Personalized Immunotherapy Strategies Using Neoantigen-Specific T-Cell Receptor Repertoires in Patients with Advanced Metastatic Melanoma: From Tumor Sequencing to Clinical Application

Vikram Menon, Dr. Priya Nair

Department of Clinical Oncology, Tata Memorial Centre, Mumbai, India

Abstract

Metastatic melanoma ranks among the most aggressive cancers, marked by a significant mutational load and mechanisms that allow it to evade the immune system. Recently, the discovery and targeting of tumor-specific neoantigens have become a groundbreaking approach in precision oncology. These neoantigens, which originate from somatic mutations, are displayed on the surfaces of tumor cells through human leukocyte antigen (HLA) molecules, making them highly immunogenic and ideal targets for personalized immunotherapies. Neoantigen-specific T-cell receptor (TCR) repertoires, which identify peptide–MHC complexes with mutated epitopes, are crucial in facilitating anti-tumor immune responses. Progress in next-generation sequencing (NGS), bioinformatics prediction tools, single-cell immunogenomics, and adoptive cell transfer technologies has made it possible to identify, expand, and therapeutically use neoantigen-reactive T cells in melanoma patients. This comprehensive research article offers an integrated framework for personalized immunotherapy using neoantigen-specific TCR repertoires in advanced metastatic melanoma, covering tumor sequencing, neoantigen prediction, TCR repertoire mapping, functional validation, and clinical application. A thorough literature review sheds light on the development of neoantigen discovery, TCR engineering, and adoptive cellular therapy methods, including tumor-infiltrating lymphocytes (TILs), TCR-engineered T cells, and personalized neoantigen vaccines. The materials and methods section describes a multi-omics workflow that includes whole-exome sequencing (WES), RNA sequencing, HLA typing, neoepitope prediction, TCR sequencing, and functional assays. Hypothetical yet biologically plausible results illustrate the identification of immunodominant neoantigens, clonal expansion of neoantigen-specific TCRs, and positive clinical outcomes following adoptive cell transfer. The discussion critically analyzes immunological mechanisms, challenges such as tumor heterogeneity and immune escape, and future possibilities including artificial intelligence-driven TCR design and combination immunotherapies. This article concludes that neoantigen-specific TCR-based personalized immunotherapy shows great potential for advanced melanoma, allowing precise targeting of tumor mutations while reducing off-target toxicity. The integration of genomics, immunology, and clinical oncology will be crucial to bring these strategies into standard clinical practice.

Keywords

Neoantigens; Repertoire of T-cell receptors; Customized immunotherapy; Advanced melanoma; Sequencing of tumors; Cell therapy adoption; Oncology precision; Prediction of neoantigens; Engineering of TCR; Lymphocytes infiltrating tumors.