Clinical outcomes of immune checkpoint inhibitors to treat non-small cell lung cancer patients harboring epidermal growth factor receptor mutations.

BACKGROUND: We aimed to determine the clinical. outcomes of various immune checkpoint inhibitor (ICI) combinations for the treatment of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. The results predicted the treatment efficacy of these combinations. METHODS: From July 15, 2016 to March 22, 2022, 85 NSCLC patients with EGFR mutations, enrolled at the Zhejiang Cancer Hospital, received ICI combinations after resistance to prior EGFR-tyrosine kinase inhibitors (EGFR-TKIs). These patients were diagnosed with EGFR mutations using an amplification refractory mutation system PCR (ARMS-PCR) and next-generation sequencing (NGS). Survival times were analyzed using the Kaplan-Meier method and log-rank test. RESULTS: Patients who received ICIs combined with anti-angiogenic therapy had longer progression-free survival (PFS) and overall survival (OS) than patients who received ICIs combined with chemotherapy. There was no significant difference in survival time between patients who received ICIs combined with chemotherapy and anti-angiogenic therapy and patients who received ICIs combined with anti-angiogenic therapy or ICIs combined with chemotherapy, which was due to the limitation sample size of patients who received ICIs combined with chemotherapy and anti-angiogenic therapy. Patients with L858R mutations had a longer PFS and OS than patients with exon 19 deletions. T790M negative patients benefited more from ICI combinations, compared with T790M positive patients. In addition, there was no significant difference in PFS and OS between patients with TP53 co-mutations and patients without a TP53 co-mutation. We also found that patients with prior first-generation EGFR-TKI resistance had longer PFS and OS than prior third-generation EGFR-TKI resistance patients. There was no new adverse event in this study. CONCLUSIONS: EGFR-mutated patients who received ICIs combined with anti-angiogenic therapy had longer PFS and OS than patients with ICIs combined with chemotherapy. Patients with L858R or without T790M mutation benefited more from ICI combinations. Besides, patients with prior first-generation EGFR-TKI resistance could benefit more from ICIs combinations than prior third-generation EGFR-TKI resistance patients.

An efficient peptide-based ELISA for differentiating fowl adenovirus 4-infected chickens from vaccinated chickens.

Fowl adenovirus serotype 4 (FAdV4), the causative agent of hepatitis-hydropericardium syndrome (HPS), has caused major economic losses to the poultry industry worldwide. Although inactivated vaccines have been deployed widely against FAdV4, a DIVA (differentiating infected from vaccinated animals) test specific for FAdV4 has not been available. We synthesized an immunogenic peptide, corresponding to regions 66-88 aa of the 22K nonstructural protein of FAdV4, and used the peptide as coating antigen to develop an indirect ELISA for a DIVA test specific to FAdV4. Specificity analysis showed that the ELISA only reacted with sera against FAdV4, and not with sera against other pathogens tested. Moreover, the ELISA could effectively differentiate FAdV4-infected chickens from vaccinated chickens. In a test of sera from experimentally infected chickens, the ELISA had 95% and 85% concordance with an indirect immunofluorescence assay (indirect IFA) and a commercial ELISA, respectively, and the concordance was 80.5% between the ELISA and the indirect IFA in detecting clinical infection samples. Our peptide-based ELISA provides an efficient DIVA test for FAdV4 in clinical samples.

Polyphyllin I reverses the resistance of osimertinib in non-small cell lung cancer cell through regulation of PI3K/Akt signaling.

Lung cancer is considered the main cause of cancer mortality worldwide. Osimertinib, a third-generation EGFR-TKI, has been approved and administrated for treating patients with either EGFR T790M mutation or EGFR sensitive mutation. However, resistance to osimertinib emerges and has been considered to be the main obstacle in lung cancer treatment. Polyphyllin I is isolated from the natural herb Paris polyphylla and exhibits anti-cancer activities. In the present study, we identify Polyphyllin I to reverse the resistance of osimertinib in vitro and in vivo. The results showed that Polyphyllin I reversed the resistance of osimertinib through promoting apoptosis, modulating the PI3K/Akt signaling, and regulating the expression of apoptosis-related proteins in osimertinib-resistant cell lines. In vivo study confirmed the results, showing that the tumor growth was significantly suppressed in the Polyphyllin I/osimertinib group compared to the osimertinib group. It has been clarified that Polyphyllin I could reverse the resistance of osimertinib in osimertinib-resistant non-small cell of lung cancer in vitro and in vivo. The underlying mechanism might be related to the downregulation of the PI3K/Akt signaling and increase of the expression of apoptosis-related proteins, suggesting that Polyphyllin I was a promising therapeutic agent for reversing the resistance of osimertinib.