According to the Chinese and Japanese Gastric Cancer Treatment Guidelines 2021, when regional lymph nodes are fixed and fused into clusters or when metastases are present outside the regional lymph nodes, the cancer is classified as stage IV (M1) or unresectable (Wang et al. 2021; Japanese Gastric Cancer Treatment Guidelines 2021). Trastuzumab combination chemotherapy is recommended as the first-line treatment of HER-2-positive unresectable advanced GC. However, combination therapy with ICIs, trastuzumab, and neoadjuvant chemotherapy is not recommended because of the lack of evidence regarding its survival benefits, as per the Japanese Gastric Cancer Treatment Guidelines 2021 (Japanese Gastric Cancer Treatment Guidelines 2021). In the present study, CT scans revealed that all patients initially presented with large huge tumors and retroperitoneal lymph node metastasis, indicating the involvement of the out-regional lymph nodes at diagnosis. None of the patients achieved R0 resection at the time of the CT scan. After 3–5 cycles of neoadjuvant therapy, the size of the tumor and lymph nodes significantly reduced. A post-therapy evaluation revealed that all patients had achieved R0 resection. The European Society for Medical Oncology Treatment Guidelines for GC also recommended preoperative chemotherapy for patients with stage IB or more advanced resectable GC (Lordick,, et al. 2022). Salah et al. studied two different groups, FLOT and ECF/ECX, undergoing chemotherapy in German hospitals from Aug 8, 2010, to Feb 10, 2015. The FLOT group exhibited a significant increase in the OS compared to that shown by the ECF/ECX group in cases of locally advanced GC (Al-Batran et al. 2019). In our study, three patients received three cycles of a combination therapy including SOX, sintilimab, and trastuzumab. The last remaining patient had a highly aggressive and large tumor, and hence was treated with five cycles of the FLOT combination therapy with sintilimab and trastuzumab. At the end of the neoadjuvant therapy, the tumor size dramatically decreased in all patients, particularly in the patient who underwent five cycles of FLOT and achieved PCR. Hence, two or three cycles of neoadjuvant therapy can be safely administered to some cases with advanced GC. Besides, different chemotherapy regimens comprising ICIs and trastuzumab afford different results. In this study, we successfully used a combination therapy involving ICIs, neoadjuvant chemotherapy, and trastuzumab in unresectable G/GEJ cancer and achieved R0 resection. In addition, two of our patients even achieved pCR.

HER-2 is overexpressed in approximately 20% of patients with GC. Its overexpression indicates aggressive cancer (Oh and Bang 2020). The success of TOGA trial showed that trastuzumab therapy can be employed to improve the clinical prognosis of patients with HER-2-positive GC (Bang et al. 2010). Subsequently, several clinical trials [e.g., HERBIS-1, WJOG7212G, CGOG1001, and KSCC (Gong et al. 2016; Yuki et al. 2020; Miura et al. 2018; Kurokawa et al. 2014)] explored the benefits of combination therapy involving trastuzumab and different chemotherapies. The results indicated that patients with GC who underwent such combination therapies exhibited a better survival rate than those who received only chemotherapy. Despite this, only a few studies are available on the use of combination therapies comprising trastuzumab and ICIs for converting unresectable GC to resectable. Our study is an attempt to fill in this gap. It shows that the combination therapy involving trastuzumab and ICIs is both highly safe and effective in unresectable advanced GC.

Trastuzumab exerts its anti-tumor effects through two pathways: intracellular and extracellular (Augustin et al. 2022). The intracellular mechanism involves inhibiting downstream signal pathways, such as pSTAT3, pAKT, and pERK, or reducing the cell-surface HER-2 phosphorylation levels through accelerated endocytic degradation (Augustin et al. 2022; Zhu et al. 2021). In the extracellular pathway, trastuzumab acts via immune antibody-dependent cell-mediated cytotoxicity (ADCC). For tumor cells treated with trastuzumab, monocytes and NK cells are the major effectors of ADCC (Augustin et al. 2022). Besides, immune activity of trastuzumab exceeds its impact upon cell signaling by changing anti-tumor immune cells activity (Augustin et al. 2022; Clynes et al. 2000; Jaime-Ramirez et al. 2011). In addition, the combination therapy involving trastuzumab and ICIs enhances HER-2-specific T-cell responses, promotes immune-cell trafficking, and induces the expansion of peripheral memory T cells (Park et al. 2010; Taylor et al. 2007; Stagg et al. 2011; Mortenson et al. 2013; Müller, et al. 2015). These results suggested that trastuzumab may exhibit a synergistic effect with ICIs. Recently, Kohei et al. showed that trastuzumab can regulate the expression of PD-L1 when HER-2-amplified GC cell lines are co-cultured with peripheral blood mononuclear cells (PBMCs) and NK cells. Immunohistochemistry analysis also suggested that trastuzumab treatment in clinical samples leads to PD-L1 upregulation (Yamashita et al. 2021). In our study, IHC confirmed that all the patients were HER-2 positive. Hence, they were administered a combination therapy comprising trastuzumab and sintilimab along with various chemotherapy regimens. All the patients were achieved R0 resection including two of them with pCR and there is no evidence of tumor recurrence when the last follow-up. The patient with the longest survival were 30 months and the patient with the shortest survival were 12 months without recurrence and metastasis.

The advent of immunotherapy has revolutionized cancer treatment. Several types of immunotherapy, including ICIs and adoptive cell transfer (ACT), have been employed to achieve reliable clinical responses. However, the efficacy of the immunotherapy varies. In addition, only a few subsets of patients benefit from it. The KEYNOTE-061 trial demonstrated that pembrolizumab did not significantly improve the OS compared to that achieved using paclitaxel in second-line therapy. However, pembrolizumab was associated with higher 24-month OS rates than those obtained using paclitaxel. Its use increased the OS even with PD-L1 enrichment among patients with PD-L1-positive GC/GEJ cancer (Fuchs et al. 2022). A phase-3 randomized clinical trial involving 763 patients, randomly assigned to pembrolizumab, pembrolizumab plus chemotherapy, or chemotherapy alone groups, demonstrated that neither pembrolizumab alone nor pembrolizumab plus chemotherapy afford superior OS and/or PFS benefits compared to that achieved with chemotherapy alone in patients with a CPS score of ≥ 1, untreated, advanced G/GEJ cancer (Shitara et al. 2020). However, the efficacy of ICIs when combined with other treatment regimens in the conversional treatment of GC, especially for unresectable GC, has not yet been clearly elucidated.

Clinical trials, such as KEYNOTE-012, ATTRACTION-2, and KEYNOTE-059, confirmed the efficacy of ICIs in the prognosis of advanced GC/GEJ cancer (Fuchs et al. 2018; Muro et al. 2016). A randomized multicenter clinical trial involving patients with untreated, HER-2-negative, unresectable advanced, or recurrent G/GEJ cancer, conducted across Japan, South Korea, and Taiwan, showed that in the nivolumab plus chemotherapy group, the median PFS was 10.45 months and the OS was 17.45 months, while they were 8.34 months and 17.15 months, respectively, in the placebo plus chemotherapy group (Kang et al. 2022). However, no study has yet reported the efficacy and safety of ICIs in the conversional therapy for GC. We recommend that the immune therapy should be used as the first-line therapy for conversional therapy. Moreover, patients with unresectable or metastatic GC with MSI-H and EBV positivity also experience significant clinical benefit from the ICI treatment, because it upregulates the PD-L1 expression (Marabelle et al. 2020; Chao et al. 2021; Rodriquenz, et al. 2020). However, not all patients reported a positive treatment outcome. Immunotherapy-induced tumor hyperprogressive disease was observed in 10% of patients with advanced GC who were treated with anti-PD-1 monoclonal antibodies (mAb) (Kamada et al. 2019). Therefore, the disease progression should be closely monitored during immunotherapy treatment.

One major limitation of our study was that the design was a single-center case analysis. In the future, more randomized prospective clinical trials are still needed to confirm the reliability and validity of our study results.