In July 2017, two independent clinical Phase I trials published in the British scientific journal 《Nature》. In the trails, scientists searched for neoantigen specifically expressed by gene mutations through DNA and RNA sequencing of tumor cells, and then made tumor vaccines which could recognize neoantigen and kill tumor cells after infused. It was the first successful cancer vaccines study in clinical trials.
Compared to normal somatic cells, gene mutations which led to uncontrolled proliferation were always found in the cancer cells. The amino acid sequence would be changed due to gene mutations, and these variant proteins were hydrolyzed by intracellular proteases, bound to MHC molecules and presented to the cell surface, and then activated a cancer immune response after recognized by T cells. These variant proteins caused by gene mutations are called tumor "neoantigen”.
Neoantigen is an abnormal protein produced by cell point mutations, deletion mutations, gene fusion, etc., which is different from proteins expressed by normal cells. It can be digested into polypeptide fragments which are presented as antigens to T cells via DC cells and cause T cells to become mature activated T cells to recognize new tumor antigens. Base on the immunological activity of neoantigen, we design a new antigen vaccine or new antigen EIE cells to help the patients fight cancer.
1、the design process of neoantigen immunotherapy, as shown in the following figures:
1) Obtain tumor and normal cells’s DNA and RNA
2) Whole exon sequencing of tumor cells (WES)
3) Analysis of somatic mutations in tumor cells, calculation of mutant new antigens with binding affinity to HLA
4) Synthesis of new antigens and immunoassay in vitro
5) Test the number of T cells that specifically bind to neoantigen
Neoantigen can not only activate cytotoxic T cells, but also activate T helper cells. In addition to bind short peptides (8-11 amino acids) of HLA class I molecules, the neoantigen may also bind long peptides (~17 amino acids) of HLA class II molecules. We do the immunoassay in vitro and in vivo to confirm that neoantigen can activate specific immune responses.
2、several key steps in the neoantigen immunotherapy
(1) Accurate sequencing and design, which must rely on continuous optimization of algorithms, including HLA typing, calculation of binding force between new antigen and MHC, and TCR analysis.
(2) Break through the barrier and successfully submit it.
(3) activation of specific T cells (neoantigen-specific CTL) can accurately accumulate in tumor tissue
(4) The inhibitory factors of T cells should be removed in time.
There are still many links in the neoantigen immunotherapy that need to be further optimized. In any case, the neoantigen immunotherapy provides patients with a new method to treat cancer, which has the advantages of small side effects, multiple targets, no cancer restriction, and immune memory. The institute has a new clinical project for tumor neoantigen therapy (NCT03914768, NCT04085159), benefiting the majority of patients.
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