Neoantigen polypeptide vaccines induce effective antitumor response in colorectal cancer

Abstract

Background: The role of neoantigens in cancer immunotherapy is crucial. However, the effectiveness and safety of personalized neoantigen vaccines in colorectal cancer (CRC), especially in Chinese population, has not been well studied. This paper mainly explores the feasibility and effectiveness of personalized neoantigen vaccines in CRC treatment. Methods: Whole-exome sequencing and transcriptome sequencing were used to identify somatic mutations, RNA expression and human leukocyte antigen (HLA) alleles. Neoantigens were predicted, and the immunogenicity of neoantigen candidates was evaluated by ELISPOT in vitro. To verify the immunogenicity in vivo, neoantigen candidates from HLA-A0201+PW11 were used to immunized female 6-8-week-old HLA-A2.1/Kb-transgenic (Tg) mice. Neoantigen-reactive T cells (NRTs) were induced by immunogenic peptides from autologous HLA-A2.1/Kb to adoptive transfer transgenic mice, and C57BL/6nu/nu mice were used for in vivo antitumor response assays.Results: Compared to medium alone (no peptide) or the unrelated peptide VSV-NP43-69, the neoantigens TSHZ3-L523P, RARA-R83H, TP53-R248W, EYA2-V333I and NRAS-G12D from Patient 4 (PW4); HAVCR2-F39V, SEC11A-R11L, TASP1-P161L, RAP1GAP-S215R, MOSPD1-V63I and NAV2-D1973N from Patient 10 (PW10); and SMPDL3B-T452M, LRFN3-R118Q and ULK1-S248L from Patient 11 (PW11) induced notable peptide-specific T cell responses. The results indicated that about half of the predicted neoantigens for all 3 patients can stimulate T cell responses and antitumor effects in CRC. In addition, predicted neoantigens from PW11 (HLA-A0201) showed promising antitumor efficacy in HLA-A2.1/Kb-Tg mice and tumor-bearing mouse models.Conclusion: With the application of next-generation sequencing (NGS) sequencing of patient specimens, neoantigen prediction and a rapid immunoassay system, an evaluation system utilizing in vitro studies and in vivo transgenic and tumor-bearing mouse models can be used to screen strong immunogenic neoantigens in CRC patients. Accurate identification of neoantigens with strong immunogenicity would promote personalized cancer vaccine development.

Neo‐Antigen‐Reactive T Cells Immunotherapy for Colorectal Cancer: A More Personalized Cancer Therapy Approach

“…[38] For instance, TSHZ3-L523P, RARA-R83H, TP53-R248W, EYA2-V333I, and NRAS-G12D specific-patient neoantigens were predicted to induce NRT antitumor responses in CRC. [19] Although neoantigens are potential targets for personalized vaccines and NRT therapy, most neoantigen-targeted therapies are customized and costly. To overcome these limitations, "shared neoantigens" could be more suitable for patients.…”

“…[9][10][11] Despite the increase in the survival of CRC patients through the implementation of screening programs and targeted therapy in recent decades, the relative five-year survival of CRC patients is still only ≈68%. [12] Evidence demonstrated that MSI-H CRC is associated with increased frequency of tumor-infiltrating lymphocytes (TILs) and high rates of tumor mutation, which justifies the use of various T cell-associated immunotherapies, such as using immune checkpoint inhibitors, neoantigen-reactive T cell (NRT) therapy and chimeric antigen receptor (CAR)-T cells in MSI-H CRC. [13] However, immunotherapy for CRC treatment still has a long way to go because immune checkpoint blockers' effectiveness and success rate have been very low.…”

“…[18] Recently it has been reported that the adoptive NRTs transferring induced by cancer vaccines containing mutant peptides effectively repressed tumor cell growth in CRC-bearing mice models. [19] Moreover, the coexpression of CD39 and CD103 is a hallmark of neoantigen-specific CD8 + T cells in patients with MMR-proficient CRC and low mutation burden. Consequently, identifying these subsets for engineering TCRs and adoptive T cell transfer might be a potential therapeutic approach to treat patients with CRC.…”

Identification of Candidate Antigens and Immune Subtypes in Colon Cancer for mRNA Vaccine Development

“…[12][13][14][15] Active immunotherapy consists mainly of tumor vaccines against peptides, DNA, RNA, or dendritic and tumor cell types. [16][17][18][19][20] For patients who do not respond to other treatments for CC, tumor vaccines represent a promising treatment method. Two biomarkers, CCR8 and GUCY2C, were considered feasible as tumor vaccines in an animal trial, and a dendritic cell vaccine was shown to improve the prognosis of CC patients with surgically amenable liver metastases.…”

“…[21,22] Combined with surgery, chemotherapy, or other treatment patterns, tumor vaccines can delay disease progression to a certain extent. [16][17][18][19][20][21][22] However, except for RNA vaccines, tumor vaccines have shown some fatal flaws. For example, peptide vaccines easily allow antigenic escape and have low immunogenicity, DNA vaccine integration into the host genome makes it ineffective, and dendritic cell vaccines have high resource costs.…”