Anti-pd-1 antibodies(Shanghai Yunyi Health Technology Development)

This study addresses the lack of a comprehensive meta-analysis comparing the efficacy and safety of first-line anti-blocking the programmed cell death 1 (PD-1) and anti-programmed death ligand 1 (PD-L1) therapies in patients with extensive-stage small-cell lung cancer, using reconstructed individual patient data.

Through systematic review, we extracted relevant studies from PubMed and EMBASE databases, spanning January 1, 2010 to November 28, 2024. Only phase III randomized controlled trials assessing anti-PD-1 inhibitors plus chemotherapy (CT) versus anti-PD-L1 inhibitors plus CT were selected. To compare survival outcomes, we employed WebPlotDigitizer and R software for survival curve reconstruction, aiming to elucidate the comparative effectiveness and safety of the 2 therapies.

Our analysis of 7 randomized controlled trials, involving 3339 patients, revealed no significant difference in progression-free survival (PFS) or overall survival (OS) between anti-PD-1 inhibitors plus CT and anti-PD-L1 inhibitors plus CT. The combined 6-, 12-, and 18-month PFS rates were 42.4% versus 43.3%, 19.9% versus 17.0%, and 14.6% versus 13.6% for the anti-PD-1 and anti-PD-L1 groups, respectively (hazard ratio: 0.98, 95% confidence interval: 0.88–1.09, P = .691). The combined 6-, 12-, 18-, and 24-month OS rates were 86.6% versus 85.5%, 58.7% versus 56.9%, 38.8% versus 36.8%, and 28.9% versus 25.4% for the anti-PD-1 and anti-PD-L1 groups, respectively (hazard ratio: 0.94, 95% confidence interval: 0.84–1.06, P = .305). The analysis showed a slightly lower incidence of grade ≥3 adverse events (AEs), serious AEs, any-grade immune-related adverse events, grade ≥3 immune-related adverse events, and events leading to death or treatment discontinuation in the anti-PD-L1 group compared to the anti-PD-1 group (P < .001). However, no significant differences were observed in the risk of any-grade AEs.

This research provides detailed analyses of PFS, OS, and treatment safety for these 2 treatment regimens, making it a valuable resource for clinicians in routine care. Our results demonstrate that both anti-PD-1 and anti-PD-L1 therapies, when combined with chemotherapy, are equally effective. However, anti-PD-L1 therapies appear to offer a safer first-line treatment option for extensive-stage small-cell lung cancer.

Rationale: Tetrahydromagnolol (THM) is a bioactive compound derived from Magnolia officinalis. Although other compounds from this plant, such as magnolol and honokiol, have shown significant anticancer potential, the anticancer activities of THM remain unreported. This study aims to investigate the anticancer effects and underlying molecular mechanisms of THM in pancreatic cancer cells. Methods: In this study, the effects of THM on pancreatic cancer cells were investigated by various experiments both in vitro and in vivo. The molecular target of THM in pancreatic cancer cells was determined by transcriptomics, ligand coupled epoxy-activated magnetic beads, CETSA, SPR analysis, ITC analysis, LC-MS/MS analysis, and MD simulations. Results: Our findings reveal that THM significantly suppresses pancreatic cancer cell proliferation and induces cell death. Autophagic cell death is demonstrated to predominantly contribute to THM-triggered cell death. Importantly, YTHDF2, the m⁶A reader protein, is identified as a direct anticancer target of THM. Further investigations have shown that THM binds to YTHDF2, blocking its ability to recognize m⁶A modifications on the autophagy-related gene mRNAs ATG5 and ATG7. Notably, a medium dose of THM exhibits anticancer efficacy comparable to gemcitabine (GEM), the first-line treatment for pancreatic cancer, and the high dose of THM showing superior anticancer effects than GEM treatment. Moreover, THM enhances the efficacy of anti-PD-1 immunotherapy in pancreatic cancer models. Conclusions: This study presents the first evidence that THM promotes cell death in pancreatic cancer cells by inducing autophagy and YTHDF2 is identified as a direct binding target of THM. Targeting YTHDF2 is a critical determiner for THM-induced autophagic cell death and the immunosensitizing effect of THM with anti-PD-1 inhibitor in pancreatic cancer. Therefore, THM may function as a candidate anticancer drug for pancreatic cancer treatment, either alone or in combination with anti-PD-1 immunotherapy.