Beyond PD-1 Immunotherapy in Malignant Melanoma

Dermatol Ther (Heidelb) https://doi.org/10.1007/s13555-019-0292-3 REVIEW Beyond PD-1 Immunotherapy in Malignant Melanoma Dominika Kwiatkowska . Piotr Kluska . Adam Reich Received: January 26, 2019 Ó The Author(s) 2019 ABSTRACT For many years, the standard therapy for malignant melanoma was based mainly on surgical resection. Unfortunately, this treatment is curative only in the early localized stage of this malignancy. The metastatic stage of malignant melanoma still remains a huge therapeutic challenge. Despite the many new therapeutic options that have become available over the last years, there is a constant need for safer and more effective treatment modalities. There has been a dynamic development of various anti-cancer immunotherapies directed against new molecular targets. A number of clinical trials are currently being conducted to confirm their effectiveness and safety. In this review of the literature, we summarize the contemporary knowledge on promising new immunotherapies beyond the currently available treatment options for malignant melanoma, including oncolytic immunotherapy, Enhanced digital features To view enhanced digital features for this article go to https://doi.org/10.6084/ m9.figshare.7857098. D. Kwiatkowska
A. Reich (&) Department of Dermatology, University of Rzeszow, Rzeszów, Poland e-mail: P. Kluska Wroclaw University of Science and Technology, Wrocław, Poland selective inhibitors of indoleamine 2,3-dioxygenease, anti-PD-(L)1 (programmed death ligand 1) drugs, immune checkpoint protein LAG-3 antibodies, inhibitors of histone deacetylase (HDAC) and inhibitors of B7-H3. Keywords: Atezolizumab; Epacadostat; Immunotherapy; Indoximod; LAG3 inhibitors; Malignant melanoma; Oncolytic immunotherapy; Talimogene laherparepvec Abbreviations AE Adverse events BRAF B-Raf proto-oncogene CTLA4 Cytotoxic T-lymphocyte associated protein 4 DLTs Dose-limiting toxicities GM-CSF Granulocyte macrophage-colonystimulating factor HDAC Inhibitors of histone deacetylase IDO1 Indoleamine 2,3-dioxygenase 1 IDO2 Indoleamine 2,3-dioxygenase 2 IFN-c Interferon gamma LAG-3 Lymphocyte activation gene 3 MEK Mitogen-activated protein kinase ORR Overall response rate PD1 Programmed cell death protein 1 PDL-1 Programmed death ligand 1 SAE Serious adverse event T-VEC Talimogene laherparepvec Tregs Tumor-associated regulatory T cells Dermatol Ther (Heidelb) INTRODUCTION Malignant melanoma is one of the most fatal skin tumors with a consistent increase of incidence reported over the last 3 decades [1]. The data from the World Health Organization (WHO) show that every year 132,000 new cases of this neoplasm are diagnosed around the world [2]. For years, prognosis for patients with unresectable stage III–IV tumors was poor. Responses to systemic therapy, with the exception of the small group of patients reacting well to high doses of interleukin 2 (IL-2), were unsatisfactory [3, 4]. During the last years, significant progress has been made in the development of new targeted therapies and immunotherapies [5], which has given hope to patients with advanced stage malignant melanoma and markedly changed the future directions of progress in contemporary oncology. Although new treatments have already been introduced with many studies confirming their effectiveness, other therapeutic options are still needed for this group of patients. In this review, we have presented current trends in the development of therapy for malignant melanoma and its future potential impact on the survival of patients with this tumor. METHODS For the purpose of this report, the PubMed and ClinicalTrials.gov database were searched (Fig. 1). Articles were included for analysis if they concerned the following malignant melanoma treatments: oncolytic immunotherapy (e.g., talimogene laherparepvec and other oncolytic viruses), selective inhibitors of indoleamine 2,3-dioxygenease (e.g., epacadostat, indoximod), anti-PD-(L)1 (programmed death ligand 1) (e.g., atezolizumab), immune checkpoint protein LAG-3 (lymphocyte-activation gene 3) antibodies (e.g., relatlimab, eftilagimod alpha, LAG525), selective histone deacetylase (HDAC) inhibitors (e.g., entinostat), B7H3 inhibitors (e.g., enoblituzumab) and selected combinations of the above-mentioned therapies with other medications. The research data had to be published and available before 31 December 2018. Reports were excluded if they contained a description of current standard therapy of advanced melanoma, such as: checkpoint inhibitors—anti-PD1 antibodies (nivolumab and pembrolizumab), anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) immunoglobulin (ipilimumab) and targeted therapy (BRAF inhibitor, MEK inhibitor) unless these therapies were used in combination with previously mentioned drugs. Additional articles were included manually during investigation of papers’ references if they were found relevant for current review. This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors. Talimogene Laherparepvec and Other Oncolytic Viruses The development of oncolytic immunotherapy has resulted in a promising treatment strategy, which in the future could yield improvement of the overall survival of patients with metastatic or unresectable malignant melanoma [6, 7]. Oncolytic viruses (OVs) act through selective infection and lysis of tumor cells as well as enhancement of the anti-tumor immune response [8]. Talimogene laherparepvec (T-VEC) is the first and currently the only oncolytic herpes simplex virus type 1 (HSV1) used for the treatment of inoperable stage III and IV malignant melanoma approved by the FDA (Food and Drug Administration). To prevent toxicity, which was until recently a significant limitation associated with a therapeutic viral infection, HSV1 has been genetically modified to achieve T-VEC. Inactivation of neurovirulence factor ICP34.5 resulted in increased replication of the virus in tumor cells and reduced pathogenicity through the protection of normal cells [9]. This effect is enhanced by simultaneous insertion of the US11 gene [10]. Further modification by deleting the ICP47 gene allows the presentation of an antigen that has previously been inhibited by the virus [11]. T-VEC also has the ability to express GM-CSF, which potentially augments Dermatol Ther (Heidelb) Fig. 1 Process of searching the PubMed database (BRAF B-Raf proto-oncogene, MEK mitogen-activated protein kinase, PD1 programmed cell death protein 1, CTLA4 cytotoxic T-lymphocyte associated protein 4) the systemic T-cell immune response of the host to neoplasm cells [12]. As mentioned above, the T-VEC mode of action is defined by two mechanisms: selective infection and termination of tumor cells as well as the induction of local and distant anti-tumor host immunity. In studies carried out by Kaufman et al. in patients with unresectable stage IIIc and IV metastatic melanoma, i (...truncated)