Neoepitope

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Neoepitopes are a class of major histocompatibility complex (MHC) bounded peptides. [1] They represent the antigenic determinants of neoantigens. Neoepitopes are recognized by the immune system as targets for T cells and can elicit immune response to cancer. [2] [3]

Contents

Description

Epitopes, also referred to as antigenic determinants, are parts of an antigen that are recognized by the immune system. A neoepitope is an epitope the immune system has not encountered before. Therefore it is not subject to tolerance mechanisms of the immune system. [4] As the mutant gene product is only expressed in tumors and is not found in non-cancerous cells, neoepitopes may evoke a vigorous T cell response. [5] Tumor Mutational Burden (TMB, the number of mutations within a targeted genetic region in the cancerous cell's DNA) correlates with the number of neoepitopes, and have been suggested to correlate with patient survival post immunotherapy, although the findings about the neoantigen/immunogenicity association are disputed. [6] [7] [8] [9]

Neoepitopes arise from post-translational modifications. The mRNA translates information from the DNA into polypeptide composed of 20 standard amino acids and then proteins. Several of the standard amino acids can be posttranslationally modified by enzymatic processes, or can be altered through spontaneous (nonenzymatic) biochemical reactions. [10]

There is increasing evidence that immune recognition of neoepitopes produced by cancer-specific mutations is a key mechanism for the induction of immune-mediated tumor rejection. Opportunities for therapeutic targeting of cancer specific neoepitopes are under investigation. [11]

As target for immunotherapy

Cancer is a patient-specific disease, and no two tumors are alike. Thus, the immunogenicity of each tumor is unique. [12] A novel strategy against cancer is epitope selection for mutanome-directed individualized cancer immunotherapy. [4]

Individualized cancer immunotherapy leverages the adaptive immune system by targeting T cells to tumor cells that have a tumor specific mutant antigen (neoantigen) with neoepitopes recognized by a receptor on T cells. [13] One challenge is to identify the neoepitopes that trigger a suitable immune response, that is, to find out which neoepitopes in the individual tumor are highly immunogenic. [14]

Cancer vaccines

Individualized cancer immunotherapy includes vaccination with tumor mutation-derived neoepitopes. The concept is based on a mapping of the tumor-specific individual mutanome with identification of a range of suitable neoepitopes for a patient-specific vaccine. [15] It is expected that the neoepitopes in the vaccine will trigger T cell responses to the specific cancer. For the concept of individualized cancer vaccination first data are available. [16] [17] [18] [19]

Related Research Articles

<span class="mw-page-title-main">Antigen</span> Molecule triggering an immune response (antibody production) in the host

In immunology, an antigen (Ag) is a molecule, moiety, foreign particulate matter, or an allergen, such as pollen, that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response.

Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress are classified as suppression immunotherapies. Immunotherapy is under preliminary research for its potential to treat various forms of cancer.

An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The part of an antibody that binds to the epitope is called a paratope. Although epitopes are usually non-self proteins, sequences derived from the host that can be recognized are also epitopes.

A cancer vaccine, or oncovaccine, is a vaccine that either treats existing cancer or prevents development of cancer. Vaccines that treat existing cancer are known as therapeutic cancer vaccines or tumor antigen vaccines. Some of the vaccines are "autologous", being prepared from samples taken from the patient, and are specific to that patient.

<span class="mw-page-title-main">Cancer immunotherapy</span> Artificial stimulation of the immune system to treat cancer

Cancer immunotherapy (immuno-oncotherapy) is the stimulation of the immune system to treat cancer, improving the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer immunology and a growing subspecialty of oncology.

<span class="mw-page-title-main">Monoclonal antibody therapy</span> Form of immunotherapy

Monoclonal antibodies (mAbs) have varied therapeutic uses. It is possible to create a mAb that binds specifically to almost any extracellular target, such as cell surface proteins and cytokines. They can be used to render their target ineffective, to induce a specific cell signal, to cause the immune system to attack specific cells, or to bring a drug to a specific cell type.

<span class="mw-page-title-main">Ipilimumab</span> Pharmaceutical drug

Ipilimumab, sold under the brand name Yervoy, is a monoclonal antibody medication that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system.

Antigenic escape, immune escape, immune evasion or escape mutation occurs when the immune system of a host, especially of a human being, is unable to respond to an infectious agent: the host's immune system is no longer able to recognize and eliminate a pathogen, such as a virus. This process can occur in a number of different ways of both a genetic and an environmental nature. Such mechanisms include homologous recombination, and manipulation and resistance of the host's immune responses.

<span class="mw-page-title-main">Cancer immunology</span> Study of the role of the immune system in cancer

Cancer immunology (immuno-oncology) is an interdisciplinary branch of biology and a sub-discipline of immunology that is concerned with understanding the role of the immune system in the progression and development of cancer; the most well known application is cancer immunotherapy, which utilises the immune system as a treatment for cancer. Cancer immunosurveillance and immunoediting are based on protection against development of tumors in animal systems and (ii) identification of targets for immune recognition of human cancer.

<span class="mw-page-title-main">CTAG1B</span> Protein-coding gene in humans

Cancer/testis antigen 1 also known as LAGE2 or LAGE2B is a protein that in humans is encoded by the CTAG1B gene. It is most often referenced by its alias NY-ESO-1.

Peptide-based synthetic vaccines are subunit vaccines made from peptides. The peptides mimic the epitopes of the antigen that triggers direct or potent immune responses. Peptide vaccines can not only induce protection against infectious pathogens and non-infectious diseases but also be utilized as therapeutic cancer vaccines, where peptides from tumor-associated antigens are used to induce an effective anti-tumor T-cell response.

Gustav Gaudernack is a scientist working in the development of cancer vaccines and cancer immunotherapy. He has developed various strategies in immunological treatment of cancer. He is involved in several ongoing cellular and immuno-gene therapeutic clinical trials and his research group has put major efforts into the development of various T cell-based immunotherapeutic strategies.

Immunodominance is the immunological phenomenon in which immune responses are mounted against only a few of the antigenic peptides out of the many produced. That is, despite multiple allelic variations of MHC molecules and multiple peptides presented on antigen presenting cells, the immune response is skewed to only specific combinations of the two. Immunodominance is evident for both antibody-mediated immunity and cell-mediated immunity. Epitopes that are not targeted or targeted to a lower degree during an immune response are known as subdominant epitopes. The impact of immunodominance is immunodomination, where immunodominant epitopes will curtail immune responses against non-dominant epitopes. Antigen-presenting cells such as dendritic cells, can have up to six different types of MHC molecules for antigen presentation. There is a potential for generation of hundreds to thousands of different peptides from the proteins of pathogens. Yet, the effector cell population that is reactive against the pathogen is dominated by cells that recognize only a certain class of MHC bound to only certain pathogen-derived peptides presented by that MHC class. Antigens from a particular pathogen can be of variable immunogenicity, with the antigen that stimulates the strongest response being the immunodominant one. The different levels of immunogenicity amongst antigens forms what is known as dominance hierarchy.

Cancer/testis (CT) antigens are a group of proteins united by their importance in development and in cancer immunotherapy. In general, expression of these proteins is restricted to male germ cells in the adult animal. However, in cancer these developmental antigens are often re-expressed and can serve as a locus of immune activation. Thus, they are often classified as tumor antigens. The expression of CT antigens in various malignancies is heterogeneous and often correlates with tumor progression. CT antigens have been described in melanoma, liver cancer, lung cancer, bladder cancer, and pediatric tumors such as neuroblastoma. Gametogenesis offers an important role for many of these antigens in the differentiation, migration, and cell division of primordial germ cells, spermatogonia spermatocytes and spermatids. Because of their tumor-restricted expression and strong in vivo immunogenicity, CT antigens are identified as ideal targets for tumor specific immunotherapeutic approaches and prompted the development of several clinical trials of CT antigens-based vaccine therapy. CT antigens have been found to have at least 70 families so far, including about 140 members, most of which are expressed during spermatogenesis. Their expression are mainly regulated by epigenetic events, specifically, DNA methylation.

Individualized medicine tailors treatment to a single patient. The term refers to an individual, truly personalized medicine that strives to treat each patient on the basis of his own individual biology.

The mutanome is the entirety of somatic cancer mutations in an individual tumor.

Individualized cancer immunotherapy, also referred to as individualized immuno-oncology, is a novel concept for therapeutic cancer vaccines that are truly personalized to a single individual.

<span class="mw-page-title-main">Uğur Şahin</span> German oncologist and immunologist (born 1965)

Uğur Şahin is a German oncologist and immunologist. He is the founder and CEO of BioNTech, which developed one of the major vaccines against COVID-19. His main fields of research are cancer research and immunology.

<span class="mw-page-title-main">Özlem Türeci</span> German physician, scientist and entrepreneur

Özlem Türeci is a German physician, scientist and entrepreneur. In 2008, she co-founded the biotechnology company BioNTech, which in 2020 developed the first messenger RNA-based vaccine approved for use against COVID-19. Türeci has served as BioNTech's chief medical officer since 2018. Since 2021, she has been Professor of Personalized Immunotherapy at the Helmholtz Institute for Translational Oncology (HI-TRON) and Johannes Gutenberg University Mainz. Türeci and her spouse, Uğur Şahin, have won a number of awards.

Whole-cell vaccines are a type of vaccine that has been prepared in the laboratory from entire cells. Such vaccines simultaneously contain multiple antigens to activate the immune system. They induce antigen-specific T-cell responses.

References

  1. ↑ Leclerc M, Mezquita L, Guillebot De Nerville G, Tihy I, Malenica I, Chouaib S, Mami-Chouaib F (2019). "Recent Advances in Lung Cancer Immunotherapy: Input of T-Cell Epitopes Associated With Impaired Peptide Processing". Frontiers in Immunology. 10: 1505. doi: 10.3389/fimmu.2019.01505 . PMC   6616108 . PMID   31333652.
  2. ↑ Vormehr M, Diken M, Boegel S, Kreiter S, Türeci Ö, Sahin U (April 2016). "Mutanome directed cancer immunotherapy". Current Opinion in Immunology. 39: 14–22. doi:10.1016/j.coi.2015.12.001. PMID   26716729.
  3. ↑ Katsnelson A (February 2016). "Mutations as munitions: Neoantigen vaccines get a closer look as cancer treatment". Nature Medicine. 22 (2): 122–4. doi:10.1038/nm0216-122. PMID   26845402. S2CID   26454626.
  4. 1 2 Vormehr M, Türeci Ö, Sahin U (January 2019). "Harnessing Tumor Mutations for Truly Individualized Cancer Vaccines". Annual Review of Medicine. 70: 395–407. doi:10.1146/annurev-med-042617-101816. PMID   30691374. S2CID   59341051.
  5. ↑ Heemskerk B, Kvistborg P, Schumacher TN (January 2013). "The cancer antigenome". The EMBO Journal. 32 (2): 194–203. doi:10.1038/emboj.2012.333. PMC   3553384 . PMID   23258224.
  6. ↑ Gurjao C, Tsukrov D, Imakaev M, Luquette LJ, Mirny LA (2020-09-04). "Limited evidence of tumour mutational burden as a biomarker of response to immunotherapy". bioRxiv: 2020.09.03.260265. doi:10.1101/2020.09.03.260265. S2CID   221565320.
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  9. ↑ Wood MA, Weeder BR, David JK, Nellore A, Thompson RF (March 2020). "Burden of tumor mutations, neoepitopes, and other variants are weak predictors of cancer immunotherapy response and overall survival". Genome Medicine. 12 (1): 33. doi: 10.1186/s13073-020-00729-2 . PMC   7106909 . PMID   32228719.
  10. ↑ James EA, Pietropaolo M, Mamula MJ (June 2018). "Immune Recognition of β-Cells: Neoepitopes as Key Players in the Loss of Tolerance". Diabetes. 67 (6): 1035–1042. doi: 10.2337/dbi17-0030 . PMC   5961411 . PMID   29784651.
  11. ↑ Wilson EA, Anderson KS (December 2018). "Lost in the crowd: identifying targetable MHC class I neoepitopes for cancer immunotherapy". Expert Review of Proteomics. 15 (12): 1065–1077. doi:10.1080/14789450.2018.1545578. PMID   30408427. S2CID   53242832.
  12. ↑ Brennick CA, George MM, Corwin WL, Srivastava PK, Ebrahimi-Nik H (March 2017). "Neoepitopes as cancer immunotherapy targets: key challenges and opportunities". Immunotherapy. 9 (4): 361–371. doi: 10.2217/imt-2016-0146 . PMID   28303769.
  13. ↑ Feng YY, Griffith OL, Griffith M (August 2017). "Clinical implications of neoepitope landscapes for adult and pediatric cancers". Genome Medicine. 9 (1): 77. doi: 10.1186/s13073-017-0470-9 . PMC   5577778 . PMID   28854952.
  14. ↑ Saini SK, Rekers N, Hadrup SR (December 2017). "Novel tools to assist neoepitope targeting in personalized cancer immunotherapy". Annals of Oncology. 28 (suppl_12): xii3–xii10. doi: 10.1093/annonc/mdx544 . PMID   29092006.
  15. ↑ Türeci Ö, Vormehr M, Diken M, Kreiter S, Huber C, Sahin U (April 2016). "Targeting the Heterogeneity of Cancer with Individualized Neoepitope Vaccines". Clinical Cancer Research. 22 (8): 1885–96. doi: 10.1158/1078-0432.CCR-15-1509 . PMID   27084742.
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  18. ↑ Hilf N, Kuttruff-Coqui S, Frenzel K, Bukur V, Stevanović S, Gouttefangeas C, et al. (January 2019). "Actively personalized vaccination trial for newly diagnosed glioblastoma". Nature. 565 (7738): 240–245. Bibcode:2019Natur.565..240H. doi:10.1038/s41586-018-0810-y. PMID   30568303. S2CID   56480674.
  19. ↑ Keskin DB, Anandappa AJ, Sun J, Tirosh I, Mathewson ND, Li S, et al. (January 2019). "Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial". Nature. 565 (7738): 234–239. doi:10.1038/s41586-018-0792-9. PMC   6546179 . PMID   30568305.
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