Identification and Targeting of Mutant Peptide Neoantigens in Cancer Immunotherapy

SIMPLE SUMMARY: Cancerous cells acquire genetic mutations that can lead to changes in the amino acid sequence of proteins. These altered amino acid sequences, or “neoantigens” allow the immune system to recognize the mutated cells as “non-self” and eliminate them. This review outlines discoveries that identified neoantigens as a key immune target. Further, we discuss the development of bioinformatic and DNA sequencing technologies used to detect patient-specific mutations giving rise to neoantigens, and the methods by which neoantigens can be targeted in cancer therapy. ABSTRACT: In recent decades, adoptive cell transfer and checkpoint blockade therapies have revolutionized immunotherapeutic approaches to cancer treatment. Advances in whole exome/genome sequencing and bioinformatic detection of tumour-specific genetic variations and the amino acid sequence alterations they induce have revealed that T cell mediated anti-tumour immunity is substantially directed at mutated peptide sequences, and the identification and therapeutic targeting of patient-specific mutated peptide antigens now represents an exciting and rapidly progressing frontier of personalized medicine in the treatment of cancer. This review outlines the historical identification and validation of mutated peptide neoantigens as a target of the immune system, and the technical development of bioinformatic and experimental strategies for detecting, confirming and prioritizing both patient-specific or “private” and frequently occurring, shared “public” neoantigenic targets. Further, we examine the range of therapeutic modalities that have demonstrated preclinical and clinical anti-tumour efficacy through specifically targeting neoantigens, including adoptive T cell transfer, checkpoint blockade and neoantigen vaccination.