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 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 200210 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.
Durability versus Chronic Treatment
Long before the clinical use of targeted therapies, immunotherapy was extensively studied as a therapeutic approach to mRCC. In nonrandomized clinical trials, high-dose interleukin-2 (HD IL-2) demonstrated durable complete responses, achieving recurrence-free, treatment-free survival exceeding 10 years in around 8 % of patients with advanced or mRCC who were treated. Despite the established benefit of HD IL-2, and that patients progressing through IL-2 generally remain eligible for subsequent targeted therapies, the population treated with immune therapy with IL-2 remains limited. The bases for the limited utilization of HD IL-2 include toxicity, cost, hospital time, and the lack of benefit in the majority of patients. Regarding toxicity, short-term side effects with IL-2 can be contrasted with more chronic but less severe side effects associated with open-ended treatments on targeted therapies. Regarding drug costs, the overall cumulative cost with targeted therapy can be similar or more than treatment with HD IL-2, particularly for the patient with disease features that predict for multiyear survival. Of course, the duration of treatment used, the patient selection, and the fact that IL-2 is followed by targeted therapy in most cases makes comparisons difficult.
Almost all mRCC patients on targeted therapies eventually experience disease progression, with long-term remissions represented only in isolated cases, and not in the larger phase III studies. Increased understanding of the limitations of the targeted therapies over the last few years and recent advances in the cancer immunotherapies in general has led to a resurgence of interest in the investigation of immunotherapy as a major treatment strategy, with HD IL-2 and other approaches such as checkpoint inhibition and vaccination being investigated in the treatment of mRCC.13,14 This article will review current research investigating immunologic therapy in mRCC with emphasis on the approved therapy with IL-2.
Immunotherapy as a Therapeutic Approach to Metastatic Renal Cell Carcinoma
For the most part, RCC has not shown a significant response to traditional cytotoxic therapy, and this helped to drive interest in other approaches; immunotherapy is known to result in rare but dramatic responses in some RCC. The observation of mRCC apparently showing spontaneous regression in placebo groups of clinical trials is presumably a result of the isolated events of the host immune response waxing stronger over time.15
The antigenic features of certain cancers that make them responsive to immunotherapy are poorly understood and are the subject of considerable research. Melanoma is a particularly immunogenic cancer, for which many tumor antigens are well characterized. An enhanced understanding of the differences in antigenic features between mRCC and melanoma would accelerate the development of immunotherapies for mRCC. One potential difference lies in tumor-associated antigens (TAAs) that trigger the cell-mediated immune response. Tumor-infiltrating lymphocytes (TILs) are found in high numbers in RCC tumors; however, they are not directed at TAAs and have not demonstrated clinical efficacy in mRCC, a contrast with the melanoma experiences. Treatment with CD8+ TILs did not improve response rate or survival in RCC patients treated with lowdose IL-2 after nephrectomy.16 Reasons for lower frequency of clinically useful immune response of the treatment may include a lack of TAA or of more tumor-induced local or systemic immunosuppression. Although preclinical evaluations suggested that adoptive cell transfer (ACT) could be a promising approach in mRCC patients,17 a recent meta-analysis identified five hindrances to the lack of success of such approaches, including high degree of personalization, unsuitable response assessment criteria, inadequate identification of TAAs, lack of effective combination treatments, and insufficient attention paid to the quality of ACT products.18
Removal of the primary tumor by surgical resection may cause a change to the immunologic environment. Since the primary tumor bulk is immunosuppressive, removal of the tumor has a theoretically favorable immunotherapeutic effect.19 Clinical studies have demonstrated that early nephrectomy in patients with good performance status confers a survival advantage.20,21 However, it is important to consider individual risk assessments in any decisions around nephrectomy.22–24 There are also opportunities in the context of clinical trials to integrate nephrectomy with subsequent immunotherapy, including IL-2, but also with others such as dendritic cell (DC)-based vaccines based on primary tumor tissue.25
The greatest body of clinical experience with immunotherapy in mRCC is in the use of cytokine therapy with interferon alpha (IFN-a) or HD IL-2 (Proleukin®), which are the only immunotherapies recommended in treatment guidelines (see Figure 1)26 and have been a standard of care for over 20 years. However, IFN-a has only a modest impact on survival in selected patients (nonbulky pulmonary and/or soft tissue metastases with performance status ratings of 0–1, according to the Eastern Cooperative Oncology Group [ECOG] rating scale, and no weight loss). In clinical trials, IFN-a proved inferior to HD IL-2,27 to sunitinib,28 and to the combination of bevacizumab + interferon.29,30
IL-2 (aldesleukin) is a recombinant protein that has numerous antitumor actions including enhancing cytotoxic immune cell functions; limiting tumor escape mechanisms such as defective tumor cell expression of class I or II molecules or expansion of regulatory T cells (Tregs); and indirect effects on the tumor microenvironment.31 IL-2 received US Food and Drug Administration (FDA) approval in 1992 for the treatment of mRCC, based on the results of seven phase II clinical trials.32 A subsequent randomized clinical trial (n=156) demonstrated that outcomes could be improved with the higher dosage (HD IL-2).33 A phase III clinical trial (n=192) found superior survival with intravenous HD IL-2 compared with subcutaneous IL-2 plus IFN-a (IL-2/IFN-a). The response rate was 23.2 % for HD IL-2 versus 9.9 % for IL-2/IFN-a (p=0.018). The median response durations were 24 and 15 months, respectively. The median survivals were 17.5 and 13 months (p=0.24).27 A 20-year analysis of patients treated at the National Cancer Institute from 1986 to 2006 (n=259) showed an overall response rate of 20 % with complete response in 9 % of patients with mRCC after treatment with HD IL-2. Median survivals of the partial responders and nonresponders were 39.1 and 15.1 months, respectively. The median survival of the complete responders had not yet been reached after several years, at the time of last follow-up.34