Identification and Targeting of Mutant Peptide Neoantigens in Cancer Immunotherapy

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.

Comprehensive Landscape of RRM2 with Immune Infiltration in Pan-Cancer

“…MSI manifested DNA-mismatch repair-deficiency and it is a marker for a good response to immunotherapy [ 47 ]. NEO is mainly a tumor-specific antigen generated by mutations and is only expressed in tumor cells, which is considered a breakthrough in immunotherapy [ 48 ]. CTL expresses the CD8 coreceptor and is the preferred immune cell for killing cancer cells, so the density of CTL infiltrated is also a predictor for evaluating immunotherapy outcomes [ 49 ].…”

Therapeutic Potential of Intrabodies for Cancer Immunotherapy: Current Status and Future Directions

“…Neoantigen identification is routinely performed by several sequential steps: Neoantigens are identified by whole-exon sequencing with high efficiency, wide coverage and low false negative rate [ 77 , 78 ]. Alignment of exome DNA and RNA sequencing (RNA-seq data of tumor cells and normal cells, somatic and germline variant detection and RNA-seq expression estimation leads to expressed neoantigen transcripts [ 20 ]. The identified characterized neoantigens can be directly used for the selection of appropriate intrabodies using phage display antibody repertoires ( Figure 1 ).…”

“…To select an appropriate neoepitope for adoptive T-cell therapy and cancer vaccines, several additional evaluation steps using bioinformatics and immunological screening assays are necessary [ 3 , 20 , 21 , 22 ].…”

Identification of cryptic neoepitopes generated by chimeric transcripts in ovarian cancer

“…Current interests in cancer vaccines rely on discovery of effective tumor-speci c neoepitopes [8][9][10][11] , since they elicit T-cell responses that are not subject to host central tolerance, and also lower extent of autoimmune toxicities [12][13] . Conventionally, tumor-speci c non-synonymous mutations 'reorganize' the ORFs of protein-coding genes and perturbcanonical protein sequences to generate neoepitopes that may be recognized and bound by speci c T-cell receptors [14][15][16] .…”