Published OnlineFirst November 10, 2017; DOI: 10.1158/1078-0432.CCR-17-2267 Review Clinical Cancer Research Primary and Acquired Resistance to Immune Checkpoint Inhibitors in Metastatic Melanoma Tuba N. Gide1,2, James S. Wilmott1,2, Richard A. Scolyer1,2,3, and Georgina V. Long1,2,4,5 Abstract Immune checkpoint inhibitors have revolutionized the treat- involves various components of the cancer immune cycle, ment of patients with advanced-stage metastatic melanoma, as and interactions between multiple signaling molecules and well as patients with many other solid cancers, yielding long- pathways. Due to this complexity, current knowledge on resis- lasting responses and improved survival. However, a subset of tance mechanisms is still incomplete. Overcoming therapy patientswhoinitiallyrespondtoimmunotherapy,laterrelapse resistance requires a thorough understanding of the mechan- and develop therapy resistance (termed "acquired resistance"), isms underlying immune evasion by tumors. In this review, we whereas others do not respond at all (termed "primary resis- explore the mechanisms of primary and acquired resistance to tance"). Primary and acquired resistance are key clinical barriers immunotherapy in melanoma and detail potential therapeutic to further improving outcomes of patients with metastatic strategies to prevent and overcome them. Clin Cancer Res; 24(6); melanoma, and the known mechanisms underlying each 1260–70. Ó2017 AACR. Introduction Drugs targeting the programmed cell death receptor 1 (PD-1, PDCD1) showed a further increase in response rates, PFS (2), and Immune checkpoint inhibitors have revolutionized the treat- OS (14–16) compared with anti–CTLA-4 blockade. PD-1 is also ment of advanced melanoma (1–5) and have significant clinical expressed on the surface of activated T cells and binds to the activity across an increasing range of many other solid malignan- programmed cell death ligand 1 (PD-L1, CD274) to negatively cies, including non–small cell lung cancer (6, 7), renal cell regulate T-cell activation and differentiation. PD-L1 is constitu- carcinoma (8), head and neck cancer (9), Merkel cell carcinoma tively expressed by T cells, macrophages, and dendritic cells (DC), (10), and bladder cancer (11, 12). Understanding the biology as well as by some tumor cells including melanoma (17). Follow- behind response and resistance to immune checkpoint blockade up data from phase I clinical trials of the fully human IgG4 is critical to further improving outcomes of patients with meta- monoclonal antibody, nivolumab, showed a median OS of static melanoma. 17.3 months, with a 5 year OS rate of 34% (18). In a phase III The first immune checkpoint to be clinically targeted, the study of nivolumab versus dacarbazine in patients with BRAF cytotoxic T-lymphocyte antigen 4 (CTLA-4), is expressed on the wild-type metastatic melanoma, the median OS was not reached surface of activated T cells and binds to its ligands, B7-1 and B7-2, for nivolumab at the most recent analysis, versus 11.2 months for on antigen-presenting cells (APC), resulting in the transmission of dacarbazine [hazard ratio (HR), 0.43, P < 0.001], and the 1- and inhibitory signals to T cells. In patients with metastatic melano- 2-year OS rates were 73% and 58%, respectively, for nivolumab ma, phase III clinical trials of ipilimumab, a fully human IgG1 (1, 14). Pembrolizumab, a humanized IgG4 monoclonal anti- monoclonal antibody inhibiting CTLA-4, demonstrated a signif- body against PD-1, also showed 1-, 2-, and 3-year OS rates icant improvement in progression-free survival (PFS) and overall of 67%, 50%, and 40%, respectively, in a phase I trial of survival (OS) when compared with a gp100 vaccine (13) or ipilimumab-treated and ipilimumab-na€ve patients with dacarbazine chemotherapy (4). advanced melanoma (3). Furthermore, in a phase III trial of pembrolizumab versus ipilimumab, the 2-year OS rates were 55% versus 43%, respectively (5, 15). More recently, combined anti–CTLA-4 and anti–PD-1 immu- 1Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia. notherapies have shown improved response rates and clinical 2Sydney Medical School, The University of Sydney, Sydney, NSW, Australia. outcomes in comparison to ipilimumab monotherapy (the study 3 4 Royal Prince Alfred Hospital, Sydney, NSW, Australia. Royal North Shore was not powered to compare the two nivolumab treating arms: 5 Hospital, Sydney, NSW, Australia. Mater Hospital, North Sydney, NSW, nivolumab plus ipilimumab and nivolumab alone). A phase III Australia. study showed an increase in the median PFS of patients treated Note: Supplementary data for this article are available at Clinical Cancer with nivolumab and ipilimumab (11.5 months; HR, 0.42, P < Research Online (http://clincancerres.aacrjournals.org/). 0.001) and nivolumab alone (6.9 months; HR, 0.57, P < 0.001) Corresponding Author: Georgina V. Long, Melanoma Institute Australia, The compared with ipilimumab alone (2.9 months; ref. 2). At a Poche Centre, 40 Rocklands Road, North Sydney, NSW, 2060, Australia. Phone: minimum follow-up of 28 months, the median OS had not been 612-9911-7336; Fax: 612-9954-9290; E-mail: [email protected] reached in the combination or nivolumab-alone groups and doi: 10.1158/1078-0432.CCR-17-2267 was 20 months for ipilimumab alone [HR: combination vs. Ó2017 American Association for Cancer Research. ipilimumab, 0.55 (P < 0.0001); nivolumab vs. ipilimumab, 1260 Clin Cancer Res; 24(6) March 15, 2018 Downloaded from clincancerres.aacrjournals.org on September 29, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst November 10, 2017; DOI: 10.1158/1078-0432.CCR-17-2267 Resistance to Immunotherapy in Melanoma Primary resistance Primary resistance • Poor immunogenicity • Downregulation of • Impaired DC chemokines maturation • Upregulation of Figure 1. Acquired resistance Antigen T-cell endothelin B receptor The cancer immune cycle. The • Loss of B2M presentation trafficking • Overexpression of VEGF induction of an effective antitumor and T-cell and tumor immune response requires activation infiltration successful (i) antigen presentation Therapeutic strategies Therapeutic strategies and T-cell activation, (ii) T-cell • Radiotherapy • Oncolytic viruses trafficking and tumor infiltration, • Oncolytic viruses • HDAC inhibitors and (iii) T-cell killing activity within • CTLA-4 inhibitors the tumor microenvironment. • HDAC inhibitors T-cell killing activity Various immune escape within the tumor mechanisms present at each of microenvironment these stages can result in primary or acquired resistance to immunotherapy. Potential therapeutic strategies can be used at each stage to overcome Primary resistance immunotherapy resistance. • Upregulation of PD-L1 A2AR, A2A receptor; B2M, • Induction of IDO beta-2-microglobulin; HDAC, • Upregulation of Tregs histone deacetylase; JAK1/JAK2, • Upregulation of Therapeutic strategies janus kinases 1 and 2; IDO, CD73/adenosine • PD-1/PD-L1 inhibitors indoleamine 2,3-dioxygenase; • Expression of IPRES • IDO inhibitors – IPRES, innate anti PD-1 resistance • Loss-of-function mutations • LAG-3 inhibitors signature; LAG-3, lymphocyte • TIM-3 inhibitors activation gene 3; TIM-3, T-cell Acquired resistance • CD73/A2AR inhibitors immunoglobulin and mucin domain • Mutations in JAK1/JAK2 3; Tregs, regulatory T cells; VEGF, • Upregulation of PD-L1 vascular endothelial growth factor. • Upregulation of immune checkpoint markers © 2017 American Association for Cancer Research 0.63 (P < 0.0001); ref. 16]. The two-year OS rates were 64%, 59%, tumors evade the immune system, and strategies to overcome or and 45% in the combination, nivolumab, and ipilimumab prevent resistance in the future. groups, respectively (16). The results of these clinical trials highlight the significant impact immunotherapies have had on the clinical management Primary Resistance of patients with advanced-stage metastatic melanoma. However, Primary resistance to immune checkpoint blockade occurs although approximately 35% to 60% of patients have a RECIST in approximately 40% to 65% of patients with melanoma treated response (10%–12% a complete response) to anti–PD-1-based with anti–PD-1 based therapy (Fig. 2), depending on whether immunotherapy (2, 14, 15), 40% to 65% have shown minimal or anti–PD-1 is given upfront or after progression on other therapies no RECIST response at the outset, and 43% of responders develop (2, 14, 15), and >70% of those treated with anti–CTLA-4 therapy acquired resistance by 3 years (3). The underlying mechanisms (4, 13). This key unsolved clinical problem occurs when there is driving these variations in response are not yet well understood. failure to induce an effective antitumor immune response at any For an immunotherapy to elicit an efficient antitumor immune of the three stages of the cancer immune cycle (Fig. 1). To date, the response, the cancer immune cycle must be initiated and the clinicopathologic factors that have been associated with primary subsequent steps successfully completed. This involves efficient resistance are elevated levels of baseline serum LDH (23), (i) antigen presentation and T-cell activation, (ii) T-cell trafficking increased baseline tumor burden (24), lack of PD-L1 expression and tumor infiltration, and (iii) T-cell killing activity within the in baseline melanoma tissue samples (Fig. 3; ref. 25), lack of T-cell tumor microenvironment (Fig. 1). Studies examining possible infiltration (Fig. 3; ref. 21), the absence of PD-1 T cells