The use of immune checkpoint blockade (ICB) using antibodies against programmed death receptor (PD)-1, PD ligand (PD-L)-1, and cytotoxic T-lymphocyte antigen 4 (CTLA-4) has redefined the therapeutic landscape in solid tumors, including skin, lung, bladder, liver, renal, and breast tumors. However, overall response rates to ICB therapy remain limited in PD-L1-negative patients. Thus, rational and effective combination therapies will be needed to address ICB treatment resistance in these patients, as well as in PD-L1-positive patients who have progressed under ICB treatment. DNA damage repair inhibitors (DDRis) may activate T-cell responses and trigger inflammatory cytokines release and eventually immunogenic cancer cell death by amplifying DNA damage and generating immunogenic neoantigens, especially in DDR-defective tumors. DDRi may also lead to adaptive PD-L1 upregulation, providing a rationale for PD-L1/PD-1 blockade. Thus, based on preclinical evidence of efficacy and no significant overlapping toxicity, some ICB/DDRi combinations have rapidly progressed to clinical testing in breast and ovarian cancers. Here, we summarize the available clinical data on the combination of ICB with DDRi agents for treating breast and ovarian cancers and discuss the mechanisms of action and other lessons learned from translational studies conducted to date. We also review potential biomarkers to select patients most likely to respond to ICB/DDRi combination therapy.
Several immune checkpoint blockades (ICBs) capable of overcoming the immunosuppressive roles of the tumor immune microenvironment have been approved by the US Food and Drug Administration as front-line treatments of various tumor types. However, due to the considerable heterogeneity of solid tumor cells, inhibiting one target will only influence a portion of the tumor cells. One way to enhance the tumor-killing efficiency is to develop a multiagent therapeutic strategy targeting different aspects of tumor biology and the microenvironment to provide the maximal clinical benefit for patients with late-stage disease. One such strategy is the administration of anti-PD1, an ICB, in combination with the humanized monoclonal antibody bevacizumab, an anti-angiogenic therapy, to patients with recurrent/metastatic malignancies, including hepatocellular carcinoma, metastatic renal cell carcinoma, non-small cell lung cancer, and uterine cancer. Radiotherapy (RT), a critical component of solid cancer management, has the capacity to prime the immune system for an adaptive antitumor response. Here, we present an overview of the most recent published data in preclinical and clinical studies elucidating that RT could further potentiate the antitumor effects of immune checkpoint and angiogenesis dual blockade. In addition, we explore opportunities of triple combinational treatment, as well as discuss the challenges of validating biomarkers and the management of associated toxicity.
The incidence of lung cancer with intraocular metastasis is low, of which choroidal metastasis is the most painful metastatic lesion. The clinical symptoms resulting from choroidal metastasis from lung cancer easily detected although they are rarely identified prior to the diagnosis of the primary malignancy. The quality of life of patients is inevitably impaired. Some lung cancer patients complain of ocular symptoms as the first manifestation of lung cancer. Early diagnosis and treatment can significantly overcome or delay the visual impairment and improve prognosis. The main therapeutic modalities include systemic and local treatments, while observation is also a treatment option. Currently, the feasibility and effectiveness of various treatment options are controversial worldwide. Herein, we summarize the underlying mechanisms, epidemiology, clinical features, auxiliary examinations, diagnosis, and recent treatment options for intraocular metastases.
ACT001 is a novel sesquiterpene lactone derivative with anticancer effects, including the reversal of tamoxifen resistance in estrogen receptor-positive breast cancer cells. However, few studies have investigated the anticancer effects of ACT001 in triple-negative breast cancer (TNBC), a highly aggressive cancer with a poor prognosis. This study aimed to investigate the effects of ACT001 on TNBC and the potential mechanism underlying these effects. Materials and Methods: The anticancer effects of ACT001 on the murine TNBC cell line 4T1 were evaluated by Cell Counting Kit-8 assay, animal experiments, TUNEL staining, flow cytometry, immunofluorescence, enzyme-linked immunosorbent assay, and Western blotting analysis. Results: ACT001 induced apoptosis in 4T1 cells by upregulating B cell lymphoma 2-associated X protein expression. Moreover, ACT001 markedly decreased levels of secretory granulocytemacrophage colony stimulating factor (GM-CSF) in 4T1 tumors, decreased the number of myeloidderived suppressor cells (MDSCs), and reduced angiogenesis. Furthermore, GM-CSF promoted angiogenesis and the proliferation of MDSCs in a dose-dependent manner. Finally, ACT001 suppressed phospho-NF-κB and IκB-α levels in 4T1 cells, thereby further decreasing GM-CSF levels. Conclusion: Our results suggest that ACT001 exerts its anticancer effects by inducing apoptosis in murine TNBC cell line 4T1 and regulates the tumor microenvironment by attenuating angiogenesis and accumulation of MDSCs in 4T1 tumors. The underlying mechanism may involve the suppression of NF-κB activity.
BackgroundPrimary pulmonary lymphoepithelioma-like carcinoma (LELC) is a rare type of non-small cell lung cancer (NSCLC). Currently, anti-programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) has become an important treatment for NSCLC. Anti-human PD-1 monoclonal antibodies, such as nivolumab, significantly prolong the survival time of patients with advanced lung adenocarcinoma and lung squamous cell carcinoma. However, there are few reports on the therapeutic effect, drug resistance mechanism, and strategies to overcome resistance to anti-PD-1/PD-L1 treatment in advanced pulmonary LELC. We report the case of a patient with advanced pulmonary LELC harboring fibroblast growth factor receptor (FGFR)3 gene amplification that showed resistance to nivolumab. After treatment with anlotinib, a multi-targeted small-molecule tyrosine kinase inhibitor, the patient’s resistance to nivolumab was reversed. She achieved long-term disease remission with a combination of anlotinib and nivolumab treatment.Case PresentationA 68-year-old woman was diagnosed with stage IVA pulmonary LELC. After multiple-line chemotherapy, her disease progressed. Since the PD-L1 expression rate of the patient was 90%, nivolumab was administered. However, the therapeutic effect of nivolumab was not ideal; the disease continued to progress, and a new cervical lymph node metastasis appeared. FGFR3 gene amplification was detected in lymph node metastasis. Based on this gene abnormality, we added anlotinib to the treatment. After two cycles of anlotinib and nivolumab, the metastatic focus of the patient was significantly reduced. The patient continued to receive this combined treatment and achieved remission for more than 15 months.ConclusionPulmonary LELC with FGFR3 gene amplification may not respond well to nivolumab monotherapy. The combination of anlotinib and nivolumab can reverse the resistance to nivolumab in pulmonary LELC with FGFR3 gene amplification.
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