Combining Immune Checkpoint Inhibitors: Established and Emerging Targets and Strategies to Improve Outcomes in Melanoma

REVIEW published: 19 March 2019 doi: 10.3389/fimmu.2019.00453 Combining Immune Checkpoint Inhibitors: Established and Emerging Targets and Strategies to Improve Outcomes in Melanoma Edited by: Christian Ostheimer, Martin Luther University of Halle-Wittenberg, Germany Reviewed by: Nicole Joller, University of Zurich, Switzerland Daniel Olive, Aix Marseille Université, France *Correspondence: Sophia N. Karagiannis Specialty section: This article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Immunology Received: 30 August 2018 Accepted: 20 February 2019 Published: 19 March 2019 Citation: Khair DO, Bax HJ, Mele S, Crescioli S, Pellizzari G, Khiabany A, Nakamura M, Harris RJ, French E, Hoffmann RM, Williams IP, Cheung A, Thair B, Beales CT, Touizer E, Signell AW, Tasnova NL, Spicer JF, Josephs DH, Geh JL, MacKenzie Ross A, Healy C, Papa S, Lacy KE and Karagiannis SN (2019) Combining Immune Checkpoint Inhibitors: Established and Emerging Targets and Strategies to Improve Outcomes in Melanoma. Front. Immunol. 10:453. doi: 10.3389/fimmu.2019.00453 Duaa O. Khair 1 , Heather J. Bax 1,2 , Silvia Mele 1 , Silvia Crescioli 1 , Giulia Pellizzari 1 , Atousa Khiabany 1 , Mano Nakamura 1 , Robert J. Harris, Elise French 1 , Ricarda M. Hoffmann 1,2 , Iwan P. Williams 1 , Anthony Cheung 1,3 , Benjamin Thair 1 , Charlie T. Beales 1 , Emma Touizer 1 , Adrian W. Signell 1 , Nahrin L. Tasnova 1 , James F. Spicer 2 , Debra H. Josephs 1,2 , Jenny L. Geh 4 , Alastair MacKenzie Ross 4 , Ciaran Healy 4 , Sophie Papa 2 , Katie E. Lacy 1 and Sophia N. Karagiannis 1* 1 St. John’s Institute of Dermatology, School of Basic & Medical Biosciences, Guy’s Hospital, King’s College London, London, United Kingdom, 2 School of Cancer & Pharmaceutical Sciences, Guy’s Hospital, King’s College London, London, United Kingdom, 3 Breast Cancer Now Research Unit, School of Cancer & Pharmaceutical Sciences, Guy’s Cancer Centre, King’s College London, London, United Kingdom, 4 Department of Plastic Surgery at Guy’s, King’s, and St. Thomas’ Hospitals, London, United Kingdom The immune system employs several checkpoint pathways to regulate responses, maintain homeostasis and prevent self-reactivity and autoimmunity. Tumor cells can hijack these protective mechanisms to enable immune escape, cancer survival and proliferation. Blocking antibodies, designed to interfere with checkpoint molecules CTLA-4 and PD-1/PD-L1 and counteract these immune suppressive mechanisms, have shown significant success in promoting immune responses against cancer and can result in tumor regression in many patients. While inhibitors to CTLA-4 and the PD-1/PD-L1 axis are well-established for the clinical management of melanoma, many patients do not respond or develop resistance to these interventions. Concerted efforts have focused on combinations of approved therapies aiming to further augment positive outcomes and survival. While CTLA-4 and PD-1 are the most-extensively researched targets, results from pre-clinical studies and clinical trials indicate that novel agents, specific for checkpoints such as A2AR, LAG-3, IDO and others, may further contribute to the improvement of patient outcomes, most likely in combinations with anti-CTLA-4 or anti-PD-1 blockade. This review discusses the rationale for, and results to date of, the development of inhibitory immune checkpoint blockade combination therapies in melanoma. The clinical potential of new pipeline therapeutics, and possible future therapy design and directions that hold promise to significantly improve clinical prognosis compared with monotherapy, are discussed. Keywords: checkpoint inhibitors, combination immunotherapy, immunooncology therapeutics, melanoma, CTLA4, PD-1, PD-L1, antibody engineering Frontiers in Immunology | www.frontiersin.org 1 March 2019 | Volume 10 | Article 453 Khair et al. Checkpoint Inhibitor Combination Strategies for Melanoma INTRODUCTION shown promise in pre-clinical and clinical studies, either alone or combined with established agents. Focusing on malignant melanoma as the tumor type for which the first pivotal immunotherapy breakthroughs were demonstrated, in this review, we discuss current and future checkpoint blockade and other immunooncology combination therapies, and the rationale for potential synergistic effects (Table 2). Immune-mediated destruction of tumors has long been considered a potential route of therapeutic intervention. Partial spontaneous regression of melanoma lesions has previously been associated with the presence of endogenous tumor infiltrating lymphocytes (TILs) and the presence of TILs in patient samples has been shown to correlate with improved clinical outcomes and better prognosis (1). Infusion with CD8+ TILs has been reported to induce some responses in patients when combined with other treatments including IL-2 (2). Immunotherapy via cytokine infusion has also been extensively trialed, with IL-2, IL-12, and IFNα2b to activate T cells, showing anti-tumor effects in pre-clinical models and clinical trials, with IL-2 and IFNα2b approved for clinical use (3, 4). Cytokine treatments have however been associated with severe adverse effects resembling severe systemic infections and sometimes resulting in toxic shock or capillary leak syndrome as reported in randomized clinical trials (5, 6). Though not without challenges, these trials confirmed the possibility of reigniting components of the immune system as a cancer therapy. Increased understanding of tumor evolution and the complex interactions in the tumor microenvironment (TME) has revealed numerous mechanisms by which tumors may escape immune destruction and actively suppress immune activity (7). Immunosuppression by tumor cells may partially be mediated through FoxP3+ regulatory T cell (T-reg) recruitment via tumorsecreted chemokines as shown in an ex vivo study (8, 9). Critically, tumor resident T-reg can highly express cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), an important checkpoint that acts as a negative regulator of effector T cell (T-eff) activity in vivo, studied in different models including CTLA-4-deficient mice (10) (Figure 1). Suppression may also be mediated by tumor expression of the Programmed-death ligand 1 (PD-L1; B7-H1; CD274), known to trigger T cell apoptosis in vivo in mouse tumors (11) and to promote formation of FoxP3+ T-regs upon interaction with the T cell-associated checkpoint receptor Programmed-death 1 (PD-1, also known as CD279) (12) (Figure 1). These checkpoints, have become therapeutic targets in immune checkpoint blockade therapy, with the aim of overcoming TME-mediated immunosuppression and restoring anti-tumor immune activity (13). Monoclonal antibodies targeting CTLA-4 and PD-1 have now been approved for the treatment of melanoma. These new therapeutic modalities were developed in parallel with targeted MAPK pathway inhibitor therapies, such as vemurafenib and dabrafenib, app (...truncated)