Cancer immunology, immunotherapy : CII · 2025
Exploration of the benefits and resistance mechanisms of immunotherapy based on PD-L1 expression, circulating tumor DNA and T-cell receptor profiles in advanced gastric cancer.
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Gou Miaomiao, Qian Niansong, Zhang Yong, Yan Bingfa, Wang Zhikuan, Dai Guanghai
Аннотация
BACKGROUND: Combination regimens of immunotherapy and chemotherapy have become the standard treatment for HER2-negative advanced gastric cancer (AGC). Here, we evaluate the therapeutic efficacy of first-line treatment regimens across different PD-L1 expression, circulating tumor DNA (ctDNA) and T-cell receptor (TCR).
METHODS: This study retrospectively recruited 245 patients with AGC. 55 blood samples from 20 patients were prospectively collected before immunotherapy, after two cycles of treatment, and during disease progression.
RESULTS: In the CPS < 5 cohort, chemotherapy + PD-1 inhibitor + anti-angiogenic treatment showed a higher progression-free survival (PFS). In the CPS ≥ 5 cohort, chemotherapy + PD-1 inhibitor improved median PFS (p = 0.04) and ORR (p = 0.014) over chemotherapy alone. ctDNA analysis revealed that at various time points, patients in the short-PFS group exhibited significantly elevated maxVAF and ctDNA levels. Post-treatment, ctDNA levels decreased in 50% of patients in the long-PFS group, whereas only 25% in the short-PFS group. The short-PFS group had a lower TCR clone count, while no significantly different in the diversity of the TCR repertoire compared with long-PFS groups.
CONCLUSIONS: These findings suggest the different efficacy of first-line treatment regimens across varying levels of PD-L1 expression, and the molecular characteristics of patients with long-term benefits from immunotherapy.
METHODS: This study retrospectively recruited 245 patients with AGC. 55 blood samples from 20 patients were prospectively collected before immunotherapy, after two cycles of treatment, and during disease progression.
RESULTS: In the CPS < 5 cohort, chemotherapy + PD-1 inhibitor + anti-angiogenic treatment showed a higher progression-free survival (PFS). In the CPS ≥ 5 cohort, chemotherapy + PD-1 inhibitor improved median PFS (p = 0.04) and ORR (p = 0.014) over chemotherapy alone. ctDNA analysis revealed that at various time points, patients in the short-PFS group exhibited significantly elevated maxVAF and ctDNA levels. Post-treatment, ctDNA levels decreased in 50% of patients in the long-PFS group, whereas only 25% in the short-PFS group. The short-PFS group had a lower TCR clone count, while no significantly different in the diversity of the TCR repertoire compared with long-PFS groups.
CONCLUSIONS: These findings suggest the different efficacy of first-line treatment regimens across varying levels of PD-L1 expression, and the molecular characteristics of patients with long-term benefits from immunotherapy.