Joseph I. Clark, MD
Immunotherapy, a type of treatment designed to enhance or restore the body’s ability to fight cancerous cells by activating the immune system, has long been a mainstay of treatment for kidney cancer, and continues to attract considerable attention from oncologists and patients alike. The attention is not only due to the clinical benefits that patients continue to experience with immunotherapy, but also to the apparent promise of newer immunotherapeutic agents that are currently being investigated in clinical trials.
Although surgical resection (removal) of the kidney is often used in patients with localized kidney cancer (i.e., that which has not spread beyond the kidney), immunotherapy and molecular-targeted therapy are generally considered standard of care in patients with metastatic disease (i.e., that which has spread to other organs). Consequently, the stage of the patient’s cancer, as well as the rate and extent of metastasis (spread), will usually determine which type of therapy the patient will receive.
Immunotherapy is a type of biological response modification therapy, so called because it is designed to improve the body’s natural response to disease. A number of immunotherapeutic approaches have been investigated in the treatment of cancer. One approach focuses on cytokines, proteins secreted by cells of the immune system that serve to regulate the immune system. Cytokines such as interferons (IFNs) and interleukins have activity in the treatment of various malignancies. One type of IFN, interferon-alfa, has been shown to regulate the immune response by activating certain types of leukocytes (white blood cells) and interfering with the division of cancer cells, and may slow tumor growth. However, although IFN-alfa is indicated for the treatment of malignant melanoma, Kaposi’s sarcoma, and several hematologic (blood-based) cancers, it is only approved to treat patients with kidney cancer in combination with the targeted agent, bevacizumab. Such patients are therefore more likely to be treated with one of the interleukins, a group of related proteins produced by leukocytes and other cells in the body.
High-dose interleukin-2: the standard-bearer
Interleukin-2 (IL-2) is one of more than a dozen interleukins that have been identified. Naturally produced by activated T-cells, IL-2 enhances the proliferation of leukocytes, thereby boosting the body’s immune response to cancer. It also triggers production of antibodies by B-cells to attack cancer cells.
High-dose interleukin-2 (HD IL-2, also known as aldesleukin) is a laboratory-made interleukin that was approved by the U.S. Food and Drug Administration (FDA) in 1992 for the treatment of metastatic renal cell carcinoma (mRCC). Even after more than two decades of use in this patient population, HD IL-2 is still considered an important treatment for mRCC. In a recently published retrospective study conducted at Roswell Park Cancer Institute, researchers reported an overall response rate (ORR) of 16% among the 88 patients with mRCC who received HD IL-2, including four patients (4.5%) who had a complete response (CR). Median overall survival (OS) was 35.5 months, and 60% of the patients in this study were still alive after 2 years. Other recent HD IL-2 studies have reported ORRs in the range of 25-30%, durable CRs of 7.5-8.0%, and median OS ranging from 36.5 to 42.8 months.,
Sequential treatment for kidney cancer: when to use immunotherapy
One of the major questions oncologists face is when to administer the various types of medications that are available to treat patients with kidney cancer, and which drug to use first. In addition to immunotherapy, available drugs include tyrosine kinase inhibitors (TKIs), a group of targeted therapies that include vascular endothelial growth factor (VEGF) inhibitors and mammalian target of rapamycin (mTOR) inhibitors.
Although the VEGF inhibitors are the most commonly prescribed medications for kidney cancer, and are most frequently used as initial treatment, evidence suggests that starting with immunotherapy, and then switching to a TKI once the disease progresses, provides a longer-term benefit than that seen with targeted therapy alone. Even if patients do not respond to initial HD IL-2 therapy, some studies suggest they may benefit more from second-line TKI therapy if they first receive IL-2, based on reports of longer median OS and more durable responses than those observed in patients who were not initially treated with IL-2.2,3
The future of immunotherapy
While HD IL-2 remains an important therapy for patients with kidney cancer, newer types of immunotherapeutic agents appear to hold great promise. Such agents include PD-1 inhibitors, a type of monoclonal antibody (a laboratory-made protein that binds to cancer cells) that interferes with an immune system checkpoint known as the programmed cell death protein 1 (PD-1) pathway. Preliminary reports suggest that PD-1 inhibitors are at least as effective as HD IL-2 in patients with clear-cell renal carcinoma, in terms of the number of responders and extended survival.,, Moreover, the reported response rates and duration of benefit appear to give the PD-1 inhibitors an advantage over the TKIs, whose primary advantage is an improvement in progression-free survival (PFS), without inducing durable long-term remissions.
If the early results with the PD-1 inhibitors are borne out by future clinical trials, the pendulum may swing back to using immunotherapeutic agents as initial therapy for the majority of patients with kidney cancer, especially those with advanced disease. Additionally, the anti-PD-1 agents are designed to be administered in the outpatient setting, adding an element of convenience that may dramatically change the way kidney cancer is treated.
In the future, there will probably be more studies comparing different sequences of immunotherapy and TKIs for the treatment of kidney cancer, along with more studies of combination therapy. The latter will likely include studies in which immunotherapeutic agents and TKIs are used in combination, as well as those that combine two or more immunotherapeutic agents in a treatment regimen. Ongoing combination and sequencing studies will surely generate continued interest in these approaches.
Clearly, immunotherapy still plays an important role in the treatment of kidney cancer, and ongoing research suggests it will continue to play that role, even if not every patient benefits from it. Ten years from now, we may be talking about immunotherapy as first-line therapy for the vast majority of patients with kidney cancer. While the TKIs will also continue to have a role, these agents may be used less often in the first-line setting, and may largely be restricted to sequential therapy or to use in patients who are not considered candidates for immunotherapy.
Whatever type of therapy emerges as the most commonly used treatment, oncology researchers will continue to strive to advance our understanding of the optimal therapeutic approaches for patients with kidney cancer. That will require sufficient numbers of patients who are willing to enroll in clinical trials of investigational therapies. With the help of patients participating in clinical trials, we can learn more about how to improve the lives of individuals living with kidney cancer, and may even reach our ultimate goal of eliminating this devastating disease.
 Dandamudi UB, Ghebremichael M, Sosman JA, et al. A phase II study of bevacizumab and high dose interleukin-2 in patients with metastatic renal cell carcinoma: a cytokine working group (
 McDermott DF, Cheng SC, Signoretti S, et al. The high dose (HD IL-2) “select” trial: a trial designed to prospectively validate predictive models of response to HD IL-2 treatment in patients with metastatic renal cell carcinoma (mRCC). Submitted to Clin Cancer Res 2014.
 Morse M, McDermott DF, Daniels GA, et al. High-dose (HD) IL-2 for metastatic renal cell carcinoma (mRCC) in the targeted therapy era: extension of OS benefits beyond complete response (CR) and partial response (PR). J Clin Oncol 2014;32(5s):abstr 4523.
 Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366(26):2443-2454.
 Brahmer JR, Tykodi SS, Chow LQM, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366(26):2455-2465.
 Hammers HJ, Plimack ER, Infante JR, et al. Phase I study of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma (mRCC). J Clin Oncol 2014;32(5s):abstr 4504.