Reviews and feature article
Immune checkpoint blockade therapy

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Immune checkpoints are accessory molecules that either promote or inhibit T-cell activation. Two inhibitory molecules, cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1), got high attention, as inhibition of CTLA-4 or PD-1 signaling provides the first immune therapy that significantly improves the survival of patients with metastatic solid cancers. Inhibition of CTLA-4 or PD-1 was first studied in and approved for patients with metastatic melanoma. Blocking immune checkpoints is also efficient in non–small-cell lung cancer, renal cell cancers, hypermutated gastrointestinal cancers, and others. Immune responses, whether directed against infections or against tumors, are divided into 2 phases: an initiation phase and an activation phase, where the immune system recognizes a danger signal and becomes activated by innate signals to fight the danger. This reaction is fundamental for the control of infections and cancer, but needs to be turned off once the danger is controlled, because persistence of this activation ultimately causes severe tissue damage. Therefore, each activation of the immune system is followed by a termination phase, where endogenous immune suppressor molecules arrest immune responses to prevent harmful damage. In the case of cancer immune therapies, therapeutic approaches classically enhanced the initiation and activation of immune responses to increase the emergence and the efficacy of cytotoxic T lymphocytes (CTL) against cancers. In sharp contrast, immune checkpoint blockade focuses on the termination of immune responses by inhibiting immune suppressor molecules. It thus prevents the termination of immune responses or even awakes those CTLs that became exhausted during an immune response. Therefore, blocking negatively regulating immune checkpoints restores the capacity of exhausted CTL to kill the cancer they infiltrate. In addition, they drive surviving cancer cells into a still poorly defined state of dormancy. As the therapy also awakes self-reactive CTL, one downside of the therapy is the induction of organ-specific autoimmune diseases. The second downside is the exorbitant drug price that withdraws patients in need from a therapy that was developed by academic research, which impairs further academic treatment development and financially charges the public health system.

Section snippets

T-cell exhaustion in the tumor microenvironment

Mouse PD-1 has originally been described in 1992 as a novel member of the immunoglobulin gene superfamily that is selectively expressed on thymoma cells after apoptosis induction.29 It took about a decade to decipher the physiological role and the signaling pathways of this immunoinhibitory receptor. The first reports that PD-1 may play a crucial role in maintaining self-tolerance came from the description of PD-1 knockout mice: depending on their genetic background, these mice developed

Cancer killing and induction of cancer dormancy by reactivation of exhausted tumor-specific T cells

The concept of reactivation of exhausted, tumor-specific T cells by ICB was extensively tested in clinical trials. The treatment was especially efficient in patients with metastatic melanoma,39, 40, 48, 49 but clinical efficacy has also been shown in a series of other advanced cancers, for example, advanced non–small-cell lung cancer (NSCLC),50 Merkel cell carcinoma,51 metastatic urothelial cancer,52 or colon cancers.53 The analysis of cancer lesions and tumor markers after initiation of ICB

Ambiguous role of IFN signaling during ICB therapy

Acute antitumor immunity can arrest tumor growth by inducing tumor dormancy. In a multistage carcinogenesis model, it has been demonstrated that TH1 stop tumor development by an IFN-γ– and tumor necrosis factor (TNF) R1–dependent mechanism.85 More detailed analyses revealed that the TH1 cytokines IFN-γ and TNF drive tumor cells into permanent growth arrest, that is, cellular senescence.82, 83, 84, 86 Cellular senescence is an endogenous stress response mechanism that directly copes with the

Clinical application of ICB

A decade ago, advanced melanoma was a tumor largely resistant to all available therapeutic approaches.92 Despite worldwide efforts, especially the immunotherapeutic studies published until 2011 were restricted to highly selected patient cohorts or included only small numbers of patients with melanoma. However, in 2011, a report of a phase III trial suggested that HLA-A020.1–positive patients with melanoma treated with high-dose IL-2 combined with a gp100 peptide vaccine and incomplete Freund's

Immune checkpoint inhibitor-induced autoimmune diseases

PD-1 (also CD 279) was initially recognized as a receptor inducing a downregulation of the immune system and thus preventing autoimmune diseases. Thus, PD-1 promotes self-tolerance by suppressing T-cell–driven tissue destruction.30, 31 As immune checkpoint inhibitors antagonize exactly this brake, treatment regimens with PD-1 or CTLA-4 antagonists may initiate the development of mainly T-cell–mediated organ-specific autoimmune diseases.102, 103, 104, 105, 106 In principle, both CTLA-4 and PD-1

Summary

ICB is a novel treatment option for metastatic melanoma, which prolongs the lifespan of patients with metastatic melanoma and many different types of carcinomas. Interestingly, this very successful drug regimen seems to be based on 2 different biological mechanisms, that is, a cytotoxic immune response through reactivation of exhausted CD8-positive T cells and the induction of cytokine-mediated tumor dormancy. Besides the active role of immune cells, for example, T cells, ICB therapy needs a

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    The work of the authors is supported by the Wilhelm Sander Stiftung (grant no. 2012.056.3), the Deutsche Krebshilfe (grant no. 110664), and the Deutsche Forschungsgemeinschaft (grant nos. DFG Ro764/14-1, Ro764/15-1, WI 1279/4-1, and SFB-TR 156).

    Disclosure of potential conflict of interest: T. Eigentler received consultancy fees from Bristol-Myers Squibb, Merck-Serono, and Roche and payment for lectures from MSD and Novartis. M. Röcken received a grant from Deutsche Forschungsgemeinschaft (grant no. SFB TRR 156/1 TP B06) and Deutsche Forschungsgemeinschaft (grant no. RO 764/15-1 AOBJ) for this work and from Deutsche Forschungsgemeinschaft for other works; consultancy fees from both Almirall Hermal and Biogen Idec for other works, and Regeneron; is employed with Government Baden-Württemberg; has stock options from Bristol-Myers Squibb and Merck; received travel expenses from Deutsche Dermatologische Gesellschaft e. V., the European Academy of Dermatology and Venereology, and diverse universities and public funding organizations (eg, Deutsche Krebshilfe e. V.); and holds patent DE 10 2012 024 749.4. The rest of the authors declare that they have no relevant conflicts of interest.

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