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Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Targeting the undruggable: immunotherapy meets personalized oncology in the genomic era
S D Martin1, G Coukos2, R A Holt3
1Trev 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.
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.
Insights
Personalized oncology uses genomic data for cancer therapy. Immunotherapy targeting tumor neoantigens offers a promising approach for patients when traditional treatments fail.
Area of Science:
- Oncology
- Immunology
- Genomics
- Bioinformatics
Background:
- Genomic technologies are revolutionizing personalized oncology, tailoring treatments to individual tumor molecular profiles.
- Current personalized therapies face limitations, as most tumor mutations are not druggable by conventional pharmacological agents.
- Immunotherapy presents a viable alternative by leveraging tumor-specific mutations as therapeutic targets.
Purpose of the Study:
- To review the immunological principles of T-cell recognition of neoantigens.
- To examine recent studies utilizing genomic data for personalized immunotherapy design.
- To discuss the future prospects and challenges of integrating neoantigen-targeted immunotherapies into personalized cancer care.
Main Methods:
- Review of scientific literature on neoantigen recognition and personalized immunotherapy.
- Analysis of studies employing next-generation sequencing (NGS) for neoantigen identification.
- Examination of preclinical models and early-phase clinical trial data.
Main Results:
- Mutated proteins can generate neoantigens, specifically recognized by patient T cells.
- Neoantigen-specific T cells are implicated in clinical responses to various cancer treatments.
- Proof of concept for personalized immunotherapies targeting neoantigens has been established in mouse models and human trials.
Conclusions:
- Personalized immunotherapies targeting neoantigens hold significant promise for improving cancer patient outcomes.
- Integrating genomic insights with immunotherapy represents a key advancement in personalized oncology.
- Further research is needed to overcome challenges and optimize the clinical application of these novel therapies.
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