Mining the mutanome: developing highly personalized Immunotherapies based on mutational analysis of tumors

Journal for ImmunoTherapy of Cancer

Nicholas P Restifo²  Hans-Georg Rammensee³  Francesco M Marincola⁴  Ena Wang⁵  Willem W Overwijk¹ 

[1] Department of Melanoma Medical Oncology, The University of Texas M.D, Anderson Cancer Center, Houston, TX, USA;NIH Center for Regenerative Medicine, National Institutes of Health, Bethesda, MD, USA;Department of Immunology, Institute for Cell Biology, University of Tübingen, Tübingen, Germany;Sidra Medical and Research Centre, Doha, Qatar;Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA

关键词: Omics;    Next-generation sequencing;    Vaccine;    Exome;    Checkpoint blockade;    T lymphocyte;    Peptide epitope;    Neoantigen;    Mutation;    Mutanome;   

Others  :  815019
DOI  :  10.1186/2051-1426-1-11

 received in 2013-07-22, accepted in 2013-07-22,  发布年份 2013

【 摘 要 】

T cells can mediate remarkable tumor regressions including complete cure in patients with metastatic cancer. Genetic alterations in an individual’s cancer cells (the mutanome) encode unique peptides (m-peptides) that can be targets for T cells. The recent advances in next-generation sequencing and computation prediction allows, for the first time, the rapid and affordable identification of m-peptides in individual patients. Despite excitement about the extended spectrum of potential targets in personalized immunotherapy, there is no experience or consensus on the path to their successful clinical application. Major questions remain, such as whether clinical responses to cytokine therapy, T cell transfer, and checkpoint blockade are primarily mediated by m-peptide-specific reactivity, whether m-peptides can be effectively used as vaccines, and which m-peptides are most potently recognized. These and other technological, immunological and translational questions will be explored during a 1-day Workshop on Personalized Cancer Immunotherapy by the Society for Immunotherapy of Cancer, directly before the Annual Meeting, on November 7, 2013 at the National Harbor, MD near Washington, DC.

【 授权许可】

   
2013 Overwijk et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Khalili JS, Hanson RW, Szallasi Z: In silico prediction of tumor antigens derived from functional missense mutations of the cancer gene census. Oncoimmunology. 2012, 1:1281-1289.
• [2]Restifo NP, Dudley ME, Rosenberg SA: Adoptive immunotherapy for cancer: harnessing the T cell response. Nat Rev Immunol 2012, 12:269-281.
• [3]Wolfel T, et al.: A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. Science 1995, 269:1281-1284.
• [4]Coulie PG, et al.: A mutated intron sequence codes for an antigenic peptide recognized by cytolytic T lymphocytes on a human melanoma. Proc Natl Acad Sci USA 1995, 92:7976-7980.
• [5]Echchakir H, et al.: A point mutation in the alpha-actinin-4 gene generates an antigenic peptide recognized by autologous cytolytic T lymphocytes on a human lung carcinoma. Cancer Res 2001, 61:4078-4083.
• [6]Lennerz V, et al.: The response of autologous T cells to a human melanoma is dominated by mutated neoantigens. Proc Natl Acad Sci USA 2005, 102:16013-16018.
• [7]Segal NH, et al.: Epitope landscape in breast and colorectal cancer. Cancer Res 2008, 68:889-892.
• [8]Pieper R, et al.: Biochemical Identification of a Mutated Human Melanoma Antigen Recognized by CD4(+) T Cells. J Exp Med 1999, 189:757-766.
• [9]Heemskerk B, Kvistborg P, Schumacher TN: The cancer antigenome. EMBO J 2013, 32:194-203.
• [10]Wolchok JD, et al.: Nivolumab plus Ipilimumab in Advanced Melanoma. N Engl J Med 2013.
• [11]Robbins PF, et al.: Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells. Nat Med 2013, 19:747-752.
• [12]Walter S, et al.: Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival. Nat Med 2012, 18:1254-1261.
• [13]Hailemichael Y, et al.: Persistent antigen at vaccination sites induces tumor-specific CD8(+) T cell sequestration, dysfunction and deletion. Nat Med 2013, 19:465-472.
• [14]Matsushita H, et al.: Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature 2012, 482:400-404.
• [15]Topalian SL, et al.: Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012, 366:2443-2454.
• [16]Hamid O, et al.: Safety and Tumor Responses with Lambrolizumab (Anti-PD-1) in Melanoma. N Engl J Med 2013.
• [17]Castle JC, et al.: Exploiting the mutanome for tumor vaccination. Cancer Res 2012, 72:1081-1091.
• [18]Bassani-Sternberg M, et al.: Soluble plasma HLA peptidome as a potential source for cancer biomarkers. Proc Natl Acad Sci USA 2010, 107:18769-18776.