Based on previous feedback, identifying the most valuable predictive biomarkers and trial schemes to promote the further development of clinical trials is required. trial results of combination immunotherapy for GC are presented. Based on the outcome of combination therapy, we discuss its possible molecular mechanism and summarize effective predictive biomarkers. We also discuss possible problems stemming from results of other clinical trials of ICI treatment and propose other directions for ICI therapy. the VEGF/VEGFR axis, resulting in downregulation of anti-tumor CTL activity[26]. These above-mentioned mechanisms provide a conceivable theoretical basis for the combined therapy of anti-vascular targeted drugs and ICIs (Figure ?(Figure1).1). Kato decreasing TAMs and enhancing the activation of the interferon MI 2 (IFN) signaling pathway, upregulated the anti-tumor activity of PD-1 inhibitors paclitaxel, cisplatin, and doxorubicin)[30]. Vacchelli direct effects on cytotoxic lymphocytes and the elimination of immunosuppressive cells clinical trial results of certain chemotherapy drugs (paclitaxel, gemcitabine, and 5Fu)[31]. Traditional chemotherapy drugs are able to enhance the patients’ antitumor immune response, and ICIs could further eliminate tumor foci that are resistant to chemotherapy, correspondingly. Thus, the combination of ICI and chemotherapeutics for the treatment of advanced refractory tumors presents clinical benefits, and numerous clinical trials seem to have verified this hypothesis (KEYNOTE-659, KEYNOTE-059, and KEYNOTE-062). Moreover, additional combination treatment options are worth exploring. The combined use of two ICI drug treatments, such as the combination of TSPAN6 CTLA4 and PD-1/PD-L1 blocking antibodies, can kill T lymphocytes in the immune initial and effector stages[32]. For example, the Checkmate032 trial aims to assess the efficacy of the combination treatment of nivolumab (anti-PD-1 antibody) and ipilimumab (anti-CTL4 antibody) in patients with advanced solid tumors, including advanced GC. As a result, the combined scheme of nivolumab (1 mg/kg) + ipilimumab (3 mg/kg) had a sustained antitumor effect in the treatment of advanced GC, thereby prolonging the OS[33,34]. In addition, radiotherapy is certified to cause immunogenic cell death and has a synergistic effect on anti-tumor CTLs[35]. This principle revealed the possibility of the combined application of radiotherapy and ICI, although there has been MI 2 no corresponding clinical trial for GC at present. In a novel case report, a patient with HER2-negative advanced GC (stage IV, T4N3M1) received 4 mo of treatment with a combination of concurrent SOX regimen chemotherapy, radiotherapy, and ICI immunotherapy, which showed a satisfactory complete response for tumor lesions, even metastatic lesions (almost complete response, disappearance of all target lesions)[36]. This example demonstrated that the continuous exploration and advances of combined immunotherapy will improve the survival benefits of patients with GC significantly. PREDICTIVE BIOMARKERS FROM CLINICAL TRIALS The Cancer Genome Atlas has proposed a molecular classification dividing GC into four subtypes: EBV positive (9%), genomically stable (20%), MSI-high (22%), and chromosomal instability (50%)[37]. Among the four molecular subtypes of GC, EBV-positive tumors and MSI-high tumors show better responses to ICIs[38]. The Food and Drug Administration (FDA) has approved treatment with pembrolizumab for patients with PD-L1 positive and MSI-high/DNA mismatch repair deficiency (dMMR) advanced GC in the second- or third-line setting[39,40]. Accordingly, PD-L1 positive and MSI-high/dMMR advanced GC patients are currently the most widely applied for ICI therapy. PD-L1 expression in tumor cells is determined by immunohistochemistry using formalin-fixed paraffin-embedded sections, and the proportion of PD-L1-stained tumor cells and immune cells is calculated to obtain a clinical prediction score (CPS). The result of KEYNOTE-059 trial shows that patients with PD-L1 positive tumors (CPS 1) achieved 22.7% ORR and 2.7% complete response anti-PD-1 treatment, compared with 8.6% ORR and 3.4% complete response of individuals with PD-L1 negative tumors (CPS 1)[39]. Another randomized phase III trial, KEYNOTE-062[10], enrolled 763 individuals with HER2-negativity and CPS 1. The results showed that 281 (37% of the enrollees) experienced a CPS score of 10. The individuals were divided into three organizations by their treatment options as initial therapy: Intravenous pembrolizumab, pembrolizumab plus chemotherapy, or chemotherapy plus placebo. The primary endpoint of this trial showed that for individuals with HER2-bad, PD-L1-positive (CPS 1), advanced GC, combination treatment with pembrolizumab plus chemotherapy resulted in a better ORR and PFS compared with traditional chemotherapy. In addition, pembrolizumab resulted in a clinically meaningful OS improvement for individuals with high levels of PD-L1 manifestation (CPS 10). Microsatellites are repeated sequences of small DNA fragments that exist in the genome, and false microsatellites are produced and accumulated during replication, which is called MSI-high status. Mismatched DNA is definitely.The results showed that 281 (37% of the enrollees) had a CPS score of 10. MI 2 also discuss possible problems stemming from results of other medical tests of ICI treatment and propose additional directions for ICI therapy. the VEGF/VEGFR axis, resulting in downregulation of anti-tumor CTL activity[26]. These above-mentioned mechanisms provide a conceivable theoretical basis for the combined therapy of anti-vascular targeted medicines and ICIs (Number ?(Figure1).1). Kato reducing TAMs and enhancing the activation of the interferon (IFN) signaling pathway, upregulated the anti-tumor activity of PD-1 inhibitors paclitaxel, cisplatin, and doxorubicin)[30]. Vacchelli direct effects on cytotoxic lymphocytes and the removal of immunosuppressive cells medical trial results of particular chemotherapy medicines (paclitaxel, gemcitabine, and 5Fu)[31]. Traditional chemotherapy medicines are able to enhance the individuals’ antitumor immune response, and ICIs could further get rid of tumor foci that are resistant to chemotherapy, correspondingly. Therefore, the combination of ICI and chemotherapeutics for the treatment of advanced refractory tumors presents medical benefits, and several medical trials seem to have verified this hypothesis (KEYNOTE-659, KEYNOTE-059, and KEYNOTE-062). Moreover, additional combination treatment options are worth exploring. The combined use of two ICI drug treatments, such as the combination of CTLA4 and PD-1/PD-L1 obstructing antibodies, can destroy T lymphocytes in the immune initial and effector phases[32]. For example, the Checkmate032 trial seeks to assess the efficacy of the combination treatment of nivolumab (anti-PD-1 antibody) and ipilimumab (anti-CTL4 antibody) in individuals with advanced solid tumors, including advanced GC. As a result, the combined plan of nivolumab (1 mg/kg) + ipilimumab (3 mg/kg) experienced a sustained antitumor effect in the treatment of advanced GC, therefore prolonging the OS[33,34]. In addition, radiotherapy is qualified to cause immunogenic cell death and has a synergistic effect on anti-tumor CTLs[35]. This basic principle revealed the possibility of MI 2 the combined software of radiotherapy and ICI, although there has been no related medical trial for GC at present. In a novel case report, a patient with HER2-bad advanced GC (stage IV, T4N3M1) received 4 mo of treatment with a combination of concurrent SOX routine chemotherapy, radiotherapy, and ICI immunotherapy, which showed a satisfactory total response for tumor lesions, actually metastatic lesions (almost total response, disappearance of all target lesions)[36]. This example shown that the continuous exploration and improvements of combined immunotherapy will improve the survival benefits of individuals with GC significantly. PREDICTIVE BIOMARKERS FROM CLINICAL Tests The Malignancy Genome Atlas offers proposed a molecular classification dividing GC into four subtypes: EBV positive (9%), genomically stable (20%), MSI-high (22%), and chromosomal instability (50%)[37]. Among the four molecular subtypes of GC, EBV-positive tumors and MSI-high tumors display better reactions to ICIs[38]. The Food and Drug Administration (FDA) offers authorized treatment with pembrolizumab for individuals with PD-L1 positive and MSI-high/DNA mismatch restoration deficiency (dMMR) advanced GC in the second- or third-line establishing[39,40]. Accordingly, PD-L1 positive and MSI-high/dMMR advanced GC individuals are currently probably the most widely applied for ICI therapy. PD-L1 manifestation in tumor cells is determined by immunohistochemistry using formalin-fixed paraffin-embedded sections, and the proportion of PD-L1-stained tumor cells and immune cells is determined to obtain a medical prediction score (CPS). The result of KEYNOTE-059 trial demonstrates individuals with PD-L1 positive tumors (CPS 1) accomplished 22.7% ORR and 2.7% complete response anti-PD-1 treatment, compared with 8.6% ORR and 3.4% complete response of individuals with PD-L1 negative tumors (CPS 1)[39]. Another randomized phase III trial, KEYNOTE-062[10], enrolled 763 individuals with HER2-negativity and CPS 1. The results showed that 281 (37% of the enrollees) experienced a CPS score of 10. The individuals were divided into three organizations by their treatment options as initial therapy: Intravenous pembrolizumab, pembrolizumab plus chemotherapy, or chemotherapy plus placebo. The primary endpoint of this trial showed that for individuals with.