High-dose interleukin-2 immunotherapy is safe for patients with metastatic renal cell carcinoma on dialysis

OBJECTIVE: To report our experience of high-dose interleukin-2 immunotherapy for patients with metastatic renal cell carcinoma (RCC) on haemodialysis. PATIENTS AND METHODS: Two anephric patients with metastatic RCC on haemodialysis received interleukin-2 (600,000 IU/kg) every 8 h for a maximum of 14 doses. The patients rested for 9 days and cycles were repeated as tolerated. A nephrologist followed the patients during treatment and they received nearly daily haemodialysis. RESULTS: These two cases were treated with high-dose interleukin-2 and had no unusual toxicity or adverse events. The first patient tolerated five, five, four, four and one dose of interleukin-2 over five cycles. He had a partial response to treatment with a decrease in size of a mediastinal mass, but ultimately developed progressive disease and died 32 months later. The second patient had four cycles of interleukin-2 (13, 13, 14 and nine doses). He initially maintained stable disease throughout treatment, but the disease ultimately progressed and he died 19 months later. CONCLUSIONS: We recommend considering high-dose interleukin-2 immunotherapy in highly selected dialysis patients with metastatic RCC. Further study is required to determine the safety, efficacy and optimum dosing in this group.     

C-reactive protein: a biomarker of survival in patients with metastatic renal cell carcinoma treated with subcutaneous interleukin-2 based immunotherapy

PURPOSE: In patients with metastatic renal cell carcinoma treated with low dose subcutaneous interleukin-2 based immunotherapy we evaluated a panel of biohumoral and clinical parameters before treatment to verify their correlation with clinical outcome. MATERIALS AND METHODS: We analyzed the records of 110 patients treated at our institution. Before treatment total lymphocytes, lactate dehydrogenase, the erythrocyte sedimentation rate, albumin, C-reactive protein (CRP) and fibrinogen were analyzed and correlated with clinical parameters, namely performance status, patient age, sex, prior nephrectomy, number and sites of disease, and disease-free interval (DFI) from nephrectomy to metastatic disease. RESULTS: Median survival was 12 months (partial and complete response 33, stable disease 14 and progression 7). The overall response was 24% for a partial and complete response, 37% for stable disease and 39% for progression. On univariate analysis good performance status (p = 0.0000), prior nephrectomy (p = 0.0001), DFI longer than 12 months (p = 0.0003), bone disease site (p = 0.0013), a low number of metastatic sites (p = 0.0449), normal albumin (p = 0.0001), low/normal fibrinogen (p = 0.0140), low/normal lactate dehydrogenase (p = 0.0430) and low/normal CRP (p = 0.0000) were related to better survival. On final multivariate analysis only CRP (p = 0.002) and DFI (p = 0.0497) were found to have an independent role in survival. When we correlated clinical and biohumoral factors, only CRP correlated with DFI (p = 0.021) and prior nephrectomy (p = 0.041). CONCLUSIONS: Our data confirm that some clinical and biohumoral factors may be strongly related to survival in metastatic renal cell carcinoma. The interesting new aspect emerging from this study is the prognostic value of CRP and fibrinogen, which are able to discriminate a good from a poor prognosis.     

Dendritic cell immunotherapy for patients with metastatic renal cell carcinoma: University of Tokyo experience

BACKGROUND: Dendritic cells (DC) are the most potent antigen-presenting cells and induce host antitumor immunity through the T-cell response. A clinical study of immunotherapy using cultured DC loaded with tumor antigen, for patients with metastatic renal cell carcinoma (RCC) was performed. METHODS: Dendritic cells were generated by culturing monocytes from peripheral blood for 7 days in the presence of granulocyte-macrophage colony-stimulating factor and interleukin-4. On day 6 the DC were pulsed with lysate from autologous tumor as the antigen and with keyhole limpet hemocyanin (KLH) as immunomodulator. The patients were given four doses of lysate-pulsed DC by intradermal injection with a 2-week interval between doses. Clinical effect and immune response were, respectively, evaluated by radiological examination and delayed-type hypersensitivity (DTH) test. RESULTS: Three patients were enrolled and the immunotherapy was well tolerated without significant toxicity. The vaccination induced a positive DTH reaction to tumor lysate in two patients and to KLH in all patients. Clinical responses consisted of one case of no change and two cases of progression of disease. However, we did not see a significant reduction of tumor volume in any case. CONCLUSION: Dendritic cell vaccination can safely induce an immunological response against RCC. Further trials are needed to fully evaluate its efficacy.     

Dexamethasone and interleukin-2 combination therapy for advanced renal cell carcinoma in a patient with paraneoplastic inflammatory syndrome

Interleukin-2 (IL-2) in combination with dexamethasone was administered to a 48-year-old man with renal cell carcinoma accompanied by paraneoplastic inflammatory syndrome, including progressive multiple lung metastases and inferior vena caval tumor thrombus. Although non-steroidal anti-inflammatory drugs had no apparent antipyretic effect on the systemic inflammatory syndrome, oral administration of dexamethasone achieved complete antipyresis and improved his quality of life. After a 4-week period of IL-2 treatment, regression of metastasized lesions was demonstrated despite concurrent oral administration of dexamethasone. Steroids might reduce the action of immunotherapeutic drugs, but in some cases, combination therapy can achieve both alleviation of the paraneoplastic syndrome and tumor shrinkage.     

Telomerase pulsed dendritic cells for immunotherapy for renal cell carcinoma

PURPOSE: Renal cell carcinoma (RCC) is known for its immunological susceptibility. Unfortunately RCC lacks specific tumor antigens for the induction of specific immunotherapy. We investigated the role of telomerase as a tumor antigen and pulsed dendritic cells (DCs) as antigen presenting cells with an immunogenic peptide from telomerase. MATERIAL AND METHODS: DCs and immunological effector cells, that is cytokine induced killer (CIK) cells, from patients with RCC or healthy donors were generated. CIK cells were co-cultured with telomerase peptide pulsed DCs. CIK cells were tested for cytotoxic activity against primary cultures. Using the dimer technique we determined the percent of telomerase specific T cells. Activation status was identified using interferon-gamma secretion assay. RESULTS: After pulsing DCs with telomerase peptide co-cultured CIK cells had a significant increase in cytotoxic activity against tumor cells compared with CIK cells without co-culture, that is 100% at an effector-to-target ratio of 60:1 vs 41.7% (p <0.05). Using a complete autologous model with immunological cells derived from patients with metastatic RCC we were able to induce cytotoxicity against autologous, telomerase positive primary cell cultures. We could detect 2.4% telomerase specific effector cells after co-culture with peptide pulsed DCs, which secreted interferon-gamma after re-stimulation. CONCLUSIONS: Telomerase could serve as a specific tumor associated antigen for RCC. The presentation of telomerase peptide by DCs to lymphocytes allows the generation of antigen specific cytotoxic effector cells.     

Phase II trial of radio frequency ablation of renal cancer: evaluation of the kill zone

PURPOSE: We report on the pathological evaluation of renal tumors after intraoperative radio frequency ablation performed immediately before surgical nephrectomy. MATERIALS AND METHODS: Ten patients with renal tumors were enrolled in a prospective, Institutional Review Board approved phase II trial of radio frequency ablation. Following surgical exposure of the kidney a single 12-minute radio frequency ablation of the tumor was performed using the Radionics Cool-tip RF Radio Frequency Ablation System (Radionics, Burlington, Massachusetts). The tumor was then excised via radical or partial nephrectomy. Gross and histological evaluations of the tumor were performed, including evaluation with nicotinamide adenine dinucleotide vital staining. RESULTS: All 10 tumors were confirmed histologically to be renal cell carcinoma. Mean tumor size was 3.2 cm. (range 1.4 to 8.0). Of the 10 tumors 8 were completely ablated with a mean treatment margin of 6.75 mm. (range 2 to 13). Of the 2 tumors that were incompletely treated 1 never attained a temperature sufficient for tissue destruction and the other measured 8 cm., far exceeding the expected ablation volume of treatment protocol. CONCLUSIONS: This study represents the initial report of the histological outcome of saline cooled radio frequency ablation of renal tumors. Our data indicate that it can completely destroy renal cancers while transmitting minimal collateral damage to surrounding renal parenchyma. Further investigation is required to determine long-term oncological outcome.     

Phase I trial of a B7-1 (CD80) gene modified autologous tumor cell vaccine in combination with systemic interleukin-2 in patients with metastatic renal cell carcinoma

PURPOSE: A reason that the immune system may fail to reject tumors is that T cells encounter tumor antigen derived peptides on the surface of tumor cells in a tolerizing rather than activating context since tumor cells do not express T cell co-stimulatory molecules such as B7-1 (CD80). In preclinical models over expression of B7-1 on the surface of tumor cells has been shown to activate T cells which kill tumor cells. We conducted a phase I clinical trial testing this approach in patients with metastatic renal cell carcinoma. MATERIALS AND METHODS: Resected tumors from 15 patients were disaggregated and adapted to tissue culture, transduced with the B7-1 gene and injected subcutaneously as a vaccine. The dose of the vaccine was escalated in 3 separate cohorts of patients, and systemic interleukin-2 (IL-2) was administered as an adjuvant designed to enhance the proliferation of the vaccine activated T cells. RESULTS: Of the 15 patients 9 had measurable disease, 2 had a partial response and 2 had stable disease. Perivascular T cell infiltrates at autologous tumor delayed type hypersensitivity skin test sites developed in 3 of the 4 patients with stable disease or partial response. Although the patients experienced the usual and expected toxicity from the IL-2, there was no significant toxicity observed with the vaccine. CONCLUSIONS: The B7-1 gene modified autologous tumor cell vaccine is safe and can be combined with systemic IL-2 with acceptable toxicity. Immunological and clinical responses were observed in some of the patients. A phase II trial is reasonable to determine the efficacy of this approach.     

Current management and future perspectives of metastatic renal cell carcinoma

Over the last number of years, the treatment of metastatic renal cell cancer has evolved tremendously with the advent of targeted therapy. Previously, immunotherapies, such as interferon alpha and interleukin‐2, were the only treatment options available for this chemoresistant malignancy. Currently, seven additional agents, including sunitinib, sorafenib, axitinib, pazopanib, bevacizumab, everolimus and temsirolimus, have been approved for use in metastatic renal cell cancer, with several more in development. The efficacy of these agents depends primarily on inhibition of the vascular endothelial growth factor and mammalian target of rapamycin pathways, and have drastically improved the outcomes of patients diagnosed with metastatic renal cell cancer. This article reviews the major treatment advances that have occurred for metastatic renal cell cancer with the advent of targeted treatments, summarizes the evidence to support their use and addresses clinical issues that have arisen with them. To help guide clinicians in their decision‐making with these emerging therapeutic choices, the evidence for sequencing and combining these agents, and the need for biomarkers will be addressed. The role of surgical management options, such as cytoreductive nephrectomy and metastectomy, in the era of targeted treatment is also reviewed. Several novel treatments are also on the horizon, which might serve as future avenues for treatment advancement in metastatic renal cell cancer.     

肾癌患者手术及免疫治疗前后的血清蛋白指纹图谱的研究

目的:分析肾癌患者手术前后及免疫治疗前后的血清蛋白指纹图谱,构建并评估血清差异蛋白诊断模型。方法:首先应用弱阳离子磁珠技术富集肾癌患者手术前后、免疫治疗后及健康对照组的血清蛋白,其次用基质辅助激光解离-飞行时间质谱(MALDI-TOF-MS)技术构建肾癌患者不同时期的蛋白指纹图谱,再应用有监督以及无监督的化学计量学模式识别方法对构建的指纹图谱进行效力评价,最后应用受试者工作特征曲线(ROC)寻求区别各个时期肾癌患者血清中的差异蛋白。结果:在无监督模式识别方法(主成分分析,PCA)结果不理想的情况下,对比了不同有监督模式识别方法构建的指纹图谱模型,结果表明遗传算法(GA)对各个时期的肾癌患者均有较高的识别率,达到了97.7%;术前和术后差异蛋白只有一个,而术前和免疫治疗后、术后和免疫治疗后存在较多的差异蛋白。结论:肾癌患者经过免疫治疗后,血清蛋白质和术前及术后存在明显差异,肾癌应用遗传算法构建的血清蛋白指纹图谱可有效识别术前、术后、免疫治疗后以及正常对照组的血清差异蛋白。     

Immunotherapy against metastatic renal cell carcinoma with mature dendritic cells

OBJECTIVE: We performed a clinical trial of immunotherapy using autologous mature dendritic cells (DC) pulsed with autologous tumor lysate, for patients with metastatic renal cell carcinoma (RCC). METHODS: Patients with refractory metastatic RCC were enrolled in the study. All of them received interferon (IFN)-alpha treatment after nephrectomy and were followed over 3 months prior to this study. Autologous monocyte-derived immature DC were pulsed with lysate from autologous primary tumor as the antigen and keyhole limpet hemocyanin (KLH) as immunomodulator, and cultured in the presence of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and prostaglandin (PG)E2 to generate mature DC. Mature DC were injected intradermally near bilateral inguinal lymph nodes of the patients. A delayed-type hypersensitivity (DTH) test and enzyme-linked immunospot (ELISPOT) assay were performed to evaluate the immunological response. After 4 months from first injection, the clinical effect was evaluated by diagnostic imaging. RESULTS: The treatments were well tolerated without significant toxicity by the patients who were an average of 65.7 years old and had multiple metastases in the lung and other organs. One of the two patients developed a positive DTH reaction to tumor lysate and the other patient only to KLH. The patient with a positive DTH reaction to tumor lysate had stable disease in the clinical evaluation. CONCLUSIONS: We confirmed the safety of DC therapy in this clinical trial. The DTH test revealed that the DC therapy induced immunological response to RCC. On the other hand, it was necessary to reconsider the patient selection criteria.     

Dendritic cell therapy in combination with interferon-α for the treatment of metastatic renal cell carcinoma

Objectives:   To evaluate the safety and efficacy of dendritic cell (DC) therapy in combination with interferon-α (IFN-α) in patients with advanced renal cell carcinoma.
Methods:   Seven patients, with progressive disease following IFN-α and interleukin (IL)-2 treatment, were treated with monocyte-derived DC (Mo-DC) and IFN-α between February 2004 and September 2006. They received Mo-DC once a week for 5 weeks and then every 2 weeks either intradermally or intratumorally. IFN-α (5–6 million U) was subcutaneously administered three times a week. Tumor size was evaluated by computed tomography scans before and after the 5th and 10th DC vaccination. A delayed-type hypersensitivity test was performed after the 4th and 5th DC administration for immunological monitoring.
Results:   Five patients had stable disease while the remaining two patients had progressive disease following 4 months of vaccination. In six patients the time to progression was prolonged in comparison with the previous cytokine treatment. Six patients showed delayed-type hypersensitivity after the 4th or 5th immunization. Three patients developed high fever following DC immunization. Treatment was associated with transient flu-like symptoms.
Conclusions:   Our data indicate that DC therapy combined with IFN-α is safe and has the potential for prolonging the time to progression in patients with advanced renal cell carcinoma.     

Prognostic factors and survival of patients with sarcomatoid renal cell carcinoma.

PURPOSE: Sarcomatoid renal cell carcinoma often has an aggressive clinical course characterized by rapid disease progression. We evaluate prognostic factors for patient survival and the effect of treatment on patient outcome. MATERIALS AND METHODS: Between 1987 and 1998, 108 patients were classified as having sarcomatoid renal cell carcinoma at our institution. We reviewed the records of these patients to identify clinical and pathological prognostic variables. The Kaplan-Meier method was used to determine differences in overall survival. RESULTS: A total of 96 (89%) patients were symptomatic at presentation. Sarcomatoid renal cell carcinoma was localized to the kidney in 25 (23%) patients, whereas metastasis was present in 83 (77%). The median overall survival of all patients was 9 months. The presence of clinically localized disease was associated with longer overall survival when compared to patients with metastasis (17 versus 7 months, respectively, p <0.004). Of 86 patients who received systemic therapy partial response was seen in 28, and no complete responses were noted. Patients who had a partial response had a median survival of 19 months and those with no response 7 (p <0.005). Those patients with metastatic disease who were treated with nephrectomy followed by systemic therapy survived a median time of 8.5 months, whereas those who received systemic therapy alone 5.3 (p = 0.08). CONCLUSIONS: Patients with sarcomatoid renal cell carcinoma have poor overall survival because of the aggressive biological behavior. Survival is longer for patients presenting with clinically localized disease, single metastatic site, and exhibiting a partial response to systemic therapy.     

Gene and immune therapy for renal cell carcinoma

Conventional therapy for metastatic renal cell carcinoma is associated with a poor response rate and few patients are long-term survivors. The occurrence of spontaneous regression and the prolonged latency period between primary tumor removal and the appearance of metastases in some patients suggest the existence of important host immune responses to autologous tumor cells. With the advent of molecular gene transfer techniques and increased knowledge of the basic pathways of immune activation, the field of cancer immunotherapy has finally begun to develop novel and effective approaches for harnessing the immune system as a therapeutic agent. Current immunotherapy and gene therapy strategies, including methods of cytokine delivery and tumor-cell-based vaccines, are presented.     

Current status of pharmacotherapy against metastatic renal cell carcinoma in Japan

So far, metastatic renal cell carcinoma has been one of the most treatment‐resistant cancers. The extensive use of cytokines, such as interferon‐α and interleukin‐2, were carried out for metastatic renal cell carcinoma. However, significant advances in understanding the molecular mechanisms underlying renal cell carcinoma have led to the development of molecular target‐based drugs, which were desperately awaited for a long time, and now two types of molecular target‐based drugs are available. Two vascular endothelial growth factor receptor tyrosine kinase inhibitors and two mammalian target of rapamycin inhibitors have been approved and available in Japan. The molecular target‐based drugs have unique and characteristic adverse events, whose profile are not well understood in Japanese patients, because most of the clinical trials were carried out in Europe and America. In contrast, immunotherapy is being reconsidered in the selection of more appropriate patients or as a combined treatment form with other drugs, because of few complete responses obtained and unexpected adverse events by molecular targeted treatments. We have several molecular targeted‐drugs available at present and will have more, and we will actually use these drugs in various clinical settings, such as the presurgical setting, the adjuvant setting, sequential administration and combined administration, in addition to cytokines. Therefore, we need more elaborate studies to obtain the optimal treatment methods to maximize the effect of such agents to extend overall survival while maintaining quality of life of metastatic renal cell carcinoma patients. In this article, we reviewed the issues related to the current status of pharmacotherapy available for metastatic renal cell carcinoma.     

肿瘤肾脏切除在转移性肾细胞癌治疗中的意义

转移性肾细胞癌的治疗是肾癌治疗的难点。以往认为转移性肾细胞癌切除肿瘤原发灶是没有意义的。但随着肾癌免疫治疗和靶向治疗的发展,越来越多的证据证明肿瘤肾脏切除在转移性肾细胞癌的治疗中有着重要意义。本文通过复习相关文献对肿瘤肾脏切除术在转移性肾细胞癌治疗中的意义作简单介绍。