Immunopharmacogenomics towards personalized cancer immunotherapy targeting neoantigens

Abstract

Utilizing the host immune system to eradicate cancer cells has been the most investigated subject in the cancer research field in recent years. However, most of the studies have focused on highly variable responses from immunotherapies such as immune checkpoint inhibitors, from which the majority of patients experienced no or minimum clinical benefit. Advances in genomic sequencing technologies have improved our understanding of immunopharmacogenomics and allowed us to identify novel cancer-specific immune targets. Highly tumor-specific antigens, neoantigens, are generated by somatic mutations that are not present in normal cells. It is plausible that by targeting antigens with high tumor-specificity, such as neoantigens, the likelihood of toxic effects is very limited. However, understanding the interaction between neoantigens and the host immune system remains a significant challenge. This review focuses on the potential use of neoantigen-targeted immunotherapies in cancer treatment and the recent progress of different strategies in predicting, identifying, and validating neoantigens. Successful identification of highly tumor-specific antigens accelerates the development of personalized immunotherapy with no or minimum adverse effects and with a broader coverage of patients.

Keywords: T-cell receptor repertoire; cancer precision medicine; immune checkpoint inhibitor; neoantigen; next-generation sequencing.

Figure 1

Workflow of a neoantigen prediction pipeline. From whole‐exome sequence data (from normal and tumor DNAs) and RNA sequencing data (RNAseq; from tumor RNA), we obtain information on (1) HLA genotypes, (2) somatic mutations, and (3) the expression levels of mutated genes. Using this information, we estimate affinities of peptides to human leukocyte antigen (HLA) molecules, and list possible neoantigens (4). Mut, mutant

Figure 2

Workflow to screen neoantigen‐reactive T cells and develop T‐cell receptor (TCR)‐engineered T cells. For the neoantigen candidates from whole‐exome and RNA sequencing data, either tandem minigenes or peptides, including mutated amino acids, are synthesized. These peptides or minigenes can be expressed in patients’ autologous antigen‐presenting cells (APCs). Patients’ T cells are co‐cultured with these APCs to identify neoantigen‐reactive T cells using peptide–human leukocyte antigen multimer or enzyme‐linked immunospot (ELISPOT) assays. The peptides specifically recognized by patients’ T cells will be used for neoantigen‐based cancer vaccine treatment. Sequencing of TCR in these neoantigen‐reactive T cells can identify a TCRαβ‐pair sequence, and this TCRαβ is expressed in patients’ T cells using a lentivirus vector system. These TCR‐modified T cells are then expanded in vitro and are re‐infused back into the patient as TCR‐engineered T‐cell therapy