The use of immunotherapy in the treatment of melanoma

Achkar and Tarhini Journal of Hematology & Oncology (2017) 10:88 DOI 10.1186/s13045-017-0458-3 REVIEW Open Access The use of immunotherapy in the treatment of melanoma Tala Achkar1,2 and Ahmad A. Tarhini1,2* Abstract Patients with advanced melanoma have a compromised anti-tumor immune response leading to tumor immune tolerance and a tumor microenvironment conducive to disease progression. Immunotherapy that successfully overcomes this tumor-mediated immune suppression has made the greatest impact in the management of this disease over the past few years. This progress through immunotherapy builds upon earlier successes that interferon-α had in the treatment of melanoma in the adjuvant setting, as well as that of high-dose interleukin-2 in advanced melanoma. The development of immune checkpoint inhibitors has led to dramatic clinical activity in advanced melanoma. In particular, anti-CTLA4 and anti-PD1 monoclonal antibodies have taken us forward into the realm of longer survival and durable responses with the possibility of cure in a continuously increasing proportion of patients. Combination immunotherapeutic strategies and novel immunotherapeutic agents are being tested at an accelerated pace where the outlook for long-term survival benefits for the majority of patients appears brighter than ever. Keywords: Melanoma, Immunotherapy, Anti-CTLA4, Anti-PD1 Background The incidence of melanoma has been increasing such that it is now the fifth and seventh most common cancer among men and women, respectively, in the USA [1]. Specifically in the USA, the Surveillance, Epidemiology and End Results (SEER) data shows that among Caucasians, there has been a 60% increase in incidence over the last 30 years [2]. For many years, there has continued to be a high rate of death from metastatic melanoma with an estimated 10,130 deaths from melanoma in 2016 [3]. There has been a recent change in our ability to control and treat metastatic melanoma as a result of our better understanding of immunology and development of immunotherapy [4, 5]. In this review, we aim to discuss the development and application of immunotherapy in the clinical practice of advanced melanoma treatment. Adjuvant therapy for high-risk resected melanoma Interferon-alfa (IFNα) exerts its effects via different mechanisms including immunoregulatory, anti-angiogenic, * Correspondence: 1 University of Pittsburgh, Pittsburgh, PA, USA 2 University of Pittsburgh Cancer Institute, 5150 Centre Avenue, Room 555, Pittsburgh, PA 15232, USA differentiation-inducing, anti-proliferative, and pro-apoptotic [6]. It also acts to promote tumor immunogenicity by enhancing dendritic cell (DC) response to the tumor, as well as DC maturation and antigen presentation that contribute to anti-tumor immunity [6–8]. This shift in host immunity occurs by shifting from a Th2 predominant response to a Th1 response, thereby leading to amplification of cellmediated cytotoxicity and increased Th1 lymphocytes in the tumor environment [9–16]. High-dose IFNα High-dose IFNα (HDI) is the standard of care in the adjuvant setting for the treatment of resected stage IIB/III melanoma. In randomized controlled trials evaluating various doses of IFNα in the adjuvant treatment of highrisk melanoma (stages IIB, III, or IV), a durable impact on both relapse-free survival (RFS) and overall survival (OS) was only seen with the regimen utilizing HDI as tested in Eastern Cooperative Oncology Group (ECOG) and US Intergroup trials E1684 (n = 287; significant RFS and OS benefit vs. observation), E1690 (n = 642; only RFS benefit seen vs. observation), and E1694 (n = 880; significant RFS and OS benefit vs. vaccine) [17–19]. These studies used a HDI regimen that was administered first as a 4-week induction phase, with IFNα given © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Achkar and Tarhini Journal of Hematology & Oncology (2017) 10:88 at a dose of 20 million IU/m2/day intravenously for five consecutive days every week. This induction phase was followed by a maintenance phase of subcutaneous IFNα at a dose of 10 million IU/m2/day every other day three times each week for an additional 48 weeks. All three phase III trials (E1684, E1690, and E1694) showed significant improvement in RFS; however, there was a significant improvement in OS only in E1684 and E1694. E1684 reported a median OS of 3.82 vs. 2.78 years (P = 0.0237) in the HDI group compared with observation, at a median follow-up of 6.9 years. There were also significant improvements in RFS with a median RFS of 1.72 years vs. 0.98 years in the HDI group compared with observation (P = 0.0023) [17]. This trial led to the FDA approval of HDI in 1995. In E1694, HDI was compared with a ganglioside vaccine (GMK; ganglioside conjugate vaccine coupled to keyhole limpet hemocyanin with QS-21 as adjuvant) and demonstrated significant RFS benefit (HR 1.47; P = 0.0015) as well as OS benefit (HR 1.52; P = 0.009) in the HDI arm compared with the GMK vaccine at a median follow-up of 16 months [19]. In E1690, the HDI regimen described above was used, in addition to a low-dose regimen of IFNα (LDI; dose of 3 million units SC 3×/week for 2 years). These were compared to observation. In the HDI arm, the 5-year estimated RFS rate was 44% (P = 0.03), and this was the only arm to reach statistical significance for RFS [18]. Neither HDI nor LDI demonstrated an OS benefit compared to observation (52% HDI arm vs. 53% LDI arm vs. 55% observation arm). Of note, when the E1690 observation arm was compared to the E1684 observation arm, the E1690 arm had a higher OS (median 6 vs. 2.8 years), and the subjects in E1690 were not required to undergo a lymph node dissection unlike those in E1684. Additionally, a retrospective analysis of E1690 revealed that surgical intervention followed by IFN therapy in relapsing subjects in the observation group might have impacted the survival analysis in this study. Pegylated IFNα Pegylated IFNα (Peg-IFN) is created by covalent bonding of the IFN molecule with polyethylene glycol resulting in a compound with sustained absorption and a longer half-life. Peg-IFN was tested in EORTC 18991 and was approved in the USA in 2011 for use as adjuvant therapy in patients with high-risk melanoma with lymph node metastases [20]. The EORTC 18991 trial investigated the efficacy and safety of Peg-IFN in patients with resected AJCC stage III melanoma as compared (...truncated)