Immunotherapy
For Kidney Cancer

How is Immunotherapy for Kidney Cancer Changing the Outlook for Patients?

Reviewed by:

Sangeeta Goswami, MD, PhD
University of Texas MD Anderson Cancer Center

Immunotherapy for kidney cancer—also called renal cell cancer—has tremendously changed the treatment landscape and overall survival of patients with metastatic kidney cancer.

The kidneys, located on each side of the body toward the back of the abdominal cavity, filter blood, clear waste, and make urine. A person can live with only one functioning kidney.

About 9 out of every 10 kidney cancers are renal cell carcinomas—cancers that form in the lining of the tubules inside the kidney. About 7 out of 10 people with renal cell carcinoma have a subtype called clear cell carcinoma. Non-clear cell kidney cancers include papillary, chromophobe, mucinous tubular and spindle cell (MTSC), Xp11.2 translocation, medullary, and unclassified.

In its early stages, kidney cancer typically has no symptoms. As a tumor grows, symptoms may include blood in the urine, pain or a lump in the lower back or abdomen, fatigue, weight loss, and swelling in the ankles or legs. Often a tumor will be discovered when a patient has a CT scan or ultrasound for another reason.

Risk factors for kidney cancer include tobacco use, obesity, high blood pressure, chronic renal failure, and exposure to certain industrial chemicals, such as trichloroethylene, or radiation.

Globally, there are an estimated 400,000 cases of kidney cancer diagnosed each year, along with 175,000 deaths. Kidney cancer is the eighth most common malignancy in the United States, and there will be an estimated 82,000 new cases and 15,000 deaths in 2023. If kidney cancer is diagnosed while the cancer is still local (has not spread beyond the kidney), the five-year survival rate is 93 percent. Like most cancers, kidney cancer is difficult to treat once it has spread to other parts of the body. Metastatic kidney cancer has a five-year-survival rate of 12 percent.

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Kidney Cancer Treatment Options

Treatment for kidney cancer depends on individual factors, including the exact location of the tumor, stage of the tumor, and the person’s general health. Treatments for early stages (1-3) kidney cancer include complete and partial nephrectomy. A section of patients with high risk features might be eligible to receive immunotherapy after surgery. Patients with advanced or metastatic kidney cancer are treated with systemic therapy that includes targeted therapy and immunotherapy. Kidney cancer tends to be resistant to chemotherapy. Earlier kidney cancer was also considered to be resistant to radiotherapy. However, some preliminary studies highlight the potential role of stereotactic body radiotherapy (SBRT) in kidney cancer. 

Immunotherapy is a type of therapy that takes advantage of a person’s own immune system to help kill cancer cells. The first indication that kidney cancer might be a good target for immunotherapy came from the observation that patients with metastatic kidney cancer occasionally experienced spontaneous regressions after surgical removal of the primary tumor. In the past, immunotherapies in the form of immune-stimulating chemicals called cytokines were a common first-line therapy for advanced kidney cancer, but today are used only for cancers unresponsive to targeted therapies because of the risk of serious side effects. (The cytokines interleukin-2 (IL-2) and interferon-alpha cause kidney cancers to shrink in approximately 10-20 percent of patients and provide durable remissions in a subset of these patients.) Several newer immunotherapies, in particular PD-1/PD-L1 and CTLA-4 checkpoint inhibitors, have become an integral part of the management of advanced or metastatic kidney cancer.

There are currently seven FDA-approved immunotherapy options for kidney cancer either as a single agent or in combination with another immunotherapy or targeted therapy.

Targeted Antibodies

  • Bevacizumab (Avastin®): a monoclonal antibody that targets the VEGF/VEGFR pathway and inhibits tumor blood vessel growth; approved for subsets of patients with advanced kidney cancer

Immunomodulators

  • Aldesleukin (Proleukin®):  a cytokine that targets the IL-2/IL-2R pathway; approved for subsets of patients with advanced kidney cancer
  • Avelumab (Bavencio®): a checkpoint inhibitor that targets the PD-1/PD-L1 pathway; approved for subsets of patients with advanced kidney cancer, including as a first-line therapy in combination with chemotherapy
  • Dostarlimab (Jemperli): a checkpoint inhibitor that targets the PD-1/PD-L1 pathway; approved for subsets of patients with advanced kidney cancer that has DNA mismatch repair deficiency (dMMR)
  • Ipilimumab (Yervoy®), a checkpoint inhibitor that targets the CTLA-4 pathway; approved, in combination with nivolumab, for subsets of patients with advanced kidney cancer
  • Nivolumab (Opdivo®): a checkpoint inhibitor that targets the PD-1/PD-L1 pathway; approved for subsets of patients with advanced kidney cancer, including as a first-line therapy in combination with chemotherapy
  • Pembrolizumab (Keytruda®): a checkpoint inhibitor that targets the PD-1/PD-L1 pathway; approved for subsets of patients with kidney cancer, including as a first-line therapy

Several ongoing trials are testing the feasibility of using immunotherapy in early-stage kidney cancer, alone and in combination with surgery.

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CRI’s Impact in Kidney Cancer

The Cancer Research Institute has supported the best scientists in the field working toward the improvement of kidney cancer treatment, including funding for research on IL-2 and interferon and newer treatment approaches using checkpoint blockades. CRI also funded a clinical trial of interferon-alpha in human patients in 1978, work that demonstrated kidney cancer’s sensitivity to interferon—paving the way for treatment’s approval by the FDA.

  • In 1993, based on promising laboratory findings, CRI provided financial support for a phase 1 clinical trial for patients with metastatic renal cell carcinoma, leading to the creation of GVAX, a therapeutic cancer vaccine.
  • In 1999, CRI-funded researchers used SEREX technology in identifying tumor-related antigens in patients with renal cell carcinoma, providing a solid foundation for the theory that renal cancer could be immunogenic—recognizable by the human immune system.
  • In 2010, several CRI researchers successfully completed a phase 1 study that showed a monoclonal antibody (PD-1 blockade) could induce frequent tumor regressions in renal cancer, among other cancer types, with low toxicity rates.
  • In 2012, CRI CLIP Investigator Jeffrey Rathmell, PhD, of Vanderbilt University discovered that anti-tumor T cells in kidney cancer were found to be dependent on glucose and fail to function without it.
  • In 2015, the CRI Anna-Maria Kellen Clinical Accelerator launched a clinical study that seeks to determine the effectiveness of combining the CTLA-4 inhibitor tremelimumab, with the PD-L1 inhibitor durvalumab, in patients diagnosed with various advanced solid tumors who have failed standard therapy.

Explore CRI’s current support for kidney cancer research in our funding directory.

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Related Links

What is Immunotherapy
Immunotherapy Treatment Types
Immunotherapy by Cancer Type
Immunotherapy Stories
Understanding Clinical Trials
Immunotherapy Webinars

Kidney Cancer Statistics

>55 Years Age most commonly affected by kidney cancer

9 out of 10 Kidney cancers are renal cell carcinomas

400K Newly diagnosed patients each year globally

Kidney Cancer Clinical Trial Targets

Discover the different proteins, pathways, and platforms that scientists and physicians are pursuing to develop new cancer treatments. Use this information to consider your clinical trial options.

Targeted antibodies are proteins produced by the immune system that can be customized to target specific markers on cancer cells in order to disrupt cancerous activity, especially unrestrained growth. Antibody-drug conjugates (ADCs) are equipped with anti-cancer drugs that they can deliver to tumors. Bi-specific T cell-engaging antibodies (BiTEs) bind both cancer cells and T cells in order to help the immune system respond more quickly and effectively. Antibody targets under evaluation in kidney cancer clinical trials include:

  • Angiopoietin: this pathway can promote the growth of blood vessels in tumors
  • CD52: a protein found on the surface of mature immune cells as well as other cell types
  • CD56: a protein found on both neurons and natural killer immune cells
  • cMET: a growth-related pathway that is often abnormally activated in cancer
  • EGFR: a pathway that controls cell growth and is often mutated in cancer
  • HER2: a pathway that controls cell growth and is commonly overexpressed in cancer and  associated with metastasis
  • TROP2: a protein that is commonly overexpressed in cancer and appears to aid cancer cell self-renewal, proliferation, invasion, and survival
  • VEGF/VEGF-R: a pathway that can promote blood vessel formation in tumors

Cancer vaccines are designed to elicit an immune response against tumor-specific or tumor-associated antigens, encouraging the immune system to attack cancer cells bearing these antigens. Cancer vaccines can be made from a variety of components, including cells, proteins, DNA, viruses, bacteria, and small molecules. Cancer vaccine targets under evaluation in kidney cancer clinical trials include:

  • P53: a tumor suppressor protein that is often mutated, nonfunctional, and overexpressed in cancer
  • Personalized neoantigens: these abnormal proteins arise from mutations and are expressed exclusively by tumor cells
  • Tumor-associated antigens (TAAs): proteins often expressed at abnormally high levels on tumor cells that can be used to target them; also found on normal cells at lower levels
  • WT1: a protein that is often mutated and abnormally expressed in patients with cancer, especially Wilms’ tumor (WT)

Adoptive cell therapy takes a patient’s own immune cells, expands or otherwise modifies them, and then reintroduces them to the patient, where they can seek out and eliminate cancer cells. In CAR T cell therapy, T cells are modified and equipped with chimeric antigen receptors (CARs) that enable superior anti-cancer activity. Natural killer cells (NKs) and tumor infiltrating lymphocytes (TILs) can also be enhanced and reinfused in patients. Cell-based immunotherapy targets under evaluation in kidney cancer clinical trials include:

  • MAGE antigens: the genes that produce these proteins are normally turned off in adult cells, but can become reactivated in cancer cells, flagging them as abnormal to the immune system

Immunomodulators manipulate the “brakes” and “gas pedals” of the immune system. Checkpoint inhibitors target molecules on immune cells to unleash new or enhance existing immune responses against cancer. Cytokines regulate immune cell maturation, growth, and responsiveness. Adjuvants can stimulate pathways to provide longer protection or produce more antibodies. Immunomodulator targets under evaluation in kidney cancer clinical trials include:

  • CD40: activating this co-stimulatory pathway can kickstart adaptive immune responses
  • CD73 or A2AR: blocking these pathways can help prevent the production of immunosuppressive adenosine
  • CD137 (also known as 4-1BB): activating this co-stimulatory pathway can help promote the growth, survival, and activity of cancer-fighting T cells
  • CSF1/CSF1R: blocking this pathway can help reprogram cancer-supporting macrophages
  • CTLA-4: blocking this pathway can help expand and diversify cancer-fighting T cells
  • CXCR4: blocking this pathway can promote the migration and recruitment of immune cells
  • GITR: activating this pathway can help prevent immunosuppression and increase the survival of cancer-fighting T cells
  • IDO: blocking this enzyme’s activity can help prevent cancer-fighting T cells from being suppressed
  • IL-2/IL-2R: activating this cytokine pathway can help promote the growth and expansion of cancer-fighting T cells
  • LAG3: blocking this pathway may be able to help prevent suppression of cancer-fighting T cells
  • OX40: activating this co-stimulatory pathway can help promote T cell survival after activation
  • PD-1/PD-L1: blocking this pathway can help prevent cancer-fighting T cells from becoming “exhausted,” and can restore the activity of already-exhausted T cells
  • STING: activating this protein in the DNA-sensing pathway can help stimulate immune responses against threats such as viruses and cancer
  • Toll-like receptors (TLRs): activation of these innate immune receptors can help stimulate vaccine-like responses against tumors

Oncolytic virus therapy uses viruses that are often, but not always, modified in order to infect tumor cells and cause them to self-destruct. This can attract the attention of immune cells to eliminate the main tumor and potentially other tumors throughout the body. Viral platforms under evaluation in kidney cancer clinical trials include:

  • Vaccinia virus: the virus that was used to help vaccinate against and eliminate smallpox; rarely causes illness in humans and is associated with a rash covering the body

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