Conversion therapy is feasible in patients with oncologically unresectable hepatocellular carcinoma (HCC). However, it is challenging to prospectively identify patients who are more likely to achieve ...successful conversion before initiating systemic therapy, either alone or combined with locoregional therapy.
Criteria for identifying potentially resectable patients with initially oncologically unresectable HCC before treatment with lenvatinib plus an anti-PD-1 antibody were proposed based on real-world evidence. Multivariate Firth logistic regression was used to validate the proposed criteria in a retrospective cohort of consecutive patients with advanced HCC, who received combination therapy with lenvatinib plus an anti-PD-1 antibody between September 2018 and September 2021.
The proposed criteria were as follows: (1) Eastern Cooperative Oncology Group performance status of 0 or 1; (2) Child-Pugh class A; (3) intrahepatic tumors confined to one lobe (left, right, or middle lobe), or present in one lobe alongside a single tumor with diameter ≤5 cm or up to three tumors each with diameter ≤3 cm in the remaining lobes, with R0 resection achievable by hemihepatectomy, alone or combined with locoregional therapy to the remaining lobes during surgery; and (4) no portal vein tumor thrombus involving the contralateral liver lobe or reaching the superior mesenteric vein, no hepatic vein tumor thrombus involving more than two major hepatic vein branches on the tumor side, and no tumor thrombus of the inferior vena cava reaching the atrium. Firth logistic regression confirmed the criteria were an independent predictor of surgery following conversion therapy with lenvatinib plus an anti-PD-1 antibody.
This study proposed and validated criteria for identifying patients with initially oncologically unresectable HCC who are potentially resectable when treated with combination therapy with lenvatinib plus an anti-PD-1 antibody. The proposed criteria could help standardize conversion therapy studies in advanced HCC.
Background
Anti-PD-1 antibodies are widely used for cancer treatment including advanced renal cell carcinoma (RCC). However, their therapeutic and adverse effects vary among patients. This study ...aimed to identify genetic markers that predict outcome after nivolumab anti-PD-1 antibody treatment for advanced RCC.
Methods
This study was registered on the website of the University Hospital Medical Information Network (protocol ID, UMIN000037739). Patient enrollment was conducted at 23 institutions in Japan between August 19, 2019, and September 30, 2020. Patient follow-up ended on March 31, 2021. Patients were treated with nivolumab for advanced clear cell RCC. A genome-wide association study was performed in the development set, while genotyping of target regions in the validation set was undertaken. Single nucleotide polymorphisms (SNPs) in genes of interest CD274, PDCD1LG2 and PDCD1 were genotyped in the combined set. The primary endpoint was the association of SNPs with objective response following nivolumab treatment. As secondary endpoints, the associations of SNPs with radiographic progression-free survival (rPFS) and treatment-related grade ≥ 3 adverse events (AEs) were evaluated.
Results
A genome-wide association study followed by a validation study identified that SNPs in FARP1 (rs643896 and rs685736) were associated with objective response and rPFS but not AEs following nivolumab treatment. Furthermore, SNPs in PDCD1LG2 (rs822339 and rs1411262) were associated with objective response, rPFS, and AEs following nivolumab treatment. Genetic risk category determined according to the number of risk alleles in SNPs (rs643896 in FARP1 and rs4527932 in PDCD1LG2) excellently predicted objective response and rPFS in nivolumab treatment.
Conclusion
This study revealed that SNPs in FARP1 and PDCD1LG2 were correlated with outcome in nivolumab treatment. The use of these SNPs may be beneficial in selecting appropriate treatment for individual patients and may contribute to personalized medicine.
Tumor immunotherapy, an innovative anti-cancer therapy, has showcased encouraging outcomes across diverse tumor types. Among these, the PD-1/PD-L1 signaling pathway is a well-known immunological ...checkpoint, which is significant in the regulation of immune evasion by tumors. Nevertheless, a considerable number of patients develop resistance to anti-PD-1/PD-L1 immunotherapy, rendering it ineffective in the long run. This research focuses on exploring the factors of PD-1/PD-L1-mediated resistance in tumor immunotherapy. Initially, the PD-1/PD-L1 pathway is characterized by its role in facilitating tumor immune evasion, emphasizing its role in autoimmune homeostasis. Next, the primary mechanisms of resistance to PD-1/PD-L1-based immunotherapy are analyzed, including tumor antigen deletion, T cell dysfunction, increased immunosuppressive cells, and alterations in the expression of PD-L1 within tumor cells. The possible ramifications of altered metabolism, microbiota, and DNA methylation on resistance is also described. Finally, possible resolution strategies for dealing with anti-PD-1/PD-L1 immunotherapy resistance are discussed, placing particular emphasis on personalized therapeutic approaches and the exploration of more potent immunotherapy regimens.
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•Tumor immune escape mechanisms contribute to immunotherapy resistance.•PD-1/PD-L1 signaling pathway regulates immune evasion by tumors.•Tumor antigen deletion and T cell impact response to anti-PD-1/PD-L1 therapy.•Alterations in PD-L1 expression and metabolism impact immunotherapy resistance.•Targeted therapies and personalized treatment promise to overcome drug resistance.
Brain metastases are a common and severe complication potentially leading to death in patients with metastatic melanoma. Immunotherapy and targeted therapy have significantly improved ...progression-free survival (PFS) and overall survival (OS) in patients with advanced melanoma. Few studies focus on patients with central nervous system (CNS) metastases, and these patients are often excluded and have a poor prognosis. It has been suggested that immunotherapy could reduce the incidence of brain metastases. We tested this hypothesis in a retrospective bicentric study. We performed a retrospective, bicentric descriptive analysis on a cohort of 293 patients treated for metastatic melanoma between May 2014 and October 2017 (Toulouse, N = 202; Limoges, N = 91). Patients with brain metastasis at diagnosis were excluded from the analysis. Patients were separated into two groups according to the first line of treatment: immunotherapy immune checkpoint inhibitor (ICI) vs other and anti-PD-1 vs other. The primary endpoint was the cumulative incidence of brain metastases, and secondary endpoints were OS and PFS. At 12 months, the cumulative incidence of brain metastases was 13.78% in the ICI group 95% confidence interval (CI) 9.14-19.36 and 27.26% in the other group (95% CI 19.38-35.71), P = 0.004. The cumulative incidence was 9.49% in the anti-PD-1 group (95% CI 5.43-14.90) vs 30.11% in the other group (95% CI 22.59-37.97), P < 0.0001. In multivariable analysis (model with 277 patients), anti-PD-1 reduced the risk of brain metastases by almost 70% (hazard ratio = 0.29, 95% CI 0.15-0.56, P < 0.0001). The use of ICI (anti-PD-1/PD-L1) in advanced melanomas without initial brain metastasis shows a protective effect and prevents their occurrence.
•This study assessed the effect of ramucirumab on docetaxel after anti-PD-1/L1 therapy.•Analysis using inverse probability of treatment weighting based on propensity scores.•Ramucirumab enhanced ...docetaxel efficacy after anti-PD-1/L1 therapy.•Docetaxel/ramucirumab is an effective treatment option after anti-PD-1/L1 therapy.
: Docetaxel (DTX) efficacy increases in patients with non-small cell lung cancer (NSCLC) who had received anti-programmed cell death-1/ligand 1 (anti-PD-1/L1) therapy. However, the effect of ramucirumab (Ram) on DTX efficacy following anti-PD-1/L1 therapy is unknown. Here, we aimed to evaluate the effect of Ram on DTX efficacy following anti-PD-1/L1 therapy.
This retrospective study included 99 patients with NSCLC, who were divided into those who had (pre-ICI group) or had not (no-ICI group) received anti-PD-1/L1 antibody before DTX. Both groups were then treated with DTX or DTX plus Ram (DTX/Ram). Patient characteristics were compared between the DTX and DTX/Ram groups and adjusted with inverse probability of treatment weighting using propensity scores and the following confounding variables: age, sex, performance status, smoking status, histology, driver mutation, and line of treatment. We compared DTX/Ram and DTX in terms of efficacy in both the pre-ICI and no-ICI groups.
In the pre-ICI group, 18 and 21 patients received DTX and DTX/Ram, respectively. In the no-ICI group, 35 and 25 patients received DTX and DTX/Ram. In the no-ICI group, progression-free survival (PFS) and overall survival (OS) were not significantly different between DTX/Ram- and DTX-treated patients (median PFS, 2.6 versus 1.6 months; p = 0.30, median OS; 8.2 versus 8.0 months; p = 0.30). In the pre-ICI group, PFS was significantly longer in DTX/Ram-treated than in DTX-treated patients (median, 5.9 versus 2.8 months; p = 0.03). Hazard ratio for disease progression or death was 0.75 (95% confidence interval, 0.20–0.96). The OS of DTX/Ram-treated patients tended to be longer than that of DTX-treated patients (median, 19.8 versus 8.6 months; p = 0.10).
DTX efficacy following anti-PD-1/L1 therapy may be enhanced by Ram. Further studies are needed to validate the efficacy of inhibiting the vascular endothelial growth factor pathway following anti-PD-1/L1 therapy.
Anti-programmed cell death protein 1 (PD-1) therapy has shown promising efficacy in hepatocellular carcinoma (HCC), but its response rates in advanced HCC are lower than 20%. A critical reason for ...this is the imbalance between CD8
T cells and tumor burden. Here, a novel concept of vascular disruption and normalization dependent on a polymeric vascular disrupting agent (VDA) poly (
-glutamic acid)-
-methoxy poly (ethylene glycol)/combretastatin A4 (CA4-NPs) + a vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) inhibitor DC101 is applied to improve anti-PD-1 therapy, wherein CA4-NPs reduce tumor burden and DC101 simultaneously increases the number of intratumoral CD8
T cells, successfully regulating the abovementioned imbalance in an H22 tumor model.
Blood vessel density, tumor cell proliferation, and necrosis were evaluated to reveal the effects on reducing tumor burden by CA4-NP treatment. Pericyte coverage of blood vessels, tumor blood vessel perfusion, tumor hypoxia, and intratumoral immune cells were examined to verify their role in vascular normalization and immune cell homing of DC101. Furthermore, the effects of CA4-NPs + DC101 on reducing tumor burden and increasing the number of immune cells were studied. Finally, tumor suppression, intratumoral CD8
T cell activation, and the synergistic effects of anti-PD-1 combined with CA4-NPs + DC101 were verified.
The tumor inhibition rate of anti-PD-1 antibody combined with CA4-NPs + DC101 reached 86.4%, which was significantly higher than that of anti-PD-1 (16.8%) alone. Importantly, the Q value reflecting the synergy between CA4-NPs + DC101 and anti-PD-1 was 1.24, demonstrating a strong synergistic effect. Furthermore, CA4-NPs + DC101 improved anti-PD-1 therapy by increasing the number of intratumoral CD8
T cells (anti-PD-1, 0.31% vs triple drug combination, 1.18%).
These results reveal a novel approach to enhance anti-PD-1 therapy with VDAs + VEGF/VEGFR2 inhibitors in HCC.
Anti-programmed death-1 (PD-1) therapy has been extensively used to treat cancer. Recently, the combination of immunotherapy and anti-angiogenic therapy has emerged as a novel treatment approach. ...Therefore, we designed a study to evaluate the real-world benefit of the combination of anti-PD-1 and anti-angiogenesis therapy in patients with non-small cell lung cancer (NSCLC).We obtained the medical records of patients at the Chinese People's Liberation Army General Hospital who received either nivolumab or pembrolizumab combined with anti-angiogenesis therapy from January 2015 to December 2018. The overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated for all patients.Sixty-nine patients with NSCLC were included in our study. The ORR was 31.9% (95% CI: 20.6-43.2%) and the median PFS was 8.37 months (95% CI: 6.5-10.0 months). The subgroup analysis statistically revealed a significant difference in ORR for patients receiving first-line treatment vs other lines, and the values were 58.8% (95% CI: 32.7-84.9%) compared with 23.1% (95% CI: 11.2-34.9%). We also observed a significant improvement in PFS, with a median value of 10.5 months (95% CI: 7.4-13.1 months) for patients without EGFR mutations and 5.4 months (95% CI: 4.0-6.3 months) for patients with EGFR mutations.The real-world ORR, PFS, and OS were comparable to previous clinical trials, despite the patients' different baseline characteristics. Importantly, compared with patients having identified EGFR mutations, patients without EGFR mutations had a better PFS. Furthermore, these data support the use of anti-PD-1 combined with anti-angiogenesis therapy as a novel treatment approach for patients with NSCLC.
Objectives
The study aims to summarize publication characteristics of anti-programmed cell death protein 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) immunotherapy for esophageal cancer and ...create scientific maps to explore hotspots and emerging trends with bibliometric methods.
Methods
The publications between 2012 and 2021 were retrieved from the Web of Science Core Collection (WoSCC) on June 20, 2022. Bibliometric tools including HistCite, VOSviewer, and CiteSpace were used for statistical analysis. Data on the trend of the annual output, countries/regions, institutions, journals, authors, subject categories, keywords, and co-cited references were presented in this study.
Results
A total of 552 publications written by 3,623 authors of 872 institutions, 44 countries/regions in 250 journals were included in the bibliometric study. China, USA and Japan were the key countries in this field. Kato Ken, Bang Yung-Jue,
Frontiers in Oncology
,
Journal of Clinical Oncology
and Natl Canc Ctr were the top 1 productive author, co-cited author, productive journal, co-cited journal and prolific institution, respectively. The top 4 most present keywords were esophageal cancer, immunotherapy, esophageal squamous cell carcinoma and PD-L1. Neoadjuvant chemotherapy, response, PD-1 blockade and CD8
+
T cell were four latest research frontiers. The keywords reflected the progress from PD-1/PD-L1 expression to the clinical application of PD-1/PD-L1 inhibitors. The current researches mainly focus on neoadjuvant immunotherapy for esophageal cancer and development of biomarkers. Further research is warranted to determine effective predictive biomarkers or models, illustrate the molecular mechanism of combined treatment, and construct the optimal therapeutic strategy.
Conclusions
This study visually analyzed the global trend and hotspots of anti-PD-1/PD-L1 immunotherapy for esophageal cancer over the past decade. The results could guide scientists to comprehensively understand the global frontiers and determine future directions.
As an emerging antitumor strategy, immune checkpoint therapy is one of the most promising anticancer therapies due to its long response duration. Antibodies against the programmed death-1 (PD-1) and ...programmed death ligand-1 (PD-L1) axis have been extensively applied to various cancers and have demonstrated unprecedented efficacy. Nevertheless, a poor response to monotherapy with anti-PD-1/PD-L1 has been observed in metastatic breast cancer. Combination therapy with other standard treatments is expected to overcome this limitation of PD-1/PD-L1 blockade in the treatment of breast cancer. In the present review, we first illustrate the biological functions of PD-1/PD-L1 and their role in maintaining immune homeostasis as well as protecting against immune-mediated tissue damage in a variety of microenvironments. Several combination therapy strategies for the combination of PD-1/PD-L1 blockade with standard treatment modalities have been proposed to solve the limitations of anti-PD-1/PD-L1 treatment, including chemotherapy, radiotherapy, targeted therapy, antiangiogenic therapy, and other immunotherapies. The corresponding clinical trials provide valuable estimates of treatment effects. Notably, several combination options significantly improve the response and efficacy of PD-1/PD-L1 blockade. This review provides a PD-1/PD-L1 clinical trial landscape survey in breast cancer to guide the development of more effective and less toxic combination therapies.
Objective:
To evaluate the efficacy and safety of anti-PD-1/PD-L1 Inhibitors versus docetaxel for non-small cell lung cancer by meta-analysis.
Methods:
Randomized controlled trials (RCTs) about ...anti-PD-1/PD-L1 Inhibitors versus docetaxel on the treatment of NSCLC were searched in CNKI, WF, VIP, PubMed, EMBASE, Cochrane Library, and Web of Science databases. Two reviewers independently screened literature, extracted data and evaluated the risk of bias of eligible studies. Meta-analysis was performed by RevMan5.3 software.
Results:
Compared with the use of docetaxel chemotherapy for NSCLC, the overall survival and progression-free survival of the anti-PD-1/PD-L1 Inhibitors regimen are better overall survival: (HR= 0.73, 95%CI:0.69∼0.77, P<0.00001, progression-free survival: (HR= 0.89, 95%CI:0.83∼0.94, P<0.00001), and lower incidence of treatment-related grade 3 or higher adverse events (OR=0.20, 95% CI: 0.13∼0.31, P<0.00001).
Conclusion:
Compared with the docetaxel chemotherapy regimen, the anti-PD-1/PD-L1 Inhibitors has certain advantages in terms of efficacy and safety. The results still need to be confirmed by a multi-center, large sample, and high-quality research.
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