Personalized vaccine therapy has been one of the main hotspots in tumour immunotherapy research in recent years[17–19]. Therapeutic cancer vaccines, including peptide-, DNA-, RNA-, protein-, and tumour cell-based vaccines, aim to produce new or to enhance existing tumour-specific T-cell responses against tumor cells[20–22]. Combinations treatments with checkpoint modulators and other novel drugs that reverse immunosuppression are rapidly improving, although more research studies are needed to establish which combinations are the best, as well as determine the optimum dose scheduling for each component[23]. mRNA-based approaches have become a promising platform for cancer immunotherapy. Tuning of the administration routes and codelivery of multiple mRNA vaccines with other immunotherapeutic agents (e.g., checkpoint inhibitors) have further boosted host antitumour immunity and increased the likelihood of tumour cell eradication[24].
ESCC is the most prevalent histological type of esophageal cancer. Despite the development of multidisciplinary therapeutic approaches, its prognosis remains unfavourable. Recently, the development of monoclonal antibodies inhibiting programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) has led to marked therapeutic responses in patients with multiple malignancies, including ESCC. However, only a few patients achieve clinical benefits due to resistance[25, 26] especially patients with microsatellite-low status (MSI-L) and a low tumour mutation burden (TMB)[27, 28]. Here, we present a case of personalized mRNA vaccine combined with PD-1 inhibitor therapy in a patient with advanced ESCC of MSI-L and TMB-low ESCC.
We reported a patient with MSS esophageal cancer which is not population that typically benefits from PD-1 inhibitor treatment, but after treatment with PD-1 inhibitor and personalized mRNA vaccine for 4 cycles, the patient achieved a PR, and the PFS time was 15.2 months. In our study, the neoantigens were identified by bioinformatics analyses and 20 of them were selected then. Our results revealed that those neoantigens significantly activated the tumour-specific immune response. TCR CDR3 V-J pairing analysis showed that both the abundance of oligoclonals TCRs and clonal diversity of TCR libraries were increased. After treatment, the patient's bTMB had decreased from 7.63 to 1.53 Mut per Mb, which indicated that the growth of tumour cells was inhibited. All of those results showed that the combination of the tumour vaccine and PD-1 inhibitor activates the immune response, resulting in stronger antigen recognition and response abilities.
Currently, personalized vaccine treatment, as a new method of tumour treatment, should be give more attention and deeply explored. First, as cancer vaccine are based on neoantigen, it is the very important to analyse neoantigens quickly and accurately. WES data alone does not reflect the transcription characteristics of genes. Compared to WES, integrated analyses combined with measurement of mRNA expression – for example, combined analysis of gene mutations, HLA affinity, wild-type gene profiles, HLA affinity, transcription of mutant genes, mutant gene sharing, etc., as mentioned above – may be a more accurate method for neoantigen analysis. Second, immune recognition of mutation-derived epitopes driven by MHC II molecules and CD4+ T cells is also very important[29–31]. Both MHC class I- and II-restricted neoantigens should be analyzed in designing mRNA vaccine therapies. Third, nanoliposomes, the tumour vaccine carrier currently used in practice, may currently be one of the most important vaccine delivery platforms. Nanoliposomes deliver vaccine components into antigen-presenting cells (APCs), especially dendritic cells (DCs). It is indisputable that an efficient and accurate drug delivery platform for delivering vaccines into APC cells is one of the important requirements for the success of vaccine treatment[32, 33]. In addition, peptide vaccines combined with PD-1 immune checkpoint inhibitors have exhibited promising efficacy outcomes in patients with non-small cell lung cancer, melanoma and human papillomavirus 16-related cancer. Combination with PD-1 inhibitors has historically been a ommon method used in clinical trial for tumour vaccines. However, we must pay close attention to the adverse reactions caused by the application of PD-1 inhibitors.
However, the limitations of this study should also be pointed out. First, this study is a single case report, and further study in clinical trials is needed to confirm the efficacy and safety of personalized neoantigen-based immunotherapies in the treatment of advanced ESCC. Second, this patient is an esophageal cancer patient with lymph node metastasis. There was no tumor metastasis to organs. Patients with metastasis to lymph nodes, which are rich in immune cells, may be more likely to benefit from immunotherapy. It is unclear whether patients with esophageal cancer with organ metastasis can benefit from RNA vaccine treatment. Clinical studies need to include more patients with organ metastases to determine whether such patients with esophageal cancer can benefit from RNA vaccine treatment. Third, antigen-specific TCR sequences activated by the 20 neoantigens could be better analysed separately, as this approach could more accurately show the tumour-specific immune responses activated by the sequenced neoantigens in the future. The timing and dosage of PD-1 inhibitors could also be further explored to prevent the occurrence of moderate to severe adverse reactions related to immunotherapy in thefuture.
Herein, we reported the first case of personalized vaccine therapy with polyneoantigen-coding mRNA in a patient with MSI-L and TMB-L advanced esophageal cancer, who achieved PR. This case indicated that combining the personalized mRNA vaccine with PD-1 blockade may be an effective treatment strategy for advanced esophageal cancer. The therapies combined with vaccine therapy in vivo remain to be further explored.