Neoantigen-Based Next Gen Immunotherapy
Unveiling Disease-Specific Targets for Next-Gen Therapies
Background
Neoantigens are highly specific targets and ideal targets for immunotherapy. Degraded neoantigen peptides can bind with major histocompatibility complex (MHC) molecules, forming complexes that are subsequently transported to the cell surface. These complexes are recognized by T-cell receptor (TCR), triggering an immune response. MHC polypeptide complexes constitute a category of neoantigen targets, and their distinctive interaction with TCR holds immense importance in the advancement of neoantigen-based immunotherapies, including TCR-T cell therapy, antibody drugs, and tumor vaccines.
Identification of the affinity of peptide loaded MHC with TCR [1].
Neoantigen-based immunotherapy includes adoptive cell therapy (such as TCR-T, CAR-T), vaccines (including peptide vaccines, nucleic acid vaccines, DC vaccines) and antibody therapies (full-length antibodies, ADCs, double antibodies, etc.). However, how to excavate and accurately identify neoantigens is the first prerequisite for its clinical application.
Methods for Identification of Immunogenic Peptides
Methods to identify neoantigens currently combine sequencing, omics, algorithms, mass spectrometry, and experimental validation. First, use NGS, WES, RNA-seq, etc. to screen for mutations that can produce real proteins. At the same time, the patient's HLA genotype is determined, and the antigen peptide is screened and sorted by combining the HLA binding force and the new antigen transport process algorithm. Finally, the antigen-reactive TCR was used to verify the immune effect of the antigen peptide. Most of the antigenic peptides predicted by the presentation of MHC molecules are not immunogenic, so the experimental verification based on specific TCR is a relatively direct method, which can truly identify the antigenic epitopes that can activate specific T cells.
Neoantigen identification process [2].
A common strategy is to contact T cells with several antigenic peptides, which are determined by detecting functions such as T cell proliferation, specific killing ability, and factor release. The other is to identify antigen-reactive T cells by forming a complex polymer between MHC and the antigen peptide to be tested, and perform flow screening. These methods can not only determine the sequence information of antigenic peptides, but also identify specific T cells. A variety of new technology methods such as mass spectrometry, DNA barcode labeling and microfluidic analysis have greatly improved the detection throughput. Another is to screen the antigen peptide library through a specific TCR.
The bottleneck of neoantigen establishment is proper MHC presentation and effective TCR recognition, which is also one of the biggest challenges in the process of individualized immunotherapy. The reason is that the proportion of mutations that can cause immune effects is very small, and the authority of computer virtual screening itself is still inconclusive. Coupled with the limitation of HLA matching and the low affinity of MHC complexes to TCR, it significantly restricts the research of neoantigen-based immunotherapy. With the continuous improvement of the database and the refinement of different algorithm strategies, future neoantigen research will effectively combine computer-aided prediction and experimental verification, and gradually move closer to the high-throughput direction to achieve fast, accurate and efficient identification results.
References
[1] Xie N, Shen G, Gao W, Huang Z, Huang C, Fu L. Neoantigens: promising targets for cancer therapy. Signal Transduct Target Ther. 2023 Jan 6;8(1):9.
[2] Arnaud M, Duchamp M, Bobisse S, Renaud P, Coukos G, Harari A. Biotechnologies to tackle the challenge of neoantigen identification. Curr Opin Biotechnol. 2020 Oct;65:52-59.
