Immunotherapy for Renal Cell Carcinoma

Immunotherapy has transformed the treatment of advanced kidney cancer from a disease with limited options into one where long-term survival is a realistic goal. Renal cell carcinoma, the most common type of kidney cancer, is one of the solid tumors most responsive to immune-based treatment. Modern combinations of checkpoint inhibitors with each other or with targeted drugs now serve as first-line therapy for most patients with metastatic disease, roughly doubling response rates compared with the older standard of single-agent targeted therapy and pushing five-year survival rates into territory that was unthinkable two decades ago.

Why Kidney Cancer Responds to Immunotherapy

Kidney tumors, particularly the clear cell subtype that accounts for about 75% of cases, are densely infiltrated by immune cells. Research characterizing the tumor immune microenvironment has found that clear cell renal cell carcinoma ranks among the highest of all cancer types for both overall immune infiltration and T-cell infiltration specifically.¹ Interestingly, this immunogenicity does not stem from a high number of genetic mutations or neoantigens, which is what drives immune recognition in cancers like melanoma and lung cancer. Instead, it correlates strongly with the expression of machinery that presents molecules on the tumor cell surface for immune recognition.

This high baseline immune presence is both an advantage and a paradox. The immune system clearly sees these tumors, but the cancer co-opts suppressive signals to keep immune cells from finishing the job. That is exactly the kind of standoff that checkpoint inhibitors are designed to break. By blocking the brakes that tumors use to shut down T cells, these drugs can reactivate an immune attack that was already partially underway.

From Interleukin-2 to Checkpoint Inhibitors

Kidney cancer has a longer history with immunotherapy than most solid tumors. High-dose interleukin-2, approved in the 1990s, produced durable complete responses in a small fraction of patients, with overall response rates of roughly 12 to 20% and complete responses in about 8%.² Those complete responses could last years, sometimes amounting to functional cures. The catch was severe toxicity: high-dose IL-2 required intensive-care-level monitoring, and the higher-dose schedules that produced the most durable responses also caused the worst side effects.³ Only a minority of patients were healthy enough to tolerate it, and oncologists spent years trying to identify who would actually benefit.

The arrival of checkpoint inhibitors changed the calculus entirely. These drugs are far more tolerable than IL-2, can be given in outpatient settings, and produce higher response rates when combined with each other or with drugs that target blood-vessel growth in tumors.

First-Line Combination Regimens

Several immunotherapy-based combinations are now standard first-line treatment for advanced clear cell renal cell carcinoma. The evidence behind them comes from large randomized trials, all compared against sunitinib, which was the previous standard targeted therapy. The results vary in degree but point in the same direction: immunotherapy combinations improve survival.

The dual checkpoint inhibitor combination of nivolumab plus ipilimumab was the first to demonstrate a major survival advantage in intermediate- and poor-risk patients. At about two years of follow-up, the 18-month survival rate was 75% with the combination versus 60% with sunitinib, and the response rate was 42% versus 27%, with complete responses in 9% of patients on the combination compared with just 1% on sunitinib.⁴ This regimen is distinctive because after a short induction phase the immunotherapy component eventually stops, giving patients a defined treatment period rather than indefinite drug exposure.

Combinations pairing a checkpoint inhibitor with a targeted drug that blocks blood-vessel growth have also shown strong results across all risk groups. Five-year data from the KEYNOTE-426 trial showed that pembrolizumab plus axitinib maintained benefits in overall survival, progression-free survival, and response rate compared with sunitinib, with about 61% of patients responding to the combination versus roughly 40% on sunitinib.⁵ Earlier follow-up data from the same trial showed a median duration of response of about two years.⁶

Lenvatinib plus pembrolizumab produced the longest median progression-free survival of any first-line regimen tested so far: about 24 months versus roughly 9 months with sunitinib, along with a significant overall survival benefit.⁷ Quality-of-life assessments from that trial found that patients on the combination maintained or improved their day-to-day functioning compared with sunitinib, with significantly longer times before meaningful deterioration across multiple measures.⁸

After Surgery to Prevent Recurrence

Immunotherapy’s role is not limited to metastatic disease. Some patients who have their kidney tumor surgically removed are at high risk of the cancer returning. The KEYNOTE-564 trial tested whether a year of pembrolizumab after surgery could reduce that risk. At two years, about 77% of patients on pembrolizumab remained free of recurrence compared with 68% on placebo.⁹ With longer follow-up at 30 months, the benefit held, with roughly 75% versus 66% of patients remaining recurrence-free.¹⁰ Pembrolizumab is the only immunotherapy currently approved in this adjuvant setting for kidney cancer, though other checkpoint inhibitor trials in the same space have not shown similar benefits, making this a somewhat contentious area where patient selection matters.

There is also growing interest in giving immunotherapy before surgery. A phase II study found that nivolumab given prior to kidney removal was safe and did not delay the operation, with all patients proceeding to surgery on schedule.¹¹ The rationale is that treating before surgery exposes the immune system to the full tumor, potentially priming a stronger and longer-lasting immune response. Larger trials are still needed to determine whether this translates into better long-term outcomes.

Non-Clear Cell Subtypes

Most immunotherapy trials in kidney cancer have focused on the clear cell subtype, leaving patients with rarer forms in a relative evidence gap. Non-clear cell subtypes like papillary, chromophobe, and collecting duct carcinomas collectively make up about a quarter of kidney cancers and tend to have different biology and, historically, worse treatment options.

Recent data suggest immunotherapy combinations still have meaningful activity in these patients, though generally at somewhat lower rates than in clear cell disease. A multicenter study from Japan found that the response rate to combination immunotherapy in non-clear cell tumors was about 52%, compared with roughly 64% in clear cell tumors.¹² Among non-clear cell types, papillary histology tends to respond better than chromophobe. Phase II trials combining checkpoint inhibitors with targeted drugs have reported response rates around 60 to 70% in non-clear cell patients, numbers that would have been unimaginable with older treatments.¹³

Patients With Brain Metastases

Brain metastases from kidney cancer have traditionally been treated with surgery or radiation, and these patients were excluded from most of the landmark immunotherapy trials. A dedicated cohort within the CheckMate 920 study evaluated nivolumab plus ipilimumab in patients with untreated brain metastases. About a third of patients responded, and the median duration of those responses was two years, with some responders showing no signs of progression during follow-up. Median progression-free survival was 9 months, and the median overall survival had not been reached at the time of analysis.¹⁴ These are small numbers from a non-randomized study, but they are meaningful for a group of patients who previously had very few systemic treatment options.

Side Effects and Immune-Related Complications

Checkpoint inhibitors work by removing constraints on the immune system, and that lack of restraint can occasionally cause the immune system to attack healthy tissues. These immune-related side effects span nearly every organ system: skin rashes, thyroid dysfunction, liver inflammation, colitis, and pneumonitis are among the more common ones. Most are manageable with steroids or pausing treatment, but some can be severe.

Kidney-related side effects deserve special mention in this context. Acute kidney injury has been increasingly recognized as a complication of checkpoint inhibitors, and for patients being treated specifically for kidney cancer, this creates an added layer of complexity. Clinicians face difficult decisions about whether to restart immunotherapy after a patient develops kidney inflammation, and the evidence on how often the problem recurs with retreatment is still limited.¹⁵ Patients who have received a kidney transplant face a particularly fraught situation: checkpoint inhibitors can trigger rejection of the transplanted organ, creating a genuine conflict between treating the cancer and preserving kidney function.

Why Some Patients Do Not Respond

Despite the impressive overall statistics, a substantial fraction of patients with kidney cancer either do not respond to immunotherapy at all or initially respond but then progress. Both patterns represent distinct problems. Primary resistance, where the tumor never shrinks, may involve immune cells in the tumor environment that actively suppress T-cell activity, including certain types of immune-suppressive macrophages, regulatory T cells, and connective-tissue cells that physically shield the tumor.¹⁶

Acquired resistance, where the cancer returns after an initial response, involves additional mechanisms. Tumors can upregulate alternative immune-suppressive pathways, essentially switching to a different set of brakes once the original ones are blocked. Genetic and epigenetic changes within the tumor can also allow it to become invisible to the immune system over time.¹⁷ Understanding these distinct failure modes matters because the treatment approach after progression may depend on which type of resistance is at play.

The Biomarker Problem

In other cancers, markers like the amount of PD-L1 protein on the tumor surface or the total number of mutations help predict who will benefit from immunotherapy. Kidney cancer is an outlier: those standard biomarkers do not reliably distinguish responders from non-responders.¹⁸ This is frustrating because it means doctors cannot easily spare patients who would not benefit from treatment or steer them toward the combination most likely to work for them.

Emerging approaches focus on gene expression patterns within the tumor and specific genetic features, including loss of particular tumor-suppressor genes like VHL and PBRM-1, which may predict sensitivity to checkpoint inhibitors.¹⁹ Simple blood tests measuring inflammation may also help. A large study across multiple cancer types found that a composite score derived from routine blood counts could predict survival in kidney cancer patients on immunotherapy.²⁰ Another study developed a scoring system using the ratio of different white blood cell types alongside clinical factors like bone metastases and risk category to estimate prognosis for patients on nivolumab.²¹ None of these have matured into clinical decision-making tools yet, but they represent the direction the field is heading.

Retreatment After Progression

When a patient’s cancer progresses on first-line immunotherapy, the question of whether to try a different checkpoint-based regimen is genuinely unsettled. A study evaluating immunotherapy rechallenge found a response rate of about 23% on the second round of treatment, with no complete responses. Patients who had responded to their first immunotherapy course were somewhat more likely to respond again. However, median time before the cancer progressed was shorter with the second course, around 6 months versus 8 months on the first.²²

A systematic review looking across multiple rechallenge studies found wide variation in outcomes. Median time to progression ranged from roughly 4 to 12 months, with longer durations when the rechallenge combined a checkpoint inhibitor with a blood-vessel-targeting drug. But the only randomized phase III trial testing rechallenge directly, called CONTACT-03, did not show a benefit of adding a checkpoint inhibitor to a targeted drug versus the targeted drug alone. Rates of serious side effects were high, ranging from 28 to 65% across studies. The review concluded that rechallenge should generally happen only within clinical trials.²³

Pseudoprogression on Imaging

One pattern that can confuse both patients and doctors is pseudoprogression, where tumors initially appear to grow on imaging scans before eventually shrinking. In kidney cancer patients treated with nivolumab, this occurs in roughly 7 to 8% of cases.²⁴ The initial growth likely reflects immune cells flooding into the tumor rather than actual cancer progression. There is also a rarer and more dangerous pattern called hyperprogression, where tumor growth rate genuinely accelerates after starting immunotherapy. Distinguishing between these patterns is critical and sometimes requires serial imaging over weeks to months, along with clinical judgment about how the patient is feeling overall.

How Gut Bacteria Influence Outcomes

One of the more surprising findings in immunotherapy research is that the composition of a patient’s gut bacteria appears to influence how well checkpoint inhibitors work. In kidney cancer specifically, patients who took broad-spectrum antibiotics around the time of starting immunotherapy fared significantly worse. One study found that recent antibiotic use dropped the response rate from 28% to 9% and markedly altered the bacterial makeup of the gut, favoring species associated with poorer outcomes.²⁵

The effect of antibiotics on immunotherapy outcomes appears to be particularly pronounced in kidney cancer compared with other tumor types. One analysis found that antibiotic exposure roughly doubled the risk of progression in kidney cancer patients, an effect that was statistically larger than in lung cancer or melanoma patients. The timing mattered too: antibiotics given right before starting immunotherapy had a stronger negative impact than those given later.²⁶ This does not mean patients should skip necessary antibiotics, but it has led to increasing awareness among oncologists about avoiding unnecessary antibiotic prescriptions in the weeks leading up to immunotherapy.

The Cost Question

Immunotherapy combinations are expensive, and cost-effectiveness analyses paint a complicated picture. A study from a public payer perspective found that sunitinib remains the least expensive option at roughly $360,000 to $660,000 over a patient’s treatment course, while immunotherapy combinations ranged from about $960,000 to over $1.4 million. Nivolumab plus ipilimumab yielded the most quality-adjusted life-years at 3.6, but the additional cost per quality-adjusted life-year gained compared with sunitinib was roughly $300,000 to $350,000.²⁷

A separate analysis considering sequential treatment strategies, where the drug given after progression is factored in, found that nivolumab plus ipilimumab followed by cabozantinib at progression was the most cost-effective sequence in both the U.S. and China.²⁸ Still, a broader analysis concluded that none of the seven approved first-line immunotherapy combinations were cost-effective compared with sunitinib at standard willingness-to-pay thresholds in either the U.S. or China.²⁹ These analyses do not mean immunotherapy is not worth using. They highlight the gap between clinical benefit and affordability and underscore the importance of biosimilar development and drug-pricing reform.

CAR T-Cell Therapy and Next-Generation Approaches

For patients who have exhausted checkpoint inhibitors and targeted drugs, entirely new classes of immunotherapy are in early testing. One of the most intriguing is CTX130, an “off-the-shelf” CAR T-cell product engineered to attack a protein called CD70 that is commonly found on clear cell kidney cancer. Unlike standard CAR T-cell therapies that must be custom-built from a patient’s own cells, CTX130 uses donor cells that have been gene-edited to avoid rejection, making it available immediately rather than after weeks of manufacturing.

In a first-in-human phase I trial of 16 patients with heavily pretreated kidney cancer, CTX130 caused no dose-limiting toxicities and achieved disease control in about 81% of patients. One patient achieved a complete response that was still ongoing at three years, which the investigators noted was the first durable complete response achieved with an off-the-shelf CAR T-cell product in any solid tumor.³⁰ These are very early results in a small number of patients, but they suggest that cellular immunotherapy could eventually play a role in kidney cancer, particularly for patients who have run out of other options.

Meanwhile, researchers are also exploring new checkpoint targets beyond PD-1 and CTLA-4. TIGIT is one such target under investigation in kidney cancer. About 40% of kidney tumors contain T cells expressing TIGIT, a frequency comparable to lung cancer but lower than melanoma or head-and-neck cancers. Intriguingly, TIGIT expression in kidney tumors showed a negative correlation with PD-1 expression, meaning the two checkpoints may operate somewhat independently.³¹ If confirmed in larger studies, this could mean TIGIT-blocking drugs might help patients whose tumors resist PD-1-based therapies, though clinical trials testing this hypothesis are still in their early stages.