Anti–PD-1/PD-L1 antibodies in non-small cell lung cancer: the era of immunotherapy

Valecha, Gautam; Vennepureddy, Adarsh; Ibrahim, Uroosa; Safa, Firas; Samra, Bachar; Atallah, Jean Paul

doi:10.1080/14737140.2017.1259574

Cited by 35 publications

(32 citation statements)

References 50 publications

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“…Targeted therapies can induce deep responses in patients with NSCLC by blocking actionable mutations, such as EGFR, that are essential for tumor cell growth and progression (37). In contrast, immunotherapy agents, such as those targeting the PD-1 pathway, have demonstrated clinical activity in patients by reactivating preexisting antitumor immune responses (38) but only benefit a subset of patients. Interestingly, driver pathway segments in NSCLC such as EGFR, ALK, and KRAS show limited benefit with immunotherapy, suggesting that these oncogenes induce changes in the TME, leading to escape from tumor immunosurveillance (39).…”

Section: Discussionmentioning

confidence: 99%

The Combined Effect of FGFR Inhibition and PD-1 Blockade Promotes Tumor-Intrinsic Induction of Antitumor Immunity

Palakurthi

Kuraguchi

Zacharek

et al. 2019

Cancer Immunology Research

110

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The success of targeted or immune therapies is often hampered by the emergence of resistance and/or clinical benefit in only a subset of patients. We hypothesized that combining targeted therapy with immune modulation would show enhanced antitumor responses. Here, we explored the combination potential of erdafitinib, a fibroblast growth factor receptor (FGFR) inhibitor under clinical development, with PD-1 blockade in an autochthonous FGFR2 K660N /p53 mut lung cancer mouse model. Erdafitinib monotherapy treatment resulted in substantial tumor control but no significant survival benefit. Although anti-PD-1 alone was ineffective, the erdafitinib and anti-PD-1 combination induced significant tumor regression and improved survival. For both erdafitinib monotherapy and combination treatments, tumor control was accompanied by tumor-intrinsic, FGFR pathway inhibition, increased T-cell infiltration, decreased regulatory T cells, and downregulation of PD-L1 expression on tumor cells. These effects were not observed in a KRAS G12C-mutant genetically engineered mouse model, which is insensitive to FGFR inhibition, indicating that the immune changes mediated by erdafitinib may be initiated as a consequence of tumor cell killing. A decreased fraction of tumorassociated macrophages also occurred but only in combination-treated tumors. Treatment with erdafitinib decreased T-cell receptor (TCR) clonality, reflecting a broadening of the TCR repertoire induced by tumor cell death, whereas combination with anti-PD-1 led to increased TCR clonality, suggesting a more focused antitumor T-cell response. Our results showed that the combination of erdafitinib and anti-PD-1 drives expansion of T-cell clones and immunologic changes in the tumor microenvironment to support enhanced antitumor immunity and survival.

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Section: Discussionmentioning

confidence: 99%

The Combined Effect of FGFR Inhibition and PD-1 Blockade Promotes Tumor-Intrinsic Induction of Antitumor Immunity

Palakurthi

Kuraguchi

Zacharek

et al. 2019

Cancer Immunology Research

110

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“…In other studies, expression of programmed death-ligand 1 (PD-L1) on DCs found at tumor sites indicates poor prognosis, as lung DCs with high PD-L1 expression can retain their immature status and thus limit the activation of immunity (23, 207, 208). Hence, drugs such as monoclonal antibodies that target PD-L1 on DCs or the receptor PD-1 on T cells may boost immune responses by removing the inhibitory mechanism of DCs on T cells (209). …”

Section: Lung Mnps In Respiratory Diseasesmentioning

confidence: 99%

Human Lung Mononuclear Phagocytes in Health and Disease

et al. 2017

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The lungs are vulnerable to attack by respiratory insults such as toxins, allergens, and pathogens, given their continuous exposure to the air we breathe. Our immune system has evolved to provide protection against an array of potential threats without causing collateral damage to the lung tissue. In order to swiftly detect invading pathogens, monocytes, macrophages, and dendritic cells (DCs)—together termed mononuclear phagocytes (MNPs)—line the respiratory tract with the key task of surveying the lung microenvironment in order to discriminate between harmless and harmful antigens and initiate immune responses when necessary. Each cell type excels at specific tasks: monocytes produce large amounts of cytokines, macrophages are highly phagocytic, whereas DCs excel at activating naïve T cells. Extensive studies in murine models have established a division of labor between the different populations of MNPs at steady state and during infection or inflammation. However, a translation of important findings in mice is only beginning to be explored in humans, given the challenge of working with rare cells in inaccessible human tissues. Important progress has been made in recent years on the phenotype and function of human lung MNPs. In addition to a substantial population of alveolar macrophages, three subsets of DCs have been identified in the human airways at steady state. More recently, monocyte-derived cells have also been described in healthy human lungs. Depending on the source of samples, such as lung tissue resections or bronchoalveolar lavage, the specific subsets of MNPs recovered may differ. This review provides an update on existing studies investigating human respiratory MNP populations during health and disease. Often, inflammatory MNPs are found to accumulate in the lungs of patients with pulmonary conditions. In respiratory infections or inflammatory diseases, this may contribute to disease severity, but in cancer patients this may improve clinical outcomes. By expanding on this knowledge, specific lung MNPs may be targeted or modulated in order to attain favorable responses that can improve preventive or treatment strategies against respiratory infections, lung cancer, or lung inflammatory diseases.

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“…In recent years, immune checkpoint inhibitors (ICIs) have played an important role in the therapy of non-small-cell lung cancer (NSCLC). The utility of ICIs (e.g., cytotoxic Tlymphocyte-associated antigen 4, programmed death-ligand 1, and programmed cell death protein 1 [PD-1]) for the treatment of NSCLC has been reported in many studies (1)(2)(3)(4). Specifically, the anti-PD-1 antibody nivolumab has demonstrated superiority to docetaxel for progression-free survival and overall survival in patients with advanced NSCLC.…”

mentioning

confidence: 99%

Predictive Factors of Nivolumab-induced Hypothyroidism in Patients with Non-small Cell Lung Cancer

2018

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Background/Aim: Although immune checkpoint inhibitors play an important role in the therapy of lung cancer, they are associated with various immune-related adverse events and predictive factors of them are unclear. In this study, we investigated predictive factors of nivolumab-induced hypothyroidism which is one of the adverse events in patients with lung cancer. Patients and Methods: Patients with nonsmall-cell lung cancer who were administered nivolumab at our hospital between December 2015 and May 2016 were retrospectively enrolled. The thyroid-stimulating hormone, free triiodothyronine, free thyroxine, thyroid peroxidase (TPO) antibody, and thyroglobulin antibody levels of each patient were analyzed. Results: Of the 64 patients enrolled, 5 (7.8%) developed hypothyroidism after treatment with nivolumab. The TPO and thyroglobulin antibodies were significantly positive in patients who developed primary hypothyroidism. Conclusion: TPO and thyroglobulin antibody levels at baseline may be predictive of hypothyroidism.

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Anti–PD-1/PD-L1 antibodies in non-small cell lung cancer: the era of immunotherapy

Cited by 35 publications

References 50 publications

The Combined Effect of FGFR Inhibition and PD-1 Blockade Promotes Tumor-Intrinsic Induction of Antitumor Immunity

The Combined Effect of FGFR Inhibition and PD-1 Blockade Promotes Tumor-Intrinsic Induction of Antitumor Immunity

Human Lung Mononuclear Phagocytes in Health and Disease

Predictive Factors of Nivolumab-induced Hypothyroidism in Patients with Non-small Cell Lung Cancer

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