechanisms, and local factors within the tumor microenvironment. Recently, accumulating evidence has suggested that combining a peptide-based therapeutic vaccination with conventional chemotherapy can uncover the full potential of the antitumor immune response, increasing the success of immunotherapy. In addition, therapeutic vaccination in the preventive setting has been extremely effective in eliciting antitumor responses in preclinical tumor models and has demonstrated good promise clinically in patients with minimal residual disease. The rationale behind preventive vaccination is that patients with minimal tumor burden still have a fully competent immune system capable of developing robust antitumor responses. Finally, therapeutic CD8-positive T-cell peptide vaccines have been improved by coimmunization with T-helper epitopes expressed on long peptides.

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Section: Therapeutic Vaccines Combined With Chemotherapymentioning

confidence: 99%

A new era in anticancer peptide vaccines

Perez

Hofe

Kallinteris

et al. 2010

Cancer

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“…In several cases, the dominant peptide epitopes from a given antigen have turned out to be weak binders (reviewed in ref. 20). Monoclonal antibodies, raised against peptide-MHC combinations, have also been used to study peptide presentation, mainly by flow cytometry.…”

Section: Discussionmentioning

confidence: 99%

The HLA A*0201–restricted hTERT540–548 peptide is not detected on tumor cells by a CTL clone or a high-affinity T-cell receptor

Purbhoo¹,

Li²,

Sutton³

et al. 2007

Molecular Cancer Therapeutics

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Tumor-associated human telomerase reverse transcriptase (hTERT) is expressed in >85% of human tumors but not in most normal cells. As a result, this antigen has received considerable attention from those interested in cancer immunotherapy. Specifically, there has been strong interest in MHC class I -associated peptides derived from hTERT because these are expressed on the cell surface and thus may enable the targeting of tumor cells. Much of this interest has focused on peptide 540 -548, ILAKFLHWL, which was predicted to exhibit the strongest binding to the common HLA A*0201 presenting molecule. The hTERT 540 -548 peptide is currently being assessed in therapeutic vaccination trials; however, there is controversy surrounding whether it is naturally processed and presented on the surface of neoplastic cells. Here, we generate two highly sensitive reagents to assess the presentation of hTERT 540 -548 on tumor cells: (a) a CD8 + CTL clone, and (b) a recombinant T-cell receptor (TCR) that binds with picomolar affinity and a half-life exceeding 14 h. This TCR enables the identification of individual HLA A2-hTERT 540 -548 complexes on the cell surface. The use of both this TCR and the highly antigen-sensitive CTL clone shows that the hTERT 540 -548 peptide cannot be detected on the surface of tumor cells, indicating that this peptide is not a naturally presented epitope. We propose that, in future, rigorous methods must be applied for the validation of peptide epitopes used for clinical applications. [Mol Cancer Ther 2007;6(7):2081 -91]

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“…For infectious diseases, this may be achieved by peptide vaccination (27). However, this approach is less appealing for cancer therapy due to the poor immunogenicity of many peptides derived from tumor-associated antigens, necessitating their delivery with adjuvant and/or the manipulation of ''anchor'' residues to improve MHC class I binding or T-cell recognition (29,30). Vaccination with native tumor-associated antigen-derived peptide has generally yielded disappointing results and, in our experience, does not compare favorably with the p.DOM-peptide DNA vaccine design (data not shown).…”

Section: Discussionmentioning

confidence: 99%

DNA Fusion Vaccines Induce Epitope-Specific Cytotoxic CD8+ T Cells against Human Leukemia-Associated Minor Histocompatibility Antigens

Rice¹,

Dunn²,

Piper

et al. 2006

Cancer Research

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The graft-versus-leukemia effect of allogeneic stem-cell transplantation is believed to be mediated by T-cell recognition of minor histocompatibility antigens on recipient cells. For minor histocompatibility antigens HA-1 and HA-2, normal cell expression is restricted to hemopoietic cells, and boosting the immune response to these antigens may potentiate graft-versus-leukemia effect without accompanying graftversus-host disease. To increase efficacy, expansion of HA-1-or HA-2-specific CTL before transplantation is desirable. However, primary HA-1-or HA-2-specific CTL expanded in vitro are often of low avidity. An alternative approach is to prime specific CTL responses in vivo by vaccination. Clearly, donor vaccination must be safe and specific. We have developed DNA fusion vaccines able to induce high levels of epitope-specific CTL using linked CD4 + T-cell help. The vaccines incorporate a domain of tetanus toxin (DOM) fused to a sequence encoding a candidate MHC class I binding peptide. This design generates antitumor CD8 + T-cell responses and protective immunity in preclinical models. For clinical application, we constructed vaccines encoding HLA-A*0201-restricted peptides from human HA-1 and HA-2, which were fused to DOM, and tested their performance in HLA-A*0201-transgenic mice. Priming induced epitope-specific, IFN;-producing CD8 + T cells with cytotoxic function boosted to high levels with electroporation. Strikingly, these mouse T cells efficiently killed human lymphoblastoid cell lines expressing endogenous HA-1 or HA-2. High avidity is indicated by the independence of cytolysis from CD8/MHC class I interaction. These safe epitope-specific vaccines offer a potential strategy to prime HA-1-or HA-2-specific CTL in transplant donors before adoptive transfer.

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Rational Peptide-Based Vaccine Design for Cancer Immunotherapeutic Applications

Cited by 46 publications

References 83 publications

A new era in anticancer peptide vaccines

A new era in anticancer peptide vaccines

The HLA A*0201–restricted hTERT540–548 peptide is not detected on tumor cells by a CTL clone or a high-affinity T-cell receptor

DNA Fusion Vaccines Induce Epitope-Specific Cytotoxic CD8+ T Cells against Human Leukemia-Associated Minor Histocompatibility Antigens

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