Camrelizumab with or without Autologous Cytokine-induced Killer Cell Therapy in Patients with Refractory Clear Cell Renal Cell Carcinoma: A Randomized Pilot Study

Camrelizumab with or without Autologous Cytokine-induced Killer Cell Therapy in Patients with Refractory Clear Cell Renal Cell Carcinoma: A Randomized Pilot Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Camrelizumab with or without Autologous Cytokine-induced Killer Cell Therapy in Patients with Refractory Clear Cell Renal Cell Carcinoma: A Randomized Pilot Study Shuzhan Li, Jing Qin, Qian Sun, Hua Zhao, Yanjuan Xiong, Yang Wang, and 16 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7792293/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 07 Feb, 2026 Read the published version in Scientific Reports → Version 1 posted 11 You are reading this latest preprint version Abstract Clear cell renal cell carcinoma (ccRCC) remains a challenging malignancy to treat, with immune checkpoint inhibitors (ICIs) revolutionizing patient management. This clinical study, involving a small cohort, 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). The objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety were evaluated. Biomarker exploration was performed using peripheral blood samples from patients. A trend towards a higher ORR was observed in the trial group (55.6%) compared to the control group (41.7%). Favorable trends were also noted for median PFS (28.50 vs. 8.67 months) and median OS (not reached vs. 57.47 months) in the trial and control groups, respectively. One patient in the trial group achieved a complete metabolic response (CMR). No new safety signals were observed, and CIK cell re-transfusion did not appear to increase the frequency of adverse effects. 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 encouraging signals of antitumor activity in refractory ccRCC with a tolerable safety profile. These preliminary findings warrant further investigation, which could focus on the combination of ICIs, antiangiogenic agents, and CIK cell re-transfusion as a potential first-line therapy for metastatic or advanced ccRCC. Registry: ClinicalTrials.gov, TRN: NCT03987698, Registration date: 17 June 2019. Biological sciences/Cancer Biological sciences/Immunology Health sciences/Oncology recurrence refractory clear cell renal cell carcinoma anti-angiogenic agents anti-PD-1 antibody autologous cytokine-induced killer cell therapy Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 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 morbidity 1 , 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 RCC 3 . 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 RCC 2 . 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 presentation 8 , 9 . Anti-programmed death 1 (PD-1) antibody disrupts programmed death ligand 1 (PD-L1)-mediated immune suppressive signaling to restore antitumor immune function 10 , 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 therapy 12 . 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 nivolumab 13 . 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 groups 5 , 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) restrictions 17 – 19 . CIK cells are expanded from blood mononuclear cells cultured with cytokines ex vivo 20 , 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 TIME 22 . 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). 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 study 12 , 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 primary endpoint was the investigator-assessed PFS according to RECIST version 1.1. The secondary endpoints were ORR and OS. 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 studies 25 , 27 . The detailed manufacturing procedure for CIK is presented in section 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 a ≤ 0.05 as the test level, a sample size of 60 cases was needed when b = 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. Treatment Groups Characteristics 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 There was a trend towards a higher ORR in the combination therapy group compared to the monotherapy group (55.6% vs. 41.7%, p = 0.67) (Fig. 1 A). 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. 1 B). Figure 2 A depicts the alterations in the tumor burden according to the best response. Figure 2 B 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. 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. A trend towards a lower risk of death was observed with combination therapy versus monotherapy (HR 0.48), but this difference did not reach statistical significance (95% CI, 0.09 to 2.53; p = 0.388). 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). 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). Numerically, the hazard ratio for progression was 0.40 in favor of the trial group, but the difference was not statistically significant (95% CI, 0.12 to 1.34; p = 0.136). 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. 4 A). After administration, the PD-1 positive frequency of CD8 + T cells tended to decrease (Fig. 4 B). 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. 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. 5 A. 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. 5 B). 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 18 F-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. 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), compared to 41.7% in the control group. 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. Furthermore, favorable trends in PFS and OS were observed in the trial group, although these differences did not reach statistical significance, likely due to the small cohort size. 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. The small sample size limited the statistical power of our analyses, and the observed differences should be interpreted as hypothesis-generating trends. In the CheckMate 025 study, the survival benefit from nivolumab was independent of PD-L1 expression on ccRCC tumor cells 12 . Previous investigations have demonstrated that higher PD-L1 expression was associated with poorer survival 28 – 31 .No correlation has been observed between PD-L1 expression and immunotherapy outcomes 12 , 13 , or even a paradoxical association 32 . This indicates a different TIME of ccRCC from other “hot tumors” such as urothelial carcinoma 33 and some subtypes of NSCLC 34 , 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 tumor 35 , 36 . Braun et al. illustrated that as ccRCC advanced, there was a shift from effective to exhausted T cells 9 . It is widely recognized that anti-PD-(L)1 immunotherapy works by "releasing the brakes" to reverse the exhaustion of PD-1 hi CD8 + T cells 37 . 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 ccRCC 38 . 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 treatment 38 . 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 team 39 . 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 cells 17 . CIK cells exhibit antitumor capabilities without MHC restriction 41 , with the ability to specifically penetrate tumor tissues, thereby creating an inflammatory microenvironment within the tumor 19 . 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 showed a trend toward improvement from 41.7% in the control group to 55.6% in the CIK group, though this difference did not reach statistical significance. A trend of PFS and OS improvement was also observed. This small cohort may have caused this non-statistically significant results. 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 ICIs 42 . 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 VEGF 43 , 44 , promoting endothelial cell proliferation and survival, generating malformed neovessels with malfunctions, and building an immunosuppressive TIME 45 , 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 tumor 47 – 49 . Based on the results of the KEYNOTE-426 6 and CLEAR 50 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 groups 51 . 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 enrolled 12 , 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 an elevated trend of ORR and a prolonged trend PFS and OS in the trial group. It can be posited that the combination of ICIs, antiangiogenic agents, and CIK cell transfusion as first-line therapy may further enhance the clinical outcomes of patients with metastatic or advanced ccRCC. Further research on this regimen is warranted to evaluate its efficacy in larger cohorts. The investigation of predictive biomarkers also requires further exploration using tumor samples, peripheral blood, and multi-omics studies. Limitations This study had limitations due to its small sample size. The study was prematurely terminated due to the COVID-19 pandemic and the approval of antiangiogenic agents and ICIs as first-line therapies. It did not include a comparator arm with anti-PD-1 plus antiangiogenic therapy, which limits direct clinical applicability. Future studies should compare CIK cell combinations against current standard-of-care regimens. Limited blood sample availability precluded comprehensive and conclusive biomarker analyses. We were unable to obtain pre- and post-treatment biopsy samples. Consequently, we could not analyze the composition of the TIME in our cohort to discern differences between the pre-treatment and post-treatment phases. Additionally, other immune exhaustion markers, except for PD-1, on T cells were not measured in this study. Declarations Conflict of interest 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 to participate Informed consent was obtained from all individual participants included in the study. Consent for publication The authors affirm that participant provided informed consent for publication of the images in Fig. 5A, 5B, 5C and Figure S10. Funding This work was funded by Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-009A), 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. Author Contribution 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. Acknowledgements We are grateful to our coworkers for their contribution to the clinical management of the patients. Data Availability All data supporting the findings of this study are available within the article or its Supplementary Information. References 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). Young, M. et al. Renal cell carcinoma. Lancet (London England) . 404 , 476–491. 10.1016/s0140-6736(24)00917-6 (2024). Bukavina, L. et al. 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11:08:32","extension":"png","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":49813,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7792293/v1/a31e8b193c19b688d96c6df5.png"},{"id":95825074,"identity":"8ac2dbac-a745-44e6-8a35-1241a1761b3d","added_by":"auto","created_at":"2025-11-13 11:08:34","extension":"png","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":22772,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7792293/v1/bde223961ea0e0cb73713856.png"},{"id":95825127,"identity":"b0b5b9a0-7755-4153-af26-92516d057328","added_by":"auto","created_at":"2025-11-13 11:08:35","extension":"png","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":22088,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-7792293/v1/6683e0af5ea323984816a698.png"},{"id":95825142,"identity":"1e71aa35-d64a-48d6-95e6-aef02bbdfb57","added_by":"auto","created_at":"2025-11-13 11:08:36","extension":"png","order_by":15,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":263121,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-7792293/v1/e15f4f9d021550f4f637c8a1.png"},{"id":95825078,"identity":"41ba1322-df7f-4cb1-b51c-5580dba8d347","added_by":"auto","created_at":"2025-11-13 11:08:34","extension":"xml","order_by":16,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":151417,"visible":true,"origin":"","legend":"","description":"","filename":"6f758f4e85b54013a58204882b2c0c711structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7792293/v1/1aa9efb4a84e635727abdc78.xml"},{"id":95825071,"identity":"ddc91abf-3607-41d2-9d7e-5c9e40d2fcc3","added_by":"auto","created_at":"2025-11-13 11:08:34","extension":"html","order_by":17,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":168100,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7792293/v1/3eded3c4253ac7a629243221.html"},{"id":95825049,"identity":"0765271b-618f-4a17-8529-987b78ca831b","added_by":"auto","created_at":"2025-11-13 11:08:33","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":306067,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eObjective response rate and swimming plot of all patients (N=21).\u003c/strong\u003e 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.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7792293/v1/043ccc397a14a9a96269fa62.jpeg"},{"id":95825051,"identity":"ebe32858-b07a-46a2-9759-875f34ae19d5","added_by":"auto","created_at":"2025-11-13 11:08:33","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":262526,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eChanges in tumor burden upon treatment initiation.\u003c/strong\u003e 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.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7792293/v1/c337368cff4881d4f206fbe1.jpeg"},{"id":95825070,"identity":"c77e96d2-d1a5-494d-b1a0-cfda3e453993","added_by":"auto","created_at":"2025-11-13 11:08:34","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":118133,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eKaplan-Meier analysis of overall survival and progression-free survival. \u003c/strong\u003eA. 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.\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7792293/v1/7a4b233f19d02473c57b0acf.jpeg"},{"id":95825062,"identity":"826a014c-055e-4ccd-af99-38ca6bb344bc","added_by":"auto","created_at":"2025-11-13 11:08:33","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":97620,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePD-1 positive frequency in CD8\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e+\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003e T cells in peripheral blood at baseline and trajectory during treatment. \u003c/strong\u003eA. Baseline PD-1 positive frequency in CD8\u003csup\u003e+\u003c/sup\u003e T cells is higher in peripheral blood from partial response patients. B. Trajectory changes of PD-1 positive frequency in CD8\u003csup\u003e+\u003c/sup\u003e T cells in peripheral blood presented by objective response. C1~C6 on the x axis of figure B indicate Cycle 1~Cycle 6.\u003c/p\u003e","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7792293/v1/00116436001db6c96cae3ba4.jpeg"},{"id":95825076,"identity":"b4d93e1b-1fb5-499e-8ab9-0f9a1adc830a","added_by":"auto","created_at":"2025-11-13 11:08:34","extension":"jpeg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":657709,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eImaging of the patient with complete metabolic response and immunotherapy-related adverse effect. \u003c/strong\u003eA. 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 \u003csup\u003e18\u003c/sup\u003eF-FDG uptake was observed in any of the tumor lesions.\u003c/p\u003e","description":"","filename":"floatimage5.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7792293/v1/9d3a6256098f5086f2dcbf2c.jpeg"},{"id":102235927,"identity":"a78e21d6-ebd3-47df-b417-75ea0924f7a4","added_by":"auto","created_at":"2026-02-09 16:18:23","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2678956,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7792293/v1/cfaf69db-a6ae-46cc-b6bf-a336063550fb.pdf"},{"id":95825044,"identity":"39caf5ac-1ab9-4798-a362-0e828f4a5602","added_by":"auto","created_at":"2025-11-13 11:08:32","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":43608,"visible":true,"origin":"","legend":"","description":"","filename":"CONSORT2010Checklist.docx","url":"https://assets-eu.researchsquare.com/files/rs-7792293/v1/d2b0f3f3177d2e7a00c6111d.docx"},{"id":96239248,"identity":"b59f6232-e7e9-4c9e-9841-15259b6007b2","added_by":"auto","created_at":"2025-11-19 07:05:53","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":223200,"visible":true,"origin":"","legend":"","description":"","filename":"RESEARCHPROTOCOL.docx","url":"https://assets-eu.researchsquare.com/files/rs-7792293/v1/1ced2eee1e1be24d8e7f2328.docx"},{"id":95825081,"identity":"20fc4804-683a-49f9-a9c5-99a8c3b25afc","added_by":"auto","created_at":"2025-11-13 11:08:34","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":2682838,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementScientificReports.docx","url":"https://assets-eu.researchsquare.com/files/rs-7792293/v1/d836e9e5b5e8116c6b791e7a.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Camrelizumab with or without Autologous Cytokine-induced Killer Cell Therapy in Patients with Refractory Clear Cell Renal Cell Carcinoma: A Randomized Pilot Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eRenal 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 morbidity\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. 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 RCC\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. 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 RCC\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. The treatment of RCC has evolved from cytokine therapy to targeted agents and, more recently, to immune checkpoint inhibitors (ICIs)\u003csup\u003e\u003cspan additionalcitationids=\"CR5 CR6\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eThe 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\u003csup\u003e+\u003c/sup\u003e T cell infiltration and poor survival, and insufficient antigen presentation\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Anti-programmed death 1 (PD-1) antibody disrupts programmed death ligand 1 (PD-L1)-mediated immune suppressive signaling to restore antitumor immune function\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. 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 therapy\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. 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 nivolumab\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. 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 groups\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. 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.\u003c/p\u003e\u003cp\u003eAutologous cytokine-induced killer (CIK) cells are a heterogeneous group of immune cells, including CD3\u003csup\u003e+\u003c/sup\u003eCD56\u003csup\u003e+\u003c/sup\u003e natural killer (NK)-like T cells, which lack major histocompatibility complex (MHC) restrictions\u003csup\u003e\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. CIK cells are expanded from blood mononuclear cells cultured with cytokines \u003cem\u003eex vivo\u003c/em\u003e\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. Adoptive CIK cell therapy monotherapy is considered safe and effective for advanced or metastatic RCC, with an ORR ranging from 15% to 50%\u003csup\u003e22,23\u003c/sup\u003e. 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)\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e,\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. CIK cells have been shown to influence the TIME\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. 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.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003ePatients\u003c/h2\u003e\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eThe 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\u0026thinsp;\u0026gt;\u0026thinsp;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 \u0026gt;\u0026thinsp;10 mg of prednisone daily) or immunosuppressant therapy were excluded.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eStudy Design\u003c/h3\u003e\n\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eThis 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). 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 \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e. 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 study\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. 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.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\n\u003ch3\u003eRandomization\u003c/h3\u003e\n\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eRandomization (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.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\n\u003ch3\u003eEnd Points and Assessments\u003c/h3\u003e\n\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eThe primary endpoint was the investigator-assessed PFS according to RECIST version 1.1. The secondary endpoints were ORR and OS. 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.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\n\u003ch3\u003eCIK Cells Preparation\u003c/h3\u003e\n\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eCIK cells were prepared as described in our previous studies\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. The detailed manufacturing procedure for CIK is presented in section 5.3 of the trial protocol, as found in the supplementary materials.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eBiomarkers Expression Analysis\u003c/h2\u003e\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003ePeripheral 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).\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eStatistical analyses were conducted using R and R Studio version (2025.05.1\u0026thinsp;+\u0026thinsp;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\u0026ndash;14 months. With a one-sided a\u0026thinsp;\u0026le;\u0026thinsp;0.05 as the test level, a sample size of 60 cases was needed when b\u0026thinsp;=\u0026thinsp;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\u0026thinsp;\u0026lt;\u0026thinsp;0.05, obtained using two-sided tests.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003ePower analysis\u003c/h3\u003e\n\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003ePost-hoc statistical power analysis was performed using G*Power 3.1.9.7 (Heinrich Heine University D\u0026uuml;sseldorf, 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\u0026thinsp;=\u0026thinsp;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.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003ePatient Characteristics\u003c/h2\u003e\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eFrom 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\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eBaseline clinical characteristics of the patients.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eTreatment Groups\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCharacteristics\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eControl (N\u0026thinsp;=\u0026thinsp;12)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u003cb\u003eTrial (N\u0026thinsp;=\u0026thinsp;9)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003eTotal (N\u0026thinsp;=\u0026thinsp;21)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian age (range) \u0026mdash; years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e62 (49\u0026ndash;68)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e66 (53\u0026ndash;74)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e63 (49\u0026ndash;74)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSex \u0026mdash; no. (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8 (67)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8 (89)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e16 (76)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (33)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (11)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5 (24)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMSKCC risk group \u0026mdash; no. (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFavorable\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (33)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (56)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9 (43)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIntermediate\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6 (50)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 (33)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9 (43)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePoor\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (17)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (11)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 (14)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKPS\u0026mdash; no. (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e90\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5 (42)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (44)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9 (43)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5 (42)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (44)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9 (43)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e70\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (17)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (11)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 (14)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrevious nephrectomy \u0026mdash; no. (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9 (75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8 (89)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e17 (81)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 (25)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (11)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4 (19)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrevious cytokine therapy \u0026mdash; no. (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (44)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5 (24)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11 (92)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (56)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e16 (76)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrevious antiangiogenic regimens \u0026mdash; no. (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (11)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8 (67)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (56)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e13 (62)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 (25)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (22)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5 (24)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (11)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (10)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003eKPS, Karnofsky performance status\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eEfficacy\u003c/h2\u003e\u003cdiv id=\"Sec14\" class=\"Section3\"\u003e\u003ch2\u003eTumor response\u003c/h2\u003e\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eThere was a trend towards a higher ORR in the combination therapy group compared to the monotherapy group (55.6% vs. 41.7%, p\u0026thinsp;=\u0026thinsp;0.67) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). 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.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA depicts the alterations in the tumor burden according to the best response. Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB 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 \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003e). 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 \u003cspan refid=\"MOESM3\" class=\"InternalRef\"\u003eS3\u003c/span\u003e). 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.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eOverall Survival\u003c/h2\u003e\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eThe 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.\u0026nbsp;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. A trend towards a lower risk of death was observed with combination therapy versus monotherapy (HR 0.48), but this difference did not reach statistical significance (95% CI, 0.09 to 2.53; p\u0026thinsp;=\u0026thinsp;0.388). 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\u0026thinsp;~\u0026thinsp;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).\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eProgression-free survival\u003c/b\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eThe 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.\u0026nbsp;3B). Numerically, the hazard ratio for progression was 0.40 in favor of the trial group, but the difference was not statistically significant (95% CI, 0.12 to 1.34; p\u0026thinsp;=\u0026thinsp;0.136). 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\u0026thinsp;~\u0026thinsp;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).\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003ePD-1 expression on CD8\u003csup\u003e+\u003c/sup\u003e T cells in peripheral blood\u003c/h2\u003e\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eTo further explore the predictive biomarker of immunotherapy prognosis in recurrent or refractory ccRCC, PD-1 expression levels on CD8\u003csup\u003e+\u003c/sup\u003e 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\u003csup\u003e+\u003c/sup\u003e T cells may be associated with a better best-of-response (BoR) in both groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003eA). After administration, the PD-1 positive frequency of CD8\u003csup\u003e+\u003c/sup\u003e T cells tended to decrease (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e4\u003c/span\u003eB). The frequency of CD8\u003csup\u003e+\u003c/sup\u003e 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.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003eSafety\u003c/h2\u003e\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eTreatment-related AEs of any grade occurred in 20 of the 21 patients (95.2%) in both groups (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). 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\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, 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.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eSafety profile summary.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGroup\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eGrade 1\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eGrade 2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eGrade 3\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eHemangioma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eControl (n\u0026thinsp;=\u0026thinsp;12)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7 (58.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 (25%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1 (8.3%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eTrial (n\u0026thinsp;=\u0026thinsp;9)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (44.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (22.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eHypothyroidism\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eControl (n\u0026thinsp;=\u0026thinsp;12)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 (25%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (8.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eTrial (n\u0026thinsp;=\u0026thinsp;9)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 (33.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eAdrenocortical Insufficiency\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eControl (n\u0026thinsp;=\u0026thinsp;12)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eTrial (n\u0026thinsp;=\u0026thinsp;9)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (11.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eInterstitial Pneumonia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eControl (n\u0026thinsp;=\u0026thinsp;12)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eTrial (n\u0026thinsp;=\u0026thinsp;9)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (11.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eElevated Transaminase\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eControl (n\u0026thinsp;=\u0026thinsp;12)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (8.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eTrial (n\u0026thinsp;=\u0026thinsp;9)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eElevated CK-MB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eControl (n\u0026thinsp;=\u0026thinsp;12)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (8.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eTrial (n\u0026thinsp;=\u0026thinsp;9)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (11.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eElevated Creatinine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eControl (n\u0026thinsp;=\u0026thinsp;12)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (16.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eTrial (n\u0026thinsp;=\u0026thinsp;9)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (11.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eElevated Uric Acid\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eControl (n\u0026thinsp;=\u0026thinsp;12)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6 (50%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eTrial (n\u0026thinsp;=\u0026thinsp;9)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (11.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eHyperglycemia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eControl (n\u0026thinsp;=\u0026thinsp;12)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (8.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eTrial (n\u0026thinsp;=\u0026thinsp;9)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eThrombocytopenia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eControl (n\u0026thinsp;=\u0026thinsp;12)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (8.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eTrial (n\u0026thinsp;=\u0026thinsp;9)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eAnemia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eControl (n\u0026thinsp;=\u0026thinsp;12)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 (25%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eTrial (n\u0026thinsp;=\u0026thinsp;9)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (22.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eDiarrhea\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eControl (n\u0026thinsp;=\u0026thinsp;12)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eTrial (n\u0026thinsp;=\u0026thinsp;9)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (11.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eFatigue\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eControl (n\u0026thinsp;=\u0026thinsp;12)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 (25%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e\u003cb\u003eTrial (n\u0026thinsp;=\u0026thinsp;9)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (11.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\u003ch2\u003eOne case with CMR\u003c/h2\u003e\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eIn 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.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e5\u003c/span\u003eA. 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.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e5\u003c/span\u003eB). 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 \u003csup\u003e18\u003c/sup\u003eF-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.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eThis 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), compared to 41.7% in the control group. 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. Furthermore, favorable trends in PFS and OS were observed in the trial group, although these differences did not reach statistical significance, likely due to the small cohort size. 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\u003csup\u003e+\u003c/sup\u003e T cells and prognosis, with its frequency tending to decrease after treatment. The small sample size limited the statistical power of our analyses, and the observed differences should be interpreted as hypothesis-generating trends.\u003c/p\u003e\u003cp\u003eIn the CheckMate 025 study, the survival benefit from nivolumab was independent of PD-L1 expression on ccRCC tumor cells\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Previous investigations have demonstrated that higher PD-L1 expression was associated with poorer survival\u003csup\u003e\u003cspan additionalcitationids=\"CR29 CR30\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e.No correlation has been observed between PD-L1 expression and immunotherapy outcomes\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e, or even a paradoxical association\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. This indicates a different TIME of ccRCC from other \u0026ldquo;hot tumors\u0026rdquo; such as urothelial carcinoma\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e and some subtypes of NSCLC\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e, 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\u003csup\u003e+\u003c/sup\u003e T cells and increased VEGF expression within the tumor\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e,\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e. Braun et al. illustrated that as ccRCC advanced, there was a shift from effective to exhausted T cells\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. It is widely recognized that anti-PD-(L)1 immunotherapy works by \"releasing the brakes\" to reverse the exhaustion of PD-1\u003csup\u003ehi\u003c/sup\u003e CD8\u003csup\u003e+\u003c/sup\u003e T cells\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e. In our study, PD-1 expression on CD8\u003csup\u003e+\u003c/sup\u003e 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\u003csup\u003e+\u003c/sup\u003e 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\u003csup\u003e+\u003c/sup\u003e T cells in the peripheral blood of patients with ccRCC\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e. This study demonstrated that CD8\u003csup\u003e+\u003c/sup\u003e T cells proliferated after anti-PD-1 antibody treatment. In addition, PD-1 expression on CD8\u003csup\u003e+\u003c/sup\u003e T cells was upregulated in patients without an objective response to treatment\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e. 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 \u0026ldquo;counter-immunoediting\u0026rdquo; from immune equilibrium to elimination, as reviewed by our team\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e. A multi-omics study should be conducted to further evaluate this hypothesis.\u003c/p\u003e\u003cp\u003eFurthermore, 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%)\u003csup\u003e12,40\u003c/sup\u003e. 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.\u003c/p\u003e\u003cp\u003eCIK cells are a group of immune effector cells characterized by the properties of activated T and NK cells\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. CIK cells exhibit antitumor capabilities without MHC restriction\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e, with the ability to specifically penetrate tumor tissues, thereby creating an inflammatory microenvironment within the tumor\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. CIK cells also play a role in reducing the number of suppressive immune cells, such as myeloid-derived suppressor cells (MDSCs)\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e and regulatory T cells (Tregs)\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. 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 showed a trend toward improvement from 41.7% in the control group to 55.6% in the CIK group, though this difference did not reach statistical significance. A trend of PFS and OS improvement was also observed. This small cohort may have caused this non-statistically significant results. 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 ICIs\u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e. However, further research is required to determine whether this association between irAE and prognosis is also present in patients with ccRCC.\u003c/p\u003e\u003cp\u003eIt is well established that the rapid growth of tumor cells creates a hypoxic intratumoral environment, which subsequently induces the overexpression of VEGF\u003csup\u003e\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e,\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e, promoting endothelial cell proliferation and survival, generating malformed neovessels with malfunctions, and building an immunosuppressive TIME\u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e,\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e. 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 tumor\u003csup\u003e\u003cspan additionalcitationids=\"CR48\" citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e. Based on the results of the KEYNOTE-426\u003csup\u003e6\u003c/sup\u003e and CLEAR\u003csup\u003e\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u003c/sup\u003e 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 groups\u003csup\u003e\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u003c/sup\u003e. 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 enrolled\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e, 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 an elevated trend of ORR and a prolonged trend PFS and OS in the trial group. It can be posited that the combination of ICIs, antiangiogenic agents, and CIK cell transfusion as first-line therapy may further enhance the clinical outcomes of patients with metastatic or advanced ccRCC. Further research on this regimen is warranted to evaluate its efficacy in larger cohorts. The investigation of predictive biomarkers also requires further exploration using tumor samples, peripheral blood, and multi-omics studies.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cdiv id=\"Sec20\" class=\"Section2\"\u003e\u003ch2\u003eLimitations\u003c/h2\u003e\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eThis study had limitations due to its small sample size. The study was prematurely terminated due to the COVID-19 pandemic and the approval of antiangiogenic agents and ICIs as first-line therapies. It did not include a comparator arm with anti-PD-1 plus antiangiogenic therapy, which limits direct clinical applicability. Future studies should compare CIK cell combinations against current standard-of-care regimens. Limited blood sample availability precluded comprehensive and conclusive biomarker analyses. We were unable to obtain pre- and post-treatment biopsy samples. Consequently, we could not analyze the composition of the TIME in our cohort to discern differences between the pre-treatment and post-treatment phases. Additionally, other immune exhaustion markers, except for PD-1, on T cells were not measured in this study.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eEthics approval\u003c/h2\u003e\u003cp\u003e 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.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003cp\u003e Informed consent was obtained from all individual participants included in the study.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003cp\u003e The authors affirm that participant provided informed consent for publication of the images in Fig.\u0026nbsp;5A, 5B, 5C and Figure S10.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eThis work was funded by Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-009A), The Science \u0026amp; 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 \u0026amp; 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.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eS. 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.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e\u003cp\u003eWe are grateful to our coworkers for their contribution to the clinical management of the patients.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eAll data supporting the findings of this study are available within the article or its Supplementary Information.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSung, H. et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. \u003cem\u003eCancer J. 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Canc Netw.\u003c/em\u003e \u003cb\u003e22\u003c/b\u003e, 4\u0026ndash;16. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.6004/jnccn.2024.0008\u003c/span\u003e\u003cspan address=\"10.6004/jnccn.2024.0008\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2024).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"recurrence, refractory, clear cell renal cell carcinoma, anti-angiogenic agents, anti-PD-1 antibody, autologous cytokine-induced killer cell therapy","lastPublishedDoi":"10.21203/rs.3.rs-7792293/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7792293/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eClear cell renal cell carcinoma (ccRCC) remains a challenging malignancy to treat, with immune checkpoint inhibitors (ICIs) revolutionizing patient management. This clinical study, involving a small cohort, 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\u0026thinsp;=\u0026thinsp;12) or camrelizumab combined with CIK cell re-transfusion (trial group, n\u0026thinsp;=\u0026thinsp;9). The objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety were evaluated. Biomarker exploration was performed using peripheral blood samples from patients. A trend towards a higher ORR was observed in the trial group (55.6%) compared to the control group (41.7%). Favorable trends were also noted for median PFS (28.50 vs. 8.67 months) and median OS (not reached vs. 57.47 months) in the trial and control groups, respectively. One patient in the trial group achieved a complete metabolic response (CMR). No new safety signals were observed, and CIK cell re-transfusion did not appear to increase the frequency of adverse effects. Exploratory analysis suggested that higher baseline PD-1 expression on CD8\u003csup\u003e+\u003c/sup\u003e 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 encouraging signals of antitumor activity in refractory ccRCC with a tolerable safety profile. These preliminary findings warrant further investigation, which could focus on the combination of ICIs, antiangiogenic agents, and CIK cell re-transfusion as a potential first-line therapy for metastatic or advanced ccRCC.\u003c/p\u003e\u003cp\u003eRegistry: ClinicalTrials.gov, TRN: NCT03987698, Registration date: 17 June 2019.\u003c/p\u003e","manuscriptTitle":"Camrelizumab with or without Autologous Cytokine-induced Killer Cell Therapy in Patients with Refractory Clear Cell Renal Cell Carcinoma: A Randomized Pilot Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-13 11:08:14","doi":"10.21203/rs.3.rs-7792293/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-15T09:44:17+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-04T09:12:51+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-13T16:01:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"335943610349034193488414962089062720698","date":"2025-11-12T20:22:12+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"300735158308813737528850322766738046795","date":"2025-11-11T20:32:39+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"314945980779184170300509248680667990280","date":"2025-11-03T16:05:20+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-03T14:55:01+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-03T14:50:41+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-10-14T12:26:16+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-11T02:22:19+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-10-11T02:18:28+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8fddf230-c524-4dce-b9e3-f871fa9f0f1d","owner":[],"postedDate":"November 13th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":57895180,"name":"Biological sciences/Cancer"},{"id":57895181,"name":"Biological sciences/Immunology"},{"id":57895182,"name":"Health sciences/Oncology"}],"tags":[],"updatedAt":"2026-02-09T16:17:07+00:00","versionOfRecord":{"articleIdentity":"rs-7792293","link":"https://doi.org/10.1038/s41598-026-38881-1","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2026-02-07 15:58:43","publishedOnDateReadable":"February 7th, 2026"},"versionCreatedAt":"2025-11-13 11:08:14","video":"","vorDoi":"10.1038/s41598-026-38881-1","vorDoiUrl":"https://doi.org/10.1038/s41598-026-38881-1","workflowStages":[]},"version":"v1","identity":"rs-7792293","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7792293","identity":"rs-7792293","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}