HLA ligandome tumor antigen discovery for personalized vaccine approach

Rammensee, Hans‐Georg; Singh‐Jasuja, Harpreet

doi:10.1586/14760584.2013.836911

Cited by 87 publications

(58 citation statements)

References 48 publications

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“…Beyond the issue of prediction accuracy, we have also not yet measured the frequency of CTLs that target neoORFs-a class of neoantigens that we expect to be more specific (for lack of a wild-type counterpart) and immunogenic (as a result of bypassing thymic tolerance). Future improvements in predictive algorithms, and eventually, development of direct physical methods for detecting HLA-binding peptides using mass spectrometry, [57][58][59] will make it possible to more effectively select neoantigens presented by tumor HLA proteins. Considering the limitations described here, we conclude that there will be many more neoantigens per tumor.…”

Section: Discussionmentioning

confidence: 99%

Systematic identification of personal tumor-specific neoantigens in chronic lymphocytic leukemia

Rajasagi

Shukla

Fritsch

et al. 2014

Blood

281

235

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• Tumor neoantigens are a promising class of immunogens based on exquisite tumor specificity and the lack of central tolerance against them.• Massively parallel DNA sequencing with class I prediction enables systematic identification of tumor neoepitopes (including from CLL).Genome sequencing has revealed a large number of shared and personal somatic mutations across human cancers. In principle, any genetic alteration affecting a protein-coding region has the potential to generate mutated peptides that are presented by surface HLA class I proteins that might be recognized by cytotoxic T cells. To test this possibility, we implemented a streamlined approach for the prediction and validation of such neoantigens derived from individual tumors and presented by patient-specific HLA alleles. We applied our computational pipeline to 91 chronic lymphocytic leukemias (CLLs) that underwent whole-exome sequencing (WES). We predicted ∼22 mutated HLA-binding peptides per leukemia (derived from ∼16 missense mutations) and experimentally confirmed HLA binding for ∼55% of such peptides. Two CLL patients that achieved long-term remission following allogeneic hematopoietic stem cell transplantation were monitored for CD8 1 T-cell responses against predicted or confirmed HLA-binding peptides. Long-lived cytotoxic T-cell responses were detected against peptides generated from personal tumor mutations in ALMS1, C6ORF89, and FNDC3B presented on tumor cells. Finally, we applied our computational pipeline to WES data (N 5 2488 samples) across 13 different cancer types and estimated dozens to thousands of predicted neoantigens per individual tumor, suggesting that neoantigens are frequent in most tumors. (Blood. 2014;124(3):453-462) IntroductionRecent progress in the development of potent vaccine adjuvants, clinically effective vaccine delivery systems, and agents that overcome tumor-induced immunosuppression strongly support the possibility that long-awaited effective therapeutic cancer vaccines are feasible. [1][2][3][4] Past cancer vaccine efforts have lacked efficacy that may stem from their focus on overexpressed or selectively expressed tumor-associated native antigens as vaccine targets that require overcoming the challenging hurdles of breaking central and peripheral tolerance while risking the generation of autoimmunity. [4][5][6] The rare examples of successful cancer vaccines in humans have targeted foreign pathogen-associated antigens 7 or a mutated growth factor receptor 8 or are idiotype vaccines derived from patient-specific rearranged immunoglobulins. 9 These studies point to the importance of selecting immunogens distinct from self, where central/peripheral tolerance can be overcome and the risk of autoimmunity is minimal.A hallmark of tumorigenesis is the accumulation of mutations in cancer cells. These mutations are found as both driver and passenger events 10 and collectively provide an opportunity to specifically target tumor cells through the creation of tumor-specific novel immunogenic peptides (neoantigens). ...

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Section: Discussionmentioning

confidence: 99%

Systematic identification of personal tumor-specific neoantigens in chronic lymphocytic leukemia

Rajasagi

Shukla

Fritsch

et al. 2014

Blood

281

235

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“…Paul Ehrlich postulated that cancer cells are eliminated by the immune system [236]. Nowadays, it is well known that cancer patients can harbour CD8+ and CD4+ T cells specific for cancer or for differentiation antigens expressed in their tumors.…”

Section: Vaccination In Allergy and Cancermentioning

confidence: 99%

“…Three major types of cancer antigens that can be applied for vaccination can be distinguished: (1) neoantigens including mutations and viral antigens, (2) self proteins that are overexpressed by the tumor cells but are expressed at very low levels by other cells of adult tissue, and (3) tissue-specific ("differentiation") antigens. These three types of antigens can be used for vaccination in all forms above described, i.e., as proteins, virus constructs, DNA, RNA, long peptides, or peptides representing exactly the natural HLA ligands on tumor cells [236,238]. The literature on cancer vaccination including different tumor entities, techniques, and adjuvants as well as efficacy and immunological responses is expanding rapidly; it is beyond the scope of this paper to go into more details, but there are a number of excellent recent reviews dealing with this topic [54,126,236,237,[239][240][241][242][243][244].…”

Section: Vaccination In Allergy and Cancermentioning

confidence: 99%

Applications of immunochemistry in human health: advances in vaccinology and antibody design (IUPAC Technical Report)

Klein

Templeton

Schwenk

2014

Pure and Applied Chemistry

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This report discusses the history and mechanisms of vaccination of humans as well as the engineering of therapeutic antibodies. Deeper understanding of the molecular interactions involved in both acquired and innate immunity is allowing sophistication in design of modified and even synthetic vaccines. Recombinant DNA technologies are facilitating development of DNA-based vaccines, for example, with the recognition that unmethylated CpG sequences in plasmid DNA will target Toll-like receptors on antigen-presenting cells. Formulations of DNA vaccines with increased immunogenicity include engineering into plasmids with "genetic adjuvant" capability, incorporation into polymeric or magnetic nanoparticles, and formulation with cationic polymers and other polymeric and non-polymeric coatings. Newer methods of delivery, such as particle bombardment, DNA tattooing, electroporation, and magnetic delivery, are also improving the effectiveness of DNA vaccines. RNA-based vaccines and reverse vaccinology based on gene sequencing and bioinformatic approaches are also considered. Structural vaccinology is an approach in which the detailed molecular structure of viral epitopes is used to design synthetic antigenic peptides. Virus-like particles are being designed for vaccine deliveries that are based on structures of viral capsid proteins and other synthetic lipopeptide building blocks. A new generation of adjuvants is being developed to further enhance immunogenicity, based on squalene and other oil-water emulsions, saponins, muramyl dipeptide, immunostimulatory oligonucleotides, Toll-like receptor ligands, and lymphotoxins. Finally, current trends in engineering of therapeutic antibodies including improvements of antigen-binding properties, pharmacokinetic and pharmaceutical properties, and reduction of immunogenicity are discussed. Taken together, understanding the chemistry of vaccine design, delivery and immunostimulation, and knowledge of the techniques of antibody design are allowing targeted development for the treatment of chronic disorders characterized by continuing activation of the immune system, such as autoimmune disorders, cancer, or allergies that have long been refractory to conventional approaches.

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“…This aspect is of strategic relevance in order to dramatically improve the final clinical outcome in cancer patients. • Rammensee and Singh-Jasuja describe the most recent updates on the exploitation of the human leukocyte antigen (HLA) ligandome for identifying tumor antigens to develop personalized cancer vaccines [9]. This approach holds great promises with regards to selection of the optimal and effective target antigens to be used in the vaccine development.…”

Section: Gennaro Cilibertomentioning

confidence: 99%