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Cancer Immunology Research
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Cancer Immunology at the Crossroads: Thoracic Oncology

Immune Checkpoint Inhibitors: Making Immunotherapy a Reality for the Treatment of Lung Cancer

Julie R. Brahmer and Drew M. Pardoll
Julie R. Brahmer
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland
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Drew M. Pardoll
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland
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DOI: 10.1158/2326-6066.CIR-13-0078 Published August 2013
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    Figure 1.

    Distinct roles of CTLA-4 and PD-1 in the regulation of antitumor T-cell responses. CD28 is the master costimulatory receptor expressed on T cells and enhances T-cell activation upon antigen recognition when the antigen presenting cell (APC) expresses its ligands, B7-1 and B7-2. Tumor or tumor vaccine is the source of tumor antigens that must be processed and presented by the MHC complex to activate T cells. CTLA-4 is rapidly expressed on T cells once antigen is recognized, and it binds the same ligands (B7.1/2) as CD28 but at higher affinity, thereby counterbalancing the costimulatory effects of CD28 on T-cell activation. Tumor-specific T-cell activation leads to proliferations and effector function, but also the upregulation of PD-1. After trafficking to the tumor microenvironment, PD-1+ T cells might encounter PD-1 ligands, which can inhibit them from mediating their killing function. Thus, the CTLA-4 and PD-1 pathways provide complementary mechanisms to regulate antitumor effector T cells, and blocking each one may prove to be synergistic.

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    Figure 2.

    Potential mechanisms of therapeutic synergy between epigenetic modulation and PD-1 pathway blockade. Epigenetic modulation, originally tested in lung cancer based on its capacity to induce expression of epigenetically silenced tumor suppressor genes, also has significant immunologic activity. Treatment of lung cancer cells with the DNA-demethylating agent 5-azacytidine (AZA) can induce the type I IFN pathway as well as multiple components of antigen presentation, thereby enhancing intratumoral inflammatory responses. However, PD-L1 is also induced on tumor cells, which could blunt immunity. Concomitant blockade of the PD-1 pathway would shift the balance such that the immune-enhancing effects of epigenetic modulation would dominate. DNA demethylation also induces expression of cancer–testes (C-T) antigens, which are known targets for tumor-specific T cells. Finally, epigenetic modulation can activate silenced effector cytokine genes in anergized T cells and induce PD-1 expression. Again, concomitant PD-1 pathway blockade would favor the immune-enhancing effects of epigenetic modulators on T cells. These potential mechanisms of synergy may account for recent preliminary clinical observations in 5 patients with NSCLC treated with either anti-PD-1 or anti-PD-L1 antibodies after receiving a combination of 5-azacytodine and entinostat (a class 1-specific HDACi); durable objective responses were observed in 3 patients and stable disease for more than 6months in the other two patients. This combination approach is a potential example of leveraging the immunologic effects of “nonimmunologic” therapies.

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Cancer Immunology Research: 1 (2)
August 2013
Volume 1, Issue 2
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Immune Checkpoint Inhibitors: Making Immunotherapy a Reality for the Treatment of Lung Cancer
Julie R. Brahmer and Drew M. Pardoll
Cancer Immunol Res August 1 2013 (1) (2) 85-91; DOI: 10.1158/2326-6066.CIR-13-0078

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Immune Checkpoint Inhibitors: Making Immunotherapy a Reality for the Treatment of Lung Cancer
Julie R. Brahmer and Drew M. Pardoll
Cancer Immunol Res August 1 2013 (1) (2) 85-91; DOI: 10.1158/2326-6066.CIR-13-0078
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  • Article
    • Abstract
    • Introduction
    • Immune Resistance Mechanisms in Lung Cancer
    • CTLA-4 Inhibitors in Lung Cancer
    • Anti-PD-1 Inhibitors
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    • The Future: Beyond Single-Agent Immunotherapy
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Cancer Immunology Research
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