Discussion
tumor, MSI-H, gastric cancer
REMISSION, TUMOR, PATHOLOGY, GASTRIC CANCER
For locally advanced gastric cancer, 5-year survival rates are only 30.5%, 20.1%, and 8.3% for IIIA, IIIB, and IIIC patientsBased on preliminary data, the neoadjuvant ICI-based therapy led to good outcomes in pathological responses, especially in MSI-H or PD-L1 positive patients. This was consistent with several recent phase I/II single-armed studies in the 2021 ASCO annual meeting, which used ICI plus chemotherapy to treat cT3-4 or N+ gastric cancer patients and achieved >90% R0 resection rates, 0–25% CPR, and 22–42% MPRAs another difference from other neoadjuvant ICI-based trials using ICI plus chemotherapy, we added antiangiogenic agents for combination. Blockage of VEGF/VEGFR has been reported to inhibit angiogenesis and immune suppression in TME, synergizing with ICI to promote local immune responsesPeri-surgical antiangiogenesis may be associated with safety concerns because it is an essential step in wound healingBy comparing baseline pathology and omics data between patients with different responses, we identified potential biomarkers associated with pathological responses. The established biomarkers in advanced cancersBy comparing omics data pre- and post-treatment, we revealed the dynamic evolution of tumor subclones, TME, and T cell repertoires during the neoadjuvant treatment. Similar to the description of therapy-induced clone evolutionDynamic expansion of T cell clones in peripheral blood, rather than the baseline levels, is closely associated with pathological remission. Our CE score accurately differentiated the 4 responders from the 6 non-responders. With more feasibility and convenience than a tumor biopsy, peripheral blood TCR sequencing might be of great value in predicting the efficacy of neoadjuvant therapy or even differentiating pseudoprogression from true progression. Meanwhile, There are several limitations in this study. Due to its exploratory nature, the sample size is small without controlled arms. Several phase III trials on ICI-based neoadjuvant therapy are recruiting, such as KEYNOTE-585 (ClinicalTrials.gov Identifier: NCT03221426) and DRAGON-IV/Ahead-G208 (ClinicalTrials.gov Identifier: NCT04208347). Moreover, the multi-omics analyses might be disturbed by sampling sites and tumor purity. Large multi-omics studies are necessary to define the best predictive biomarkers of pathological responses and OS in neoadjuvant therapy. In addition, the single-arm design of this combination therapy prevents us from distinguishing the relative contributions of each component (ICI, apatinib, and chemotherapy) on treatment efficacy and immune activation. Finally, the patients in this study received relatively short durations of treatment, including the number of treatment cycles and the interval between the last dose of apatinib and surgery, which may be inadequate for a full materialized immune response, especially for the cT4 disease. Prolonging treatment duration may improve outcomes, but the optimal strategy is to be investigated.In conclusion, our data suggest that the ICI- and antiangiogenesis-based neoadjuvant/conversion therapy has good efficacy and feasibility in cT4a/bN+ gastric cancer, especially the MSI-H and PD-L1 positive patients. How to improve its efficacy in MSS and PD-L1 negative patients needs further exploration. The multi-omics findings provide some candidate efficacy-related biomarkers and help us understand the mechanisms of the treatment responses and resistances.