With the recent advances in genomics and proteomics technologies and the development of bioinformatics tools, both fundamental and clinical researches of individualised neoantigen vaccines are accelerating. Under this background, a patient with recurrent bile duct cancer who refused chemotherapy and had no actionable mutation detected was treated with first-line lenvatinib in combination with PD-1 monoclonal antibody,and was enrolled in our clinical trial after progression. The patient received neoantigen nanovaccine injections and cell transfusions. The DOR reached 25 months. No significant discomfort was experienced during the treatment course.
Bile duct carcinoma is one of the most malignant solid tumours, which has a poor prognosis. The only curative treatment is radical surgery10, but the post-operative recurrence rate exceeds 50%. The 5-year survival after of resected bile duct cancer ranges from 25–35%11. Intrahepatic region is the most common post-operative metastatic site. When metastasis occurs, treatment options are usually radiotherapy, chemotherapy or re-excision, but the prognosis is dismal, with a 5-year disease-free survival rate of only 32.1%11. In recent years, it has been shown that targeted therapy can improve the therapeutic efficiency to a certain extent in patients with bile duct cancer harbouring FGFR2 fusion mutations, however, only a small proportion of patients carry such mutations12.
Cancer vaccines are designed to destroy cancer cells by stimulating specific T-cell proliferation through proactive immunisation or activating specific T-cells already present in the body, leading to an ongoing adaptive anti-tumour immune response. Neoantigens are the gene products of tumour-related somatic mutations and can be recognised by T cells only when combined with at least one class of MHC molecules, making them a safe and effective target for T cell-based immunotherapy13. In this case, significant changes in cytokine secretion were observed in CD4 + T cells, but not in CD8 + T cells. During the course of neoantigen nanovaccine treatment, the patient had no obvious haematological abnormalities and no other discomfort. These findings suggest that the antigenic peptides of the vaccine were hydrolysed to trigger an immune response mainly binding with the MHC class II molecules, and that the vaccine is safe and effective.
Sometimes, pre-existing anti-tumour T cells may be functionally impaired and require anti-PD-1 agents to reinvigorate13,14. Based on the above studies, this patient remained on lenvatinib in combination with anti-PD-1 therapy during the vaccine treatment. In addition, to optimize the clinical efficacy, we used nanoparticle-loaded antigenic peptides for subcutaneous vaccination, which could theoretically increase the number of neoantigen-reactive T cells and effectively inhibit tumour growth while increasing the uptake and presentation of the loaded neoantigens.
Our study preliminarily demonstrated the potent immunogenicity and the ability of the neoantigen-based vaccine to target and kill cancer cells. There were no significant haematological abnormalities or discomfort during the treatment, suggesting the safety of the neoantigen nanovaccine. Although individualised neoantigen nanovaccines can bring significant clinical benefit to advanced ICC patients, the major challenge is that it 1–2 months to prepare the vaccine, frome sequencing to vaccine ready to be used.