Abstract
Clear cell renal cell carcinoma (ccRCC) remains a challenging malignancy to treat, with immune checkpoint inhibitors (ICIs) revolutionizing patient management. This pilot study, evaluated the efficacy and safety of combination therapy comprising camrelizumab, an anti-PD-1 antibody, and autologous cytokine-induced killer (CIK) cell therapy in patients with refractory ccRCC. Twenty-one patients with refractory ccRCC were randomly assigned to receive either camrelizumab monotherapy (control group, n = 12) or camrelizumab combined with CIK cell re-transfusion (trial group, n = 9). Due to early termination (21 of 60 planned patients), all endpoints were exploratory. The objective response rate (ORR) was numerically higher in the combination group (55.6% vs. 41.7%; odds ratio 1.75, 95% confidence interval [CI]: 0.32–9.51), but not statistically significant. Median progression-free survival (PFS) was 28.5 vs. 8.67 months (hazard ratio [HR] 0.40, 95% CI: 0.12–1.34), and median overall survival (OS) was not reached vs. 57.47 months (HR 0.48, 95% CI: 0.09–2.53). One patient in the trial group achieved a complete metabolic response (CMR). The combination was well-tolerated without new safety signals. Exploratory analysis suggested that higher baseline PD-1 expression on CD8+ T cells might be associated with a better response, and the frequency of PD-1 positive cells tended to decrease after camrelizumab administration. The addition of CIK cell therapy to anti-PD-1 antibody showed signals of potential benefit in refractory ccRCC with a tolerable safety profile. This pilot study suggests the combination approach appears feasible and warrants investigation in larger trials in pretreated ccRCC patients.
Registry: ClinicalTrials.gov, TRN: NCT03987698, Registration date: 17 June 2019.
Supplementary Information
The online version contains supplementary material available at 10.1038/s41598-026-38881-1.
Keywords: Refractory clear cell renal cell carcinoma, Anti-angiogenic agents, anti-PD-1 antibody, Autologous cytokine-induced killer cell therapy
Subject terms: Cancer, Immunology, Oncology
Introduction
Renal cell cancer (RCC) is the 14th most common cancer, with more than 400,000 newly diagnosed cases in 2020 globally. Compared to the Asian population, the frequency is higher in Caucasians, with an increase in morbidity1,2. High rates of early diagnosis using improved medical imaging techniques and the development of systemic therapies have contributed to the declining overall mortality rate of RCC3. Clear cell renal cell cancer (ccRCC), which represents approximately 80% of all cases, along with the remaining non-clear cell RCC, comprises the variant histology of RCC2. The treatment of RCC has evolved from cytokine therapy to targeted agents and, more recently, to immune checkpoint inhibitors (ICIs)4–7.
The tumor immune microenvironment (TIME) in ccRCC is usually suppressive, represented by T cell exhaustion and the impact of dendritic cell maturation, which leads to a paradoxical association between increased CD8+ T cell infiltration and poor survival, and insufficient antigen presentation8,9. Anti-programmed death 1 (PD-1) antibody disrupts programmed death ligand 1 (PD-L1)-mediated immune suppressive signaling to restore antitumor immune function10,11. CheckMate 025 was designed to investigate the overall survival of relapsed or refractory advanced or metastatic ccRCC treated with nivolumab, an anti-PD-1 monoclonal antibody, compared with that treated with everolimus. This clinical trial enrolled patients who received less than two lines of antiangiogenic-targeted therapy12. Long-term follow-up (FU) of CheckMate 025 demonstrated that the objective response rate (ORR) was significantly higher with nivolumab (22.9%) than with everolimus (4.1%). Progression-free survival (PFS) and overall survival (OS) were favorable with nivolumab13. Thus, a new era of immunotherapy for ccRCC had opened. ICIs in combination with antiangiogenic agents or combined PD-1 and CTLA-4 blockade are now recommended by the National Comprehensive Cancer Network (NCCN) guidelines for first-line systemic therapy of ccRCC in all International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups5,14–16. Nevertheless, the development of treatment strategies to extend PFS and OS in first-line therapy, as well as for recurrent or refractory ccRCC, remains a pressing issue that requires further investigation.
Autologous cytokine-induced killer (CIK) cells are a heterogeneous group of immune cells, including CD3+CD56+ natural killer (NK)-like T cells, which lack major histocompatibility complex (MHC) restrictions17–19. CIK cells are expanded from blood mononuclear cells cultured with cytokines ex vivo20,21. Adoptive CIK cell therapy monotherapy is considered safe and effective for advanced or metastatic RCC, with an ORR ranging from 15% to 50%22,23. In our earlier clinical studies, we demonstrated that immunotherapy with CIK cells enhanced the effectiveness of chemotherapy in patients with advanced non-small cell lung cancer (NSCLC)24,25. CIK cells have been shown to influence the TIME22. Consequently, the combination of CIK cells with anti-PD-1 antibodies could theoretically produce a synergistic effect. We designed a phase II clinical trial that enrolled patients with recurrent or refractory advanced or metastatic ccRCC who had failed previous targeted and/or cytokine therapies. Patients were randomly assigned to camrelizumab monotherapy or combined with CIK cells to evaluate the efficacy and safety of the treatment, with biomarker exploration.
Materials and methods
Patients
The main inclusion criteria were as follow: (i) patients of either gender who are between the ages of 18 and 75 years old; (ii) pathologically confirmed ccRCC; (iii) postoperative recurrence or metastatic status; iii) failure after at least one type of antiangiogenic targeted therapy and/or cytokine; (iv) at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) guidelines; (v) expected lifespan > 3 months; (vi) Karnofsky performance status (KPS) of at least 70 at the time of study entry. Patients with central nervous system metastases, prior anti-PD(L)1 monoclonal antibody therapy, or those requiring corticosteroids (equivalent to > 10 mg of prednisone daily) or immunosuppressant therapy were excluded.
Study design
This was a randomized, open-label, single-center, phase II study comparing camrelizumab with camrelizumab plus CIK cell re-transfusion (ClinicalTrials.gov number, NCT03987698, Registration date: 17 June 2019). However, due to premature termination with only 21 of the planned 60 patients enrolled, the study functions as a pilot, hypothesis-generating investigation rather than a definitive phase II trial. This study was approved by the Ethics Committee of Tianjin Medical University Cancer Hospital and Institute (No. E2017232). This study adhered to the principles of the Declaration of Helsinki. The flowchart of screening and study inclusion is shown in Supplementary Appendix Figure S1. All patients provided written informed consent for their involvement and for the publication of the results. The Memorial Sloan Kettering Cancer Center (MSKCC) prognostic risk is based on the presence of zero (favorable risk), one or two (intermediate risk), or three (poor risk) of the following prognostic factors: anemia, hypercalcemia, and poor performance status, as mentioned in the CheckMate 025 study12,26. Eligible patients received camrelizumab (200 mg, intravenous) on day 1 every 3 weeks in both groups. CIK cell therapy was administered for up to 6 cycles on day 14 in the trial group. Camrelizumab was administered until radiographic progression, unacceptable toxic effects, investigator decision, or patient withdrawal of consent. The detailed trial protocol is provided in the supplementary materials.
Randomization
Randomization (1:1 ratio) was performed with a block size of 4, with the MSKCC prognostic risk group. Randomization was performed using a computer-generated random sequence with permuted blocks (block size of 4) prepared by an independent statistician not involved in patient care or outcome assessment. To ensure allocation concealment, treatment assignments were placed in sequentially numbered, opaque, sealed envelopes. Envelopes were opened sequentially only after written informed consent was obtained, eligibility criteria were confirmed, and baseline assessments were completed. The randomization envelope was opened by the research coordinator in the presence of the enrolling investigator, and the treatment assignment was immediately documented in the patient’s medical record and case report form. Due to the nature of the intervention (autologous CIK cell therapy requiring leukapheresis and ex vivo cell expansion), blinding of patients and treating physicians was not feasible. However, to minimize detection bias, all tumor response assessments were performed by independent radiologists who were blinded to treatment allocation and clinical outcomes.
End points and assessments
The study was originally designed with PFS as the primary endpoint, with ORR and OS as secondary endpoints (ClinicalTrials.gov: NCT03987698). Due to premature termination, resulting in a final enrollment of only 21 patients, the study was significantly underpowered for its planned primary endpoint. Post-hoc power analysis confirmed only 10% power to detect the observed ORR difference. Therefore, all efficacy endpoints are reported as exploratory and hypothesis-generating. Tumors were assessed using imaging examination at baseline and every 6 weeks or when clinical symptoms aggravated. ORR was defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR). The time to response (TTR) was defined as the time from the start of treatment to the first documented objective response. Patients who did not achieve a response by the end of the follow-up period were censored at the date of their last tumor assessment. The duration of response (DoR) was a conditional endpoint, analyzed only in the subset of patients who achieved an objective response. DoR was defined as the time from the first documented response to the first documented disease progression or death from any cause. Patients who were alive and had not progressed at the time of data cutoff were censored at the date of their last valid tumor assessment. PFS was the time from the initial treatment until the date of disease progression or the date of death from any cause, whichever occurred first. OS was the time from the initial treatment until the date of death from any cause. Adverse events were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (CTCAE v4.0). The evaluation of complete metabolic response (CMR) was based on the Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) 1.0.
CIK cells preparation
CIK cells were prepared as described in our previous studies25,27. The detailed manufacturing procedure for CIK is presented in Sect. 5.3 of the trial protocol, as found in the supplementary materials.
Biomarkers expression analysis
Peripheral blood samples were obtained from patients who provided informed consent for biological specimen collection. PBMCs were isolated by Ficoll density separation using HISTOPAQUE-1077 (Sigma-Aldrich, Cat# 10771) solution, according to the manufacturer’s instructions. One million cells were stained with PerCP-Cy5 anti-human CD45 (BioLegend, Cat# 304028), FITC anti-human CD3 (BioLegend, Cat# 317306), APC anti-human CD8 (Biolegend, Cat# 344722), and APC-Cy7 anti-human PD-1 (Biolegend, Cat# 329922. Cells were washed twice with wash buffer, analyzed on a BD Aria II flow cytometer (BD Biosciences, San Diego, CA, USA), and analyzed using FlowJo software (v.10.10.0, FlowJo LLC, Ashland, OR, USA).
Statistical analysis
Statistical analyses were conducted using R and R Studio version (2025.05.1 + 513). The sample size was calculated using PASS version 15.0 software. The PFS of anti-PD-1 was approximately 4.5 months as second- or later-line therapy for advanced ccRCC; thus, it was speculated that the combined application of CIK cells and anti-PD-1 agents could increase the PFS to 11–14 months. With a one-sided α ≤ 0.05 as the test level, a sample size of 60 cases was needed when β = 0.2. Regrettably, we were compelled to terminate this study prematurely because of the COVID-19 pandemic and the approval of anti-PD-1 agents in combination with antiangiogenic drugs as first-line therapy. Only 21 patients were enrolled and randomized in this study. The distribution of TTR and DoR for each treatment group were estimated using the Kaplan-Meier (KM) method. The median TTR and DoR and their 95% confidence interval (CI) were derived from the KM curves. KM and log-rank tests were performed for overall survival and progression-free survival analyses and to assess the association with potential prognostic factors. The Cox proportional hazards model was used for multivariate analyses using the forward-likelihood ratio method. Statistical significance was set at p < 0.05, obtained using two-sided tests.
Power analysis
Post-hoc statistical power analysis was performed using G*Power 3.1.9.7 (Heinrich Heine University Düsseldorf, Germany). With 12 patients in the camrelizumab monotherapy group and 9 patients in the combination therapy group, and observed ORRs of 41.7% and 55.6% respectively, the study achieved approximately 10% statistical power (α = 0.05, two-sided) to detect this 13.9% difference in response rates. This analysis confirms that the study was significantly underpowered to draw definitive conclusions regarding treatment efficacy.
Results
Patient characteristics
From April 2019 to December 2021, 21 patients were enrolled in this clinical trial and randomly assigned to receive either camrelizumab monotherapy or camrelizumab in combination with CIK cell re-transfusion. Of these, nine patients were allocated to the trial group, while 12 patients were assigned to the control group. As of the data cutoff in May 2025, the minimum FU period was 41 months, with a median FU period of 62.23 months. The demographic and clinical characteristics of the patients are presented in Table 1.
Table 1.
Baseline clinical characteristics of the patients.
| Characteristics | Treatment groups | ||
|---|---|---|---|
| Control (N = 12) | Trial (N = 9) | Total (N = 21) | |
| Median age (range) — years | 62 (49–68) | 66 (53–74) | 63 (49–74) |
| Sex — no. (%) | |||
| Male | 8 (67) | 8 (89) | 16 (76) |
| Female | 4 (33) | 1 (11) | 5 (24) |
| MSKCC risk group — no. (%) | |||
| Favorable | 4 (33) | 5 (56) | 9 (43) |
| Intermediate | 6 (50) | 3 (33) | 9 (43) |
| Poor | 2 (17) | 1 (11) | 3 (14) |
| KPS— no. (%) | |||
| 90 | 5 (42) | 4 (44) | 9 (43) |
| 80 | 5 (42) | 4 (44) | 9 (43) |
| 70 | 2 (17) | 1 (11) | 3 (14) |
| Previous nephrectomy — no. (%) | |||
| Yes | 9 (75) | 8 (89) | 17 (81) |
| No | 3 (25) | 1 (11) | 4 (19) |
| Previous cytokine therapy — no. (%) | |||
| Yes | 1 (8) | 4 (44) | 5 (24) |
| No | 11 (92) | 5 (56) | 16 (76) |
| Previous antiangiogenic regimens — no. (%) | |||
| 0 | 0 (0) | 1 (11) | 1 (5) |
| 1 | 8 (67) | 5 (56) | 13 (62) |
| 2 | 3 (25) | 2 (22) | 5 (24) |
| 3 | 1 (8) | 1 (11) | 2 (10) |
KPS, Karnofsky performance status.
Efficacy
Tumor response
The ORR was 55.6% (5/9; 95% CI: 21.2%-86.3%) in the combination therapy group and 41.7% (5/12; 95% CI: 15.2%-72.3%) in the monotherapy group (odds ratio [OR] 1.75; 95% CI: 0.32–9.51; P = 0.68) (Fig. 1A). This numerical difference did not reach statistical significance. PR were observed in 5 patients (41.7%), and no CR was observed in nine patients who were assigned to the control group. Four PR and 1 CMR (55.6% total) were observed in the trial group (Fig. 1B). Figure 2A depicts the alterations in the tumor burden according to the best response. Figure 2B shows the changes in tumor burden during treatment, categorized by groups. The median TTR for patients who achieved an objective response in the trial group was 6.5 months (95% CI, 3.3 months to not estimable). The control group had a median TTR of 6.4 months (95% CI, 2.7 months to not estimable), among the 5 patients who responded (Supplementary Appendix Figure S2). No statistically significant difference was observed in the TTR between the groups. The DoR was 36.03 months, ranging from 6.47 to 69.97 months, for camrelizumab monotherapy, and 31.37 months, with a range of 11.73 to 71.33 months, for camrelizumab combined with CIK (Supplementary Appendix Figure S3). No statistically significant difference was observed in the DoR between the two groups. Detailed information on the patients is provided in Supplementary Appendix Table S4.
Fig. 1.
Objective response rate and swimming plot of all patients (N = 21). (A) Difference of objective response rate between treatment groups. Error bar indicates the 95% confidence interval. (B) Swimmer plot with treatment groups, risk category and event timeline. Blue arrow indicates ongoing survival. Black arrow indicates the start of following therapy. ORR, objective response rate; CMR, complete metabolic response; PR, partial response; SD, stable disease; PD, progressive disease.
Fig. 2.
Changes in tumor burden upon treatment initiation. (A) Maximal change of tumor size from base line assessed by investigator per Response Evaluation Criteria in Solid Tumors (RECIST) version1.1 (N = 21). Heatmap shows the risk category and treatment groups. The length of the bar represents the maximal decrease or minimal increase in the target lesion(s). (B) Percentage change in lesion size over time presented by groups. CMR, complete metabolic response; PR, partial response; SD, stable disease; PD, progressive disease.
Overall survival
The median OS was not reached (95% CI, 47.77 months to not estimable) in the trial group and 57.47 months (95% CI,18.73 months to not estimable) in the camrelizumab group (Fig. 3A). In the group of patients randomly assigned to receive combination therapy, 4 out of 9 (44.4%) died, whereas in the group receiving camrelizumab, 6 out of 12 patients (50%) died. The hazard ratio (HR) for death was 0.48 (95% CI, 0.09 to 2.53; p = 0.388), but this difference did not reach statistical significance. Given the very small sample size and extremely wide CI that crosses 1.0, no conclusions can be drawn regarding potential OS differences between groups. The 12-month OS rates were 100% and 83.3% in the trial and control groups, respectively. The 24-month OS rate was 88.9% in the trial group and 66.7% in the control group. The KM plot of the different risk groups for OS is shown in (Supplementary Appendix Figure S5). The univariate and multivariate Cox analyses of OS are presented in Supplementary Appendix Figure S6 ~ S7. Only prior nephrectomy showed statistical significance in both analyses. The subgroup analysis forest plot may not be an accurate reference because of the small sample size (Supplementary Appendix Figure S8).
Fig. 3.
Kaplan-Meier analysis of overall survival and progression-free survival. (A) Overall survival analysis in all patients presented by treatment groups. (B) Progression-free survival analysis in all patients presented by treatment groups. OS, overall survival; PFS, progression-free survival.
Progression-free survival
The median PFS was 28.5 months (95% CI, 10.83 to not estimable) in the trial group and 8.67 months (95% CI, 4.17 to not estimable) in the control group (Fig. 3B). The HR for progression was 0.40 (95% CI, 0.12 to 1.34; p = 0.136) favoring the combination group, but this difference was not statistically significant. The wide CI reflects the limited sample size and precludes definitive conclusions regarding PFS benefit. The 12-month PFS rates were 66.7% and 41.7% in the trial and control groups, respectively. While the 24-month PFS rates were 55.6% in the trial group and 25.0% in the control group. The KM plot of the different risk groups for PFS is shown in (Supplementary Appendix Figure S5). The univariate and multivariate Cox analyses of PFS are shown in Supplementary Appendix Figure S6 ~ S7. Similar to the OS results, prior nephrectomy showed statistical significance in both analyses. The forest plot for the subgroup analysis of PFS is presented in the Supplementary Appendix Figure S8 (without statistical significance).
PD-1 expression on CD8+ T cells in peripheral blood
To further explore the predictive biomarker of immunotherapy prognosis in recurrent or refractory ccRCC, PD-1 expression levels on CD8+ T cells were measured using Flow Cytometry. Blood samples were collected from 11 patients in both groups at baseline and subsequent time points prior to camrelizumab administration, with 6 in control group and 5 in trial group. Our data suggest that a higher baseline PD-1 expression on CD8+ T cells may be associated with a better best-of-response (BoR) in both groups (Fig. 4A). After administration, the PD-1 positive frequency of CD8+ T cells tended to decrease (Fig. 4B). The frequency of CD8+ T cells in lymphocytes showed no significant correlation with BoR at baseline, while its trajectory also presented a decreasing trend following camrelizumab administration (Supplementary Appendix Figure S9). The results mentioned above did not reach statistical significance, probably because of the insufficient sample size of the collected blood.
Fig. 4.
PD-1 positive frequency in CD8+ T cells in peripheral blood at baseline and trajectory during treatment. (A) Baseline PD-1 positive frequency in CD8+ T cells is higher in peripheral blood from partial response patients. (B) Trajectory changes of PD-1 positive frequency in CD8+ T cells in peripheral blood presented by objective response. C1 ~ C6 on the x axis of figure B indicate Cycle 1 ~ Cycle 6.
Safety
Treatment-related AEs of any grade occurred in 20 of the 21 patients (95.2%) in both groups (Table 2). It should be noted that this particular anti-PD-1 antibody has a unique adverse effect called hemangioma, which occurred in 20 patients of any grade. As shown in the Table 2, most of the AEs were grade 1/2. Treatment discontinuation occurred in 3 patients (14.3%) due to AEs, with 1 in the control group and 2 in the trial group, which were irrelevant to CIK cell re-transfusion. All three patients remained alive at the FU endpoint and were in good condition. The most common AEs were hemangiomas, hypothyroidism, elevated uric acid levels, anemia, and fatigue. CIK cell re-transfusion did not increase the frequency of AEs and was well tolerated.
Table 2.
Safety profile summary.
| Group | Grade 1 | Grade 2 | Grade 3 | |
|---|---|---|---|---|
| Hemangioma | Control (n = 12) | 7 (58.3%) | 3 (25%) | 1 (8.3%) |
| Trial (n = 9) | 4 (44.4%) | 2 (22.2%) | 0 (0%) | |
| Hypothyroidism | Control (n = 12) | 3 (25%) | 1 (8.3%) | 0 (0%) |
| Trial (n = 9) | 3 (33.3%) | 0 (0%) | 0 (0%) | |
| Adrenocortical insufficiency | Control (n = 12) | 0 (0%) | 0 (0%) | 0 (0%) |
| Trial (n = 9) | 0 (0%) | 1 (11.1%) | 0 (0%) | |
| Interstitial pneumonia | Control (n = 12) | 0 (0%) | 0 (0%) | 0 (0%) |
| Trial (n = 9) | 0 (0%) | 1 (11.1%) | 0 (0%) | |
| Elevated transaminase | Control (n = 12) | 1 (8.3%) | 0 (0%) | 0 (0%) |
| Trial (n = 9) | 0 (0%) | 0 (0%) | 0 (0%) | |
| Elevated CK-MB | Control (n = 12) | 1 (8.3%) | 0 (0%) | 0 (0%) |
| Trial (n = 9) | 1 (11.1%) | 0 (0%) | 0 (0%) | |
| Elevated creatinine | Control (n = 12) | 2 (16.7%) | 0 (0%) | 0 (0%) |
| Trial (n = 9) | 1 (11.1%) | 0 (0%) | 0 (0%) | |
| Elevated Uric Acid | Control (n = 12) | 6 (50%) | 0 (0%) | 0 (0%) |
| Trial (n = 9) | 1 (11.1%) | 0 (0%) | 0 (0%) | |
| Hyperglycemia | Control (n = 12) | 1 (8.3%) | 0 (0%) | 0 (0%) |
| Trial (n = 9) | 0 (0%) | 0 (0%) | 0 (0%) | |
| Thrombocytopenia | Control (n = 12) | 1 (8.3%) | 0 (0%) | 0 (0%) |
| Trial (n = 9) | 0 (0%) | 0 (0%) | 0 (0%) | |
| Anemia | Control (n = 12) | 3 (25%) | 0 (0%) | 0 (0%) |
| Trial (n = 9) | 2 (22.2%) | 0 (0%) | 0 (0%) | |
| Diarrhea | Control (n = 12) | 0 (0%) | 0 (0%) | 0 (0%) |
| Trial (n = 9) | 1 (11.1%) | 0 (0%) | 0 (0%) | |
| Fatigue | Control (n = 12) | 3 (25%) | 0 (0%) | 0 (0%) |
| Trial (n = 9) | 1 (11.1%) | 0 (0%) | 0 (0%) |
One case with CMR
In our study, 1 male patient in the trial group developed immunotherapy-related adverse effect (irAE) after 2 cycles of camrelizumab administration and 1 cycle of CIK cell re-transfusion. Baseline images obtained using positron emission tomography-computed tomography (PET-CT) are shown in Fig. 5A. The patient had a large tumor burden at the beginning of treatment. After the second dose of camrelizumab and before the second CIK cell re-transfusion, the patient experienced dyspnea and hypoxemia. Chest computed tomography (CT) revealed multiple small areas of ground-glass opacity (GGO) in both lungs and a large area of consolidation in the right lung (Fig. 5B). The patient was diagnosed with immunotherapy-related interstitial pneumonia. Antitumor treatment was suspended, and methylprednisolone was administered at 1 mg/kg body weight. His symptoms were relieved after several days. Imaging FU demonstrated further remission of the interstitial pneumonia (Supplementary Appendix Figure S10). The glucocorticord dosage was gradually reduced. His last PET-CT scan on May 26, 2021, 16.8 months after diagnosis of irAE, showed no 18F-FDG uptake in any of the tumor lesions, confirming CMR. The patient did not receive any antitumor therapy since the irAE occurred. He was still alive at the endpoint of FU with a high quality of life.
Fig. 5.
Imaging of the patient with complete metabolic response and immunotherapy-related adverse effect. (A) Positron emission tomography-computed tomography (PET-CT) scan prior to camrelizumab and CIK administration. (B) Computed tomography (CT) scans when the patient had dyspnea and hypoxemia. Interstitial pneumonia was diagnosed. (C) PET-CT scans at 16.8 months after the diagnosis of interstitial pneumonia. No obvious 18F-FDG uptake was observed in any of the tumor lesions.
Discussion
This exploratory study evaluated the combination of camrelizumab and CIK cell therapy in patients with refractory ccRCC. The trial group showed an ORR of 55.6% (5/9; 95% CI: 21.2%-86.3%), compared to 41.7% (5/12; 95% CI: 15.2%-72.3%) in the control group (OR 1.75, 95% CI: 0.32–9.51, P = 0.68). Two patients in the control group experienced disease progression at the first evaluation. An encouraging case of complete metabolic response with long-term survival was noted in the trial group. Numerical differences in PFS (median 28.5 vs. 8.67 months, HR 0.40) and OS (not reached vs. 57.47 months, HR 0.48) favored the combination group, but these differences did not reach statistical significance. The extremely wide CI reflect the limited statistical power of this small cohort, and the observed differences should be interpreted as hypothesis-generating signals. The combination regimen was well-tolerated, with no new safety signals emerging. In summary, these preliminary data suggest a potential benefit for adding CIK therapy to anti-PD-1 antibodies and warrant further investigation in larger clinical trials to confirm these findings. Exploratory biomarker analysis suggested a potential association between baseline PD-1 expression on CD8+ T cells and prognosis, with its frequency tending to decrease after treatment.
In the CheckMate 025 study, the survival benefit from nivolumab was independent of PD-L1 expression on ccRCC tumor cells12. Previous investigations have demonstrated that higher PD-L1 expression was associated with poorer survival28–31. No correlation has been observed between PD-L1 expression and immunotherapy outcomes12,13, or even a paradoxical association32. This indicates a different TIME of ccRCC from other “hot tumors” such as urothelial carcinoma33 and some subtypes of NSCLC34, in which high PD-L1 expression is associated with a good treatment response to anti-PD-(L)1 agents. In ccRCC, elevated PD-L1 expression is frequently associated with a higher presence of exhausted CD8+ T cells and increased VEGF expression within the tumor35,36. Braun et al. illustrated that as ccRCC advanced, there was a shift from effective to exhausted T cells9. It is widely recognized that anti-PD-(L)1 immunotherapy works by “releasing the brakes” to reverse the exhaustion of PD-1hi CD8+ T cells37. In our study, PD-1 expression on CD8+ T cells in the peripheral blood was evaluated using Flow Cytometry. A trend was observed between better prognosis and higher baseline PD-1 expression on CD8+ T cells, which decreased after anti-PD-1 antibody administration, regardless of CIK cell re-transfusion. These results contrast with previous studies on the predictive value of CD8+ T cells in the peripheral blood of patients with ccRCC38. This study demonstrated that CD8+ T cells proliferated after anti-PD-1 antibody treatment. In addition, PD-1 expression on CD8+ T cells was upregulated in patients without an objective response to treatment38. These results suggest that the change in PD-1 expression on effective immune cells pre- and post-immunotherapy may indicate a potential mechanism refunctioning from exhausted to cytotoxic status, so-called “counter-immunoediting” from immune equilibrium to elimination, as reviewed by our team39. A multi-omics study should be conducted to further evaluate this hypothesis.
Furthermore, the ORR of the camrelizumab monotherapy group (41.7%) in our study was higher than that in CheckMate 025 (25.0%) but was similar to that of the subgroup analysis of CheckMate 025 in the Japanese population (43.0%)12,40. Asian people seemed to have a better prognosis with immunotherapy than patients from Europe and North America, who were the dominant population in the CheckMate 025 study cohort. This suggests a significant variation in the TIME of ccRCC between Asian and Caucasian patients, which requires further investigation.
CIK cells are a group of immune effector cells characterized by the properties of activated T and NK cells17. CIK cells exhibit antitumor capabilities without MHC restriction41, with the ability to specifically penetrate tumor tissues, thereby creating an inflammatory microenvironment within the tumor19. CIK cells also play a role in reducing the number of suppressive immune cells, such as myeloid-derived suppressor cells (MDSCs)22 and regulatory T cells (Tregs)19,22. In theory, the combination of anti-PD-1 antibodies with CIK cells should result in a synergistic effect. Upon re-transfusion into the body, CIK cells selectively infiltrate tumor tissues, thereby inducing a localized inflammatory microenvironment. Cooperating with anti-PD-1 agents, could be transferred from immune tolerance to immune effectiveness. In our study, the ORR suggested a possible beneficial signal, increasing from 41.7% in the control group to 55.6% in the CIK group, though this difference did not reach statistical significance. Numerical improvements of PFS and OS were also observed. It should also be noted that the unique hemangioma AE of this particular drug resulted in treatment discontinuation in 2 patients. Nevertheless, these 2 patients, along with the patient who experienced immunotherapy-related interstitial pneumonia, exhibited a tendency towards longer OS than other patients. The occurrence of irAEs may indicate a more favorable prognosis in metastatic NSCLC treated with ICIs42. However, further research is required to determine whether this association between irAE and prognosis is also present in patients with ccRCC.
It is well established that the rapid growth of tumor cells creates a hypoxic intratumoral environment, which subsequently induces the overexpression of VEGF43,44, promoting endothelial cell proliferation and survival, generating malformed neovessels with malfunctions, and building an immunosuppressive TIME45,46. Agents targeting VEGF pathway, such as sunitinib, result in an equilibrium between anti- and pro-angiogenic signals, called vascular normalization, which allows tumor vessels to deliver sufficient effective immune cells into the tumor47–49. Based on the results of the KEYNOTE-4266 and CLEAR50 trials, pembrolizumab, an anti-PD-1 antibody, combined with axitinib or lenvatinib (both antiangiogenic agents), was recommended as the first-line therapy by the NCCN guidelines for all ccRCC risk groups51. The markedly improved outcomes of these combination regimens demonstrate the synergistic effect of ICIs and antiangiogenic drugs, as previously mentioned. In the second-line setting CheckMate 025, patients with ccRCC undergoing antiangiogenic therapies were enrolled12, and the TIME may have shifted from immunosuppression to immunoactivation after prior targeted therapy. This explains why patients benefit from anti-PD-1 antibody therapy, regardless of PD-L1 expression. In our cohort, similar efficacy was observed in the camrelizumab monotherapy group compared to the Japanese cohort in CheckMate 025, with numerical improvements in ORR, PFS, and OS in the combination group. These preliminary findings suggest that the addition of CIK cells to anti-PD-1 therapy appears feasible and may exhibit potential antitumor activity in pretreated patients with refractory ccRCC. Given the evolving treatment landscape, future studies could evaluate this combination approach in adequately powered trials, potentially in the setting of later-line therapy following progression on current standard-of-care regimens. The investigation of predictive biomarkers also requires further exploration using tumor samples, peripheral blood, and multi-omics studies.
Limitations
This study had several critical limitations. The extremely small sample size (n = 21, only 35% of the planned 60 patients) severely limits the statistical power and interpretation of the results. The numerical differences observed between groups cannot support definitive conclusions and require validation in adequately powered studies. Patients in this study had received prior single-agent TKI or CIK therapy, whereas the current first-line standard-of-care consists of ICI plus antiangiogenic combinations. This severely limits the external validity and generalizability of our findings to current clinical practice. Limited biomarker data from only 11 of 21 patients restricts conclusions from exploratory analyses. Tumor biopsy samples were unavailable, preventing a comprehensive assessment of the immune microenvironment. Other immune exhaustion markers, except for PD-1, on T cells were not measured in this study.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
We are grateful to our coworkers for their contribution to the clinical management of the patients.
Author contributions
S. Li and J. Qin wrote the main manuscript text. Q. Sun and H. Zhao conducted quality control and visualization. Y. Xiong, Y. Wang, Y. Han, J. Zhang, W. Zhang, M. Shen, F. Yang, B. Ren, and L. Zhou conducted data investigation and curation. R. Li, Z. Hui, X. Tian, S. Cao, and W. Du contributed to data interpretation. W. Yu performed flow cytometry assessments. L. Liu, X. Zhang, and X.Ren conceptualized the study, reviewed, and revised the whole manuscript. All authors agreed on all aspects of the work and approved the final version of the manuscript.
Funding
This work was funded by Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-009 A), The Science & Technology Development Fund of Tianjin Education Commission for Higher Education (2021KJ203), National Natural Science Foundation of China (82372779, 82373283, and 82302913), National Natural Science Foundation (NSFC) Cultivation Program of Tianjin Medical University Cancer Institute & Hospital (230103) and Doctor Startup Fund of Tianjin Medical University Cancer Institute and Hospital (B2414). This investigator-initiated trial funded by Tianjin Medical University Cancer Institute and Hospital. Drug supply: Camrelizumab was provided by Jiangsu Hengrui Medicine Co., Ltd. at no cost. Funder role: No involvement in study design, data collection, analysis, or manuscript preparation.
Data availability
All data supporting the findings of this study are available within the article or its Supplementary Information.
Declarations
Competing interests
The authors declare no competing interests.
Ethics approval
This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Tianjin Medical University Cancer Hospital and Institute (No. E2017232). All patients provided written informed consent for their involvement and for the publication of the results.
Consent for publication
The authors affirm that participant provided informed consent for publication of the images in Fig. 5A, B and C and Figure S10.
Consent to participate
Informed consent was obtained from all individual participants included in the study.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Contributor Information
Shuzhan Li, Email: lishuzhan@tjmuch.com.
Jing Qin, Email: qj1059469865@163.com.
Liang Liu, Email: liuliang@tjmuch.com.
Xinwei Zhang, Email: zhangxinwei@tjmuch.com.
Xiubao Ren, Email: renxiubao@tjmuch.com.
References
- 1.Sung, H. et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Cancer J. Clin.71, 209–249. 10.3322/caac.21660 (2021). [DOI] [PubMed] [Google Scholar]
- 2.Young, M. et al. Renal cell carcinoma. Lancet (London England). 404, 476–491. 10.1016/s0140-6736(24)00917-6 (2024). [DOI] [PubMed] [Google Scholar]
- 3.Bukavina, L. et al. Epidemiology of renal cell carcinoma: 2022 update. Eur. Urol.82, 529–542. 10.1016/j.eururo.2022.08.019 (2022). [DOI] [PubMed] [Google Scholar]
- 4.Motzer, R. J. et al. Sunitinib versus interferon Alfa in metastatic renal-cell carcinoma. N. Engl. J. Med.356, 115–124. 10.1056/NEJMoa065044 (2007). [DOI] [PubMed] [Google Scholar]
- 5.Powles, T. et al. Pembrolizumab plus axitinib versus Sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol.21, 1563–1573. 10.1016/s1470-2045(20)30436-8 (2020). [DOI] [PubMed] [Google Scholar]
- 6.Plimack, E. R. et al. Pembrolizumab plus axitinib versus Sunitinib as First-line treatment of advanced renal cell carcinoma: 43-month Follow-up of the phase 3 KEYNOTE-426 study. Eur. Urol.84, 449–454. 10.1016/j.eururo.2023.06.006 (2023). [DOI] [PubMed] [Google Scholar]
- 7.Vuky, J. & Motzer, R. J. Cytokine therapy in renal cell cancer. Urol. Oncol.5, 249–257. 10.1016/s1078-1439(00)00068-5 (2000). [DOI] [PubMed] [Google Scholar]
- 8.Xu, W. et al. Heterogeneity in tertiary lymphoid structures predicts distinct prognosis and immune microenvironment characterizations of clear cell renal cell carcinoma. J. Immunother. Cancer. 1110.1136/jitc-2023-006667 (2023). [DOI] [PMC free article] [PubMed]
- 9.Braun, D. A. et al. Progressive immune dysfunction with advancing disease stage in renal cell carcinoma. Cancer cell.39, 632–648e638. 10.1016/j.ccell.2021.02.013 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Hamid, O. & Carvajal, R. D. Anti-programmed death-1 and anti-programmed death-ligand 1 antibodies in cancer therapy. Expert Opin. Biol. Ther.13, 847–861. 10.1517/14712598.2013.770836 (2013). [DOI] [PubMed] [Google Scholar]
- 11.Iwai, Y. et al. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 Blockade. Proc. Natl. Acad. Sci. U.S.A.99, 12293–12297. 10.1073/pnas.192461099 (2002). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Motzer, R. J. et al. Nivolumab versus everolimus in advanced Renal-Cell carcinoma. N. Engl. J. Med.373, 1803–1813. 10.1056/NEJMoa1510665 (2015). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Motzer, R. J. et al. Nivolumab versus everolimus in patients with advanced renal cell carcinoma: updated results with long-term follow-up of the randomized, open-label, phase 3 checkmate 025 trial. Cancer126, 4156–4167. 10.1002/cncr.33033 (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Motzer, R. et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N. Engl. J. Med.384, 1289–1300. 10.1056/NEJMoa2035716 (2021). [DOI] [PubMed] [Google Scholar]
- 15.Powles, T. et al. Nivolumab plus Cabozantinib versus Sunitinib for first-line treatment of advanced renal cell carcinoma: extended follow-up from the phase III randomised checkmate 9ER trial. ESMO Open.9, 102994. 10.1016/j.esmoop.2024.102994 (2024). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Motzer, R. J. et al. Nivolumab plus ipilimumab versus Sunitinib in advanced Renal-Cell carcinoma. N. Engl. J. Med.378, 1277–1290. 10.1056/NEJMoa1712126 (2018). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Schmidt-Wolf, I. G. et al. Phenotypic characterization and identification of effector cells involved in tumor cell recognition of cytokine-induced killer cells. Exp. Hematol.21, 1673–1679 (1993). [PubMed] [Google Scholar]
- 18.Jiang, Y., Qiu, J., Ye, N. & Xu, Y. Current status of cytokine-induced killer cells and combination regimens in breast cancer. Front. Immunol.16, 1476644. 10.3389/fimmu.2025.1476644 (2025). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Meng, Y. et al. Cell-based immunotherapy with cytokine-induced killer (CIK) cells: from Preparation and testing to clinical application. Hum. Vaccin Immunother.. 13, 1–9. 10.1080/21645515.2017.1285987 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Zhang, Q. et al. The dual-functional capability of cytokine-induced killer cells and application in tumor immunology. Hum. Immunol.76, 385–391. 10.1016/j.humimm.2014.09.021 (2015). [DOI] [PubMed] [Google Scholar]
- 21.Gao, X. et al. Cytokine-Induced killer cells as Pharmacological tools for cancer immunotherapy. Front. Immunol.8, 774. 10.3389/fimmu.2017.00774 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Wang, Z. et al. Association of myeloid-derived suppressor cells and efficacy of cytokine-induced killer cell immunotherapy in metastatic renal cell carcinoma patients. J. Immunother. 37, 43–50. 10.1097/cji.0000000000000005 (2014). [DOI] [PubMed] [Google Scholar]
- 23.Liu, L. et al. Randomized study of autologous cytokine-induced killer cell immunotherapy in metastatic renal carcinoma. Clin. Cancer Res.18, 1751–1759. 10.1158/1078-0432.Ccr-11-2442 (2012). [DOI] [PubMed] [Google Scholar]
- 24.Han, Y. et al. Autologous cytokine-induced killer (CIK) cells enhance the clinical response to PD-1 blocking antibodies in patients with advanced non-small cell lung cancer: A preliminary study. Thorac. Cancer. 12, 145–152. 10.1111/1759-7714.13731 (2021). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Zhou, L. et al. A phase IB trial of autologous Cytokine-Induced killer cells in combination with Sintilimab, monoclonal antibody against programmed cell Death-1, plus chemotherapy in patients with advanced Non-Small-Cell lung cancer. Clin. Lung Cancer. 23, 709–719. 10.1016/j.cllc.2022.07.009 (2022). [DOI] [PubMed] [Google Scholar]
- 26.Motzer, R. J. et al. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J. Clin. Oncol.22, 454–463. 10.1200/jco.2004.06.132 (2004). [DOI] [PubMed] [Google Scholar]
- 27.Liu, L. et al. Randomized, multicenter, open-label trial of autologous cytokine-induced killer cell immunotherapy plus chemotherapy for squamous non-small-cell lung cancer: NCT01631357. Signal. Transduct. Target. Ther.5, 244. 10.1038/s41392-020-00337-x (2020). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Hong, B. et al. Differential expression of PD-L1 between sporadic and VHL-Associated hereditary Clear-Cell renal cell carcinoma and its correlation with clinicopathological features. Clin. Genitourin. Cancer. 17, 97–104e101. 10.1016/j.clgc.2018.11.001 (2019). [DOI] [PubMed] [Google Scholar]
- 29.Shen, M. et al. Association between PD-L1 expression and the prognosis and clinicopathologic features of renal cell carcinoma: A systematic review and Meta-Analysis. Urol. Int.104, 533–541. 10.1159/000506296 (2020). [DOI] [PubMed] [Google Scholar]
- 30.Donskov, F. et al. Molecular analysis and favorable clinical outcomes in real-world patients with metastatic renal cell carcinoma. Acta Oncol.61, 1268–1277. 10.1080/0284186x.2022.2119100 (2022). [DOI] [PubMed] [Google Scholar]
- 31.Yeong, J. et al. PD-L1 expression is an unfavourable prognostic indicator in Asian renal cell carcinomas. J. Clin. Pathol.73, 463–469. 10.1136/jclinpath-2019-206092 (2020). [DOI] [PubMed] [Google Scholar]
- 32.Sobottka, B. et al. Integrated analysis of immunotherapy treated clear cell renal cell carcinomas: an exploratory study. J. Immunother. 45, 35–42. 10.1097/cji.0000000000000387 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Maiorano, B. A. et al. Significance of PD-L1 in metastatic urothelial carcinoma treated with immune checkpoint inhibitors: A systematic review and Meta-Analysis. JAMA Netw. Open.7, e241215. 10.1001/jamanetworkopen.2024.1215 (2024). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Velcheti, V. et al. 5-Year Real-World outcomes with frontline pembrolizumab monotherapy in PD-L1 Expression ≥ 50% advanced NSCLC. Clin. Lung Cancer. 25, 502–508e503. 10.1016/j.cllc.2024.05.002 (2024). [DOI] [PubMed] [Google Scholar]
- 35.Zhu, Q. et al. PD-L1 expression patterns in tumour cells and their association with CD8(+) tumour infiltrating lymphocytes in clear cell renal cell carcinoma. J. Cancer. 10, 1154–1161. 10.7150/jca.29052 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Lee, K. S., Yun, S., Lee, K., Moon, S. & Choe, G. Clinicopathological implications of the expression of vascular endothelial growth factor and programmed death ligand 1 in clear-cell renal cell carcinoma. Hum. Pathol.99, 88–97. 10.1016/j.humpath.2020.03.013 (2020). [DOI] [PubMed] [Google Scholar]
- 37.Budimir, N., Thomas, G. D., Dolina, J. S. & Salek-Ardakani, S. Reversing T-cell exhaustion in cancer: lessons learned from PD-1/PD-L1 immune checkpoint Blockade. Cancer Immunol. Res.10, 146–153. 10.1158/2326-6066.Cir-21-0515 (2022). [DOI] [PubMed] [Google Scholar]
- 38.Carlisle, J. W. et al. Clinical outcome following checkpoint therapy in renal cell carcinoma is associated with a burst of activated CD8 T cells in blood. J. Immunother. Cancer. 1010.1136/jitc-2022-004803 (2022). [DOI] [PMC free article] [PubMed]
- 39.Liu, S., Sun, Q. & Ren, X. Novel strategies for cancer immunotherapy: counter-immunoediting therapy. J. Hematol. Oncol.1610.1186/s13045-023-01430-8 (2023). [DOI] [PMC free article] [PubMed]
- 40.Tomita, Y. et al. Nivolumab versus everolimus in advanced renal cell carcinoma: Japanese subgroup analysis from the checkmate 025 study. Jpn J. Clin. Oncol.47, 639–646. 10.1093/jjco/hyx049 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Nishimura, R. et al. In vivo trafficking and survival of cytokine-induced killer cells resulting in minimal GVHD with retention of antitumor activity. Blood112, 2563–2574. 10.1182/blood-2007-06-092817 (2008). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Cook, S. et al. Immune-Related adverse events and survival among patients with metastatic NSCLC treated with immune checkpoint inhibitors. JAMA Netw. Open.7, e2352302. 10.1001/jamanetworkopen.2023.52302 (2024). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Infantino, V., Santarsiero, A., Convertini, P., Todisco, S. & Iacobazzi, V. Cancer cell metabolism in hypoxia: role of HIF-1 as key regulator and therapeutic target. Int. J. Mol. Sci.2210.3390/ijms22115703 (2021). [DOI] [PMC free article] [PubMed]
- 44.Apte, R. S., Chen, D. S. & Ferrara, N. VEGF in signaling and disease: beyond discovery and development. Cell176, 1248–1264. 10.1016/j.cell.2019.01.021 (2019). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.Qian, C., Liu, C., Liu, W., Zhou, R. & Zhao, L. Targeting vascular normalization: a promising strategy to improve immune-vascular crosstalk in cancer immunotherapy. Front. Immunol.14, 1291530. 10.3389/fimmu.2023.1291530 (2023). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Mellman, I., Chen, D. S., Powles, T. & Turley, S. J. The cancer-immunity cycle: Indication, genotype, and immunotype. Immunity56, 2188–2205. 10.1016/j.immuni.2023.09.011 (2023). [DOI] [PubMed] [Google Scholar]
- 47.Tian, L. et al. Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming. Nature544, 250–254. 10.1038/nature21724 (2017). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48.Tu, J. et al. Nintedanib enhances the efficacy of PD-L1 Blockade by upregulating MHC-I and PD-L1 expression in tumor cells. Theranostics12, 747–766. 10.7150/thno.65828 (2022). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49.Allen, E. et al. Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation. Sci. Transl. Med.910.1126/scitranslmed.aak9679 (2017). [DOI] [PMC free article] [PubMed]
- 50.Choueiri, T. K. et al. Lenvatinib plus pembrolizumab versus Sunitinib as first-line treatment of patients with advanced renal cell carcinoma (CLEAR): extended follow-up from the phase 3, randomised, open-label study. Lancet Oncol.24, 228–238. 10.1016/s1470-2045(23)00049-9 (2023). [DOI] [PubMed] [Google Scholar]
- 51.Motzer, R. J. et al. NCCN Guidelines® insights: kidney Cancer, version 2.2024. J. Natl. Compr. Canc Netw.22, 4–16. 10.6004/jnccn.2024.0008 (2024). [DOI] [PubMed] [Google Scholar]
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This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
All data supporting the findings of this study are available within the article or its Supplementary Information.