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LAG3 (CD223) As a Cancer Immunotherapy Target

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LAG3 (CD223) As a Cancer Immunotherapy Target DOI: 10.1111/imr.12519 INVITED REVIEW LAG3 (CD223) as a cancer immunotherapy target Lawrence P. Andrews1 | Ariel E. Marciscano2 | Charles G. Drake3 | Dario A. A. Vignali1,4 1Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Summary PA, USA Despite the impressive impact of CTLA4 and PD1- PDL1- targeted cancer immuno- 2 Department of Radiation Oncology & therapy, a large proportion of patients with many tumor types fail to respond. Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, The Johns Consequently, the focus has shifted to targeting alternative inhibitory receptors (IRs) Hopkins School of Medicine, Baltimore, MD, and suppressive mechanisms within the tumor microenvironment. Lymphocyte activa- USA tion gene- 3 (LAG3) (CD223) is the third IR to be targeted in the clinic, consequently 3Departments of Oncology, Immunology and Urology, Sidney Kimmel Comprehensive garnering considerable interest and scrutiny. LAG3 upregulation is required to control Cancer Center, The Johns Hopkins School of overt activation and prevent the onset of autoimmunity. However, persistent antigen Medicine, Baltimore, MD, USA 4Tumor Microenvironment Center, University exposure in the tumor microenvironment results in sustained LAG3 expression, con- of Pittsburgh Cancer Institute, Pittsburgh, PA, tributing to a state of exhaustion manifest in impaired proliferation and cytokine pro- USA duction. The exact signaling mechanisms downstream of LAG3 and interplay with Correspondence other IRs remain largely unknown. However, the striking synergy between LAG3 and Dario A. A. Vignali, Department of Immunology, University of Pittsburgh School PD1 observed in multiple settings, coupled with the contrasting intracellular cytoplas- of Medicine, Pittsburgh, PA, USA. mic domain of LAG3 as compared with other IRs, highlights the potential uniqueness Email: [email protected] Charles G. Drake, Herbert Irving of LAG3. There are now four LAG3- targeted therapies in the clinic with many more in Comprehensive Cancer Center, Columbia preclinical development, emphasizing the broad interest in this IR. Given the transla- University Medical Center, New York, NY, USA. Email: [email protected] tional relevance of LAG3 and the heightened interest in the impact of dual LAG3/PD1 targeting in the clinic, the outcome of these trials could serve as a nexus; significantly Funding information National Institutes of Health, Grant/Award increasing or dampening enthusiasm for subsequent targets in the cancer immuno- Number: P01 AI108545, P50 CA097190 therapeutic pipeline. and R01 CA154555; NCI Comprehensive Cancer Center Support CORE, Grant/Award KEYWORDS Number: P30 CA047904 and P30 CA006973; Melanoma Research Association. cancer immunotherapy, CD223, immune regulation, inhibitory receptors, LAG3, monoclonal antibodies, regulatory T cells Present address: Charles G. Drake, Division of Hematology and Oncology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA 1 | INTRODUCTION elicited by CD4+ and CD8+ T cells. First described in a chronic viral setting, tolerized antigen- specific T cells display elevated expres- Upregulated expression of inhibitory receptors (IRs) is essential to sion of IRs within the tumor microenvironment, corresponding to balance co- stimulatory receptor activity and limit T- cell activation, functional unresponsiveness as measured by reduced proliferation thereby preventing autoimmunity, autoinflammation, and tissue dam- and cytokine release.1,2 Along with recruitment of regulatory T cells age. However, tumors can hijack these so- called immune checkpoint (Tregs), the resulting immune tolerance creates multiple barriers for ef- mechanisms as protection against anti- tumor immune responses fective tumor elimination.3,4 Thus, recent cancer immunotherapeutic approaches have aimed to reverse such exhaustion by targeting IRs ‘to release the brakes’ allowing re- invigoration of cytotoxic T cells to This article is part of a series of reviews covering Checkpoint Inhibitors and Cancer Immunotherapy appearing in Volume 276 of Immunological Reviews. attack tumors. 80 | © 2017 John Wiley & Sons A/S. wileyonlinelibrary.com/journal/imr Immunological Reviews 2017; 276: 80–96 Published by John Wiley & Sons Ltd ANDREWS ET AL. | 81 Early success targeting CTLA4 and PD1 resulted in impressive tumor targeted in the clinic in 2006 using a LAG3- Ig fusion protein (IMP321). remission in patients with several tumor subtypes, which led to can- Phase I clinical trials were initiated with anti- LAG3 (BMS- 986016) in cer immunotherapy being highlighted as a significant breakthrough by 2013, making it the third IR to be targeted in the clinic with an antag- the leading scientific journals in 2013.5,6 Although Ipilimumab (Bristol- onistic mAb. There are now several LAG3- modulating immunothera- Myers Squibb, New York, NY, humanized anti- CTLA4 IgG1 monoclonal peutics at various stages of clinical and preclinical development. As a antibody [mAb]), Pembrolizumab (Merck, Kenilworth, NJ, humanized result of the increased interest in LAG3 as a therapeutic target, there anti- PD1 IgG4 mAb), and Nivolumab (Bristol- Myers Squibb, humanized is considerable interest in gaining a greater understanding of the biol- anti- PD1 IgG4 mAb) can yield objective responses in a significant pro- ogy and mechanism of action of LAG3. In this review, we will provide portion of patients with a broad spectrum of tumor types, the majority an in- depth description of the functional role of LAG3, and highlight of patients do not respond.7,8 For example, only 28% of patients with its expression pattern, interacting ligands, and regulation. The transla- advanced melanoma and 21% of patients with renal cell carcinoma tional rationale for targeting LAG3, deriving from exciting preclinical (RCC) receiving Nivolumab demonstrated objective responses.8 While data in a number of murine models, will be discussed followed by a some tumor subtypes previously thought to be difficult to treat, such complete analysis of the historical and current state of clinical trials as non- small cell lung cancer (NSCLC), are responsive to PD1 block- utilizing LAG3 immunomodulators. While a thorough understanding ade, other less immunologically inflamed tumors, such as pancreatic of LAG3 biology is important for the optimal design and interpretation and prostate cancers, remain relatively resistant.9 Thus, identification of clinical trials, there are still many questions that remain regarding of additional IR targets, and a clear mechanistic understanding of their the biology and function of LAG3, along with the mechanistic interplay function, is essential to increase the activity of combinatorial cancer im- with other IRs, which will be highlighted in this review. munotherapeutic approaches. With the U.S. FDA approval of multiple therapeutics that target the PD1/PDL1 pathways, attention has turned to other IRs such as lympho- 2 | LAG3 DISCOVERY AND STRUCTURE cyte activation gene- 3 (LAG3), TIGIT, and TIM3.10–12 Moreover, clinical trials are ongoing to determine the optimal combination of immuno- LAG3 was discovered by Triebel and colleagues in 1990 as a novel therapeutics; not only combining antagonistic mAbs against different 498- amino acid type I transmembrane protein identified on activated IRs but also with other front- line modalities including chemotherapy, human NK and T- cell lines.14 The LAG3 gene is located adjacent to CD4 radiation therapy, and/or cancer vaccines. As a result, the number of on chromosome 12 in human (chromosome 6 in mouse). Furthermore, possible immunotherapy regimens has grown exponentially, giving rise LAG3 was predicted to be highly structurally homologous to CD4 with to the rationale that synergistic combinations should yield significant four extracellular immunoglobulin superfamily- like domains (D1- D4) clinical improvement compared with current monotherapies.13 (Figure 1). LAG3 and CD4 also exhibit rigidity between the D1 and D2 LAG3 (CD223) is a potential cancer immunotherapeutic target due domains and between the D3 and D4 domains due to a long, continu- to its negative regulatory role on T cells and its capacity, in combi- ous β- strand that extends between these domains, but with relative nation with PD1, to mediate a state of exhaustion.10 LAG3 was first flexibility between the D1- D2 and D3- D4 substructures.15,16 CD4 SS SS CP SS D3 D4 SS D2 D1 ε Antigen CD3 γ Presenting ζ FIGURE 1 Ligand interaction and cell α α MHC class II β TCR signal structural similarities between LAG3 and β ζ CD4. LAG3, like CD4, consists of four δ Melanoma CD3 extracellular immunoglobulin superfamily- ε cell Extra D1 30AA SS D2 loop ? like domains (D1- D4). LAG3 utilizes an D3 D4 LAG3 SS KIEELE additional 30 amino acid loop in D1 to SS SS CP bind to MHC class II with greater affinity. ? Ligation of MHC class II, expressed by LSECtin Glycosylation Site antigen- presenting cells or aberrantly ? by melanoma cells, with LAG3 mediates Galectin-3 an intrinsic negative inhibitory signal, in which the KIEELE motif in the cytoplasmic T cell domain is indispensable. LAG3 is highly glycosylated with two additional ligands Melanoma postulated, LSECtin, expressed on cell melanoma cells, and galectin- 3, expressed on stromal cells and CD8+ T cells in the tumor microenvironment 82 | ANDREWS ET AL. Although these two genes are evolutionarily similar with adjacent as (SHP)- 1/2 that are used by PD1 to limit TCR signaling.21 Mutation
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