title: Targeting the undruggable: immunotherapy meets personalized oncology in the genomic era.
abstract: Owing to recent advances in genomic technologies, personalized oncology is poised to fundamentally alter cancer therapy. In this paradigm, the mutational and transcriptional profiles of tumors are assessed, and personalized treatments are designed based on the specific molecular abnormalities relevant to each patient's cancer. To date, such approaches have yielded impressive clinical responses in some patients. However, a major limitation of this strategy has also been revealed: the vast majority of tumor mutations are not targetable by current pharmacological approaches. Immunotherapy offers a promising alternative to exploit tumor mutations as targets for clinical intervention. Mutated proteins can give rise to novel antigens (called neoantigens) that are recognized with high specificity by patient T cells. Indeed, neoantigen-specific T cells have been shown to underlie clinical responses to many standard treatments and immunotherapeutic interventions. Moreover, studies in mouse models targeting neoantigens, and early results from clinical trials, have established proof of concept for personalized immunotherapies targeting next-generation sequencing identified neoantigens. Here, we review basic immunological principles related to T-cell recognition of neoantigens, and we examine recent studies that use genomic data to design personalized immunotherapies. We discuss the opportunities and challenges that lie ahead on the road to improving patient outcomes by incorporating immunotherapy into the paradigm of personalized oncology.
authors.affiliation: Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria Interdisciplinary Oncology Program, University of British Columbia, Vancouver Michael Smith's Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, Canada.
authors.forename: S D
authors.initials: SD
authors.lastname: Martin
authors.affiliation: Ludwig Center for Cancer Research, University of Lausanne, Lausanne Hospital of the University of Lausanne (CHUV), Lausanne, Switzerland.
authors.forename: G
authors.initials: G
authors.lastname: Coukos
authors.affiliation: Michael Smith's Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, Canada Molecular Biology and Biochemistry, Simon Fraser University, Vancouver Department of Medical Genetics, University of British Columbia, Vancouver.
authors.forename: R A
authors.initials: RA
authors.lastname: Holt
authors.affiliation: Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria Department of Medical Genetics, University of British Columbia, Vancouver Department of Microbiology and Biochemistry, University of Victoria, Victoria, Canada bnelson@bccrc.ca.
authors.forename: B H
authors.initials: BH
authors.lastname: Nelson
mesh_terms: D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage; D023281:Genomics / Q000379:methods* / Q000639:trends; D006801:Humans; D007167:Immunotherapy / Q000379:methods* / Q000639:trends; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D057285:Precision Medicine / Q000379:methods* / Q000639:trends; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D019496:Cancer Vaccines
keywords: T cell; cancer; immunotherapy; neoantigen; next-generation sequencing; personalized oncology