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Genitourinary Cancer Renal Cell Carcinoma Immunologic Therapy of Renal Cell Carcinoma Neeraj Agarwal, MD 1 and Mayer Fishman, MD, PhD 2 1. Assistant Professor, Division of Medical Oncology, University of Utah Huntsman Cancer Institute, Salt Lake City, Utah, US; 2. Senior Member, Department of Genitourinary Oncology, H Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, US Abstract Interleukin-2 (IL-2) has been the mainstay of immunotherapy of metastatic renal cell carcinoma (mRCC) therapy for over 20 years. Although IL-2 treatment is limited to fit patients, a select group of these patients have derived substantial, durable benefit from it, for some translating into cures with no ongoing therapy or chronic toxicity. While targeted therapies are applicable to most patients, improvements of median survival have been measured in months. Immunotherapy, encompassing not only IL-2 but also newer checkpoint and vaccine approaches, therefore still has an important role for many as a main choice in RCC treatment. Enhanced patient selection techniques have evolved over time, and the overall response rate to high-dose (HD) IL-2 has improved among those selected patients. An increased understanding of immunotherapy has led to other novel approaches. These include checkpoint inhibitors mediating changes of T-cell behavior acting at the lymphocyte protein receptor programmed death-1 (PD-1), such as nivolumab, and vaccine immunotherapies, including peptide and dendritic cell vaccines in pivotal trials, and coordinated use of radiation therapy with IL-2, encouraging in early phase testing. Such approaches have the potential to expand the immune approach to achieve outcomes with better overall survival for many patients with mRCC. Keywords Interleukin-2, immunotherapy, programmed death-1, renal cell carcinoma, vaccines Disclosure: Neeraj Agarwal, MD, has no conflicts of interests to declare. Mayer Fishman, MD, PhD, has participated in clinical trials related to immunotherapy of kidney cancer for BMS (nivolumab), Prometheus (IL-2), and Argos (ADAPT study), holds Data and Safety Monitoring Board (DSMB) membership: Immatics (IMA=901 study), and is on the speakers bureau for Prometheus (IL-2). Acknowledgment: Editorial assistance was provided by Katrina Mountfort, PhD, at Touch Medical Media. Received: April 9, 2014 Accepted: April 22, 2014 Citation: Oncology & Hematology Review, 2014;10(1):54–60 Correspondence: Mayer Fishman, MD, PhD, Department of Genitourinary Oncology, H Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, US. E: Mayer.Fishman@moffitt.org Support: The publication of this article was supported by Prometheus. The views and opinions expressed are those of the authors and not necessarily those of Prometheus. Renal cell carcinoma (RCC) represents 2–3 % of all cancers, and is responsible for 13,570 annual US deaths. 1 Surgical resection of localized RCC can be curative, but disease recurrence eventually occurs in many patients, at rates that can be directly related to features including tumor size or grade. In addition, many patients are diagnosed with either locally advanced and unresectable or metastatic disease at the time of initial presentation. Subtypes of tumors arising in the kidney are classified according to the World Health Organization (WHO) classification system. 2 The most common subtype is clear cell RCC, which accounts for over 80  % of malignant, nonurothelial kidney tumors. 3 The molecular profile of this clear cell RCC is heterogeneous. 4 Recent studies suggest the presence of two major molecular subtypes, which may explain the variable clinical course and response to therapy among patients with clear cell RCC. 5 However, even within a single patient, substantial differences of gene expression have been observed within the primary tumor, or between the metastases and the primary. 6,7 Heterogeneity of patient clinical features is acknowledged to be a dominant factor of 54 the incident RCC population, with impacts on overall survival (OS) from the disease features greater than many treatment choices. Ultimately, however, around 70  % of RCC patients develop metastases, and until the introduction of targeted therapies, the 5-year OS of metastatic RCC (mRCC) was around 5–10 %. 8 Over the last decade, an increased understanding of tumor biology helped drive development of targeted therapies for mRCC. 9 These easily administered oral and intravenous therapies, targeted against intracellular signaling pathways such as those activated by vascular endothelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR) pathway, have revolutionized the way mRCC is treated. However, despite the advent of these newer agents, and a significant improvement of the median OS from 13 months in 2002 10 to about 28 months in 2012 to 2013, 11,12 almost all patients eventually experience disease progression, and die of their disease. The management of mRCC therefore remains a therapeutic challenge. © Tou c h ME d i ca l ME d ia 2014