Lymphocyte antibody interaction in cytotoxicity against human transitional cell carcinoma.

The interaction of antibodies and lymphocytes in their immune reaction against human transitional cell carcinomas was studied using the in vitro microcytotoxicity assay. A non-complement dependent, IgG antibody was detected in the serum of occasional transitional cell carcinoma patients, which induced cytotoxicity against transitional cell carcinoma target cells by lymphocytes from donors with and without transitional cell carcinoma. The observation that lymphocytes from transitional cell carcinoma donors were more sensitive to activation by this anti-transitional cell carcinoma, lymphocyte dependent antibody is compatible with the hypothesis that the surface of lymphocytes from some transitional cell carcinoma donors is coated in vivo with an anti-transitional cell carcinoma lymphocyte dependent antibody and that this antibody may be a significant factor in immunity to transitional cell carcinomas of the urinary tract.     

Sunitinib efficacy against advanced renal cell carcinoma

PURPOSE: We assessed the efficacy of the oral multitargeted tyrosine kinase inhibitor sunitinib in patients with metastatic clear cell renal cell carcinoma. MATERIALS AND METHODS: Patients with metastatic clear cell renal cell carcinoma were enrolled in this multicenter, phase II clinical trial. Major eligibility requirements were clear cell renal cell carcinoma histology, prior nephrectomy, measurable metastases and failed prior cytokine therapy as a result of disease progression. Sunitinib was given orally as second line therapy in 6-week cycles of 50 mg daily for 4 weeks, followed by 2 weeks off drug per treatment cycle. Response to sunitinib was rigorously assessed by an independent third party core imaging laboratory (central review). RESULTS: Of 106 patients enrolled in the study 105 were evaluated for response. As determined by independent third party assessment, the objective response rate was 33% (95% CI 24%-43%) with a median response duration of 14.0 months. Median time to progression and median progression-free survival in the 105 evaluable patients was 10.7 and 8.8 months, respectively. Median survival was 23.9 months and 43 patients remained alive at a median followup of 29.7 months. CONCLUSIONS: The results of this trial demonstrate the efficacy of sunitinib for metastatic renal cell carcinoma. The optimal integration of surgery and sunitinib treatment requires further prospective investigation.     

Synergy of radiation therapy and immunotherapy in murine renal cell carcinoma.

The treatment of metastatic renal cell carcinoma with immunotherapy has resulted in objective anti-tumor responses in 15-30% of patients. To enhance the therapeutic effects of immunotherapy, it is becoming evident that this approach should be combined with other treatment modalities. In this study, a spontaneously metastasizing murine renal adenocarcinoma (Renca), transplanted under the renal capsule, was treated with either radiation therapy, immunotherapy or a combination of both. In order to distinguish between the local and systemic effects of radiation therapy, total body irradiation was compared to irradiation of the tumor-bearing kidney only, or irradiation of the whole mouse with the tumor-bearing kidney shielded. Immunotherapy was administered with interleukin-2 (IL-2) alone or with IL-2 and lymphokine activated killer (LAK) cells. Combined radiation and immunotherapy induced a better anti-tumor response than either modality alone. The best response was obtained by local tumor irradiation and IL-2 therapy and resulted in a significant reduction in primary tumor size, elimination of lung metastases and a significant increase in survival.     

Protection against murine ascites tumours by lymphoid cell populations with T memory or cytotoxicity.

It was possible to protect irradiated C3H mice against lethal doses of allogeneic ascitic tumor cells (RBL-3 or P-815 Y) by systemic administration of low doses of syngeneic sensitized lymphoid cells. Two types of cell populations were active at similar doses: (1) spleen cells harvested 2 months after a nonlethal inoculation of tumour cells, at which time no cytotoxic lymphocytes wer in vivo sensitization or in vitro sensitized spleen cells; sucll and dose dependent and target cell specific. The findings imply that T memory cells as well as cytotoxic cells are able to protect, although it was not possible to exclude the presence of memory lymphocytes in the cytotoxic cell population. Antiserum to cytotoxic T cells (CTL) was prepared in an attempt to distinguish memory and cytotoxic effector cells. The antiserum did not react with the majority of T cells in a normal spleen or thymus, but showed specificity for the CTL cell lineage. Antiserum treatment and complement abolished protection in all types of sensitized cell populations. Since memory and cytotoxic cells appeared to share differentiation antigens, we could not establish whether memory cells are precursors or products of cytotoxic cells.     

Autologous mixed lymphocyte tumor cell culture in patients with renal cell carcinoma

Cell-mediated immunity was studied by measurement of lymphocyte response to autologous tumor cells in 19 surgically treated patients with histologically proved (mixed lymphocyte tumor cell culture) renal cell carcinoma. Tumor stage was low in 9 patients and high in 10, while grade was low in 11 and high in 8. Of 8 patients in whom a positive lymphocyte response was detected 6 had high and 2 had low stage tumors (p less than 0.05), while the grade of disease was low in 7 and high in 1 (p less than 0.05). Furthermore, the more advanced and undifferentiated the tumor the more significant the decrease in lymphocyte response (p less than 0.05). Lymphocyte response was positive in 5 of 8 patients with low stage and low grade tumors but negative in 7 with high stage and high grade disease. However, no correlation between the lymphocyte response and the degree of microscopic lymphocytic infiltration in and around the tumor was found. This study confirms that the specific immunological defense mechanism of patients with renal cell carcinoma against the tumors remains well at an earlier stage of tumor development, especially in cases with well differentiated malignancy, and showed attenuation in parallel with pathological spread or in poorly differentiated tumors.     

Augmentation of cell-mediated cytotoxicity against renal carcinoma cells by recombinant interleukin 2

The effects of recombinant interleukin 2 (IL-2) on natural killer (NK) cell activity against established renal carcinoma cell lines CaKi 1, KU-2, and freshly prepared renal carcinoma cells were studied. Augmentation of NK cell activity by IL-2 was dose- and time-dependent. The results indicate that the optimal dose of IL-2 was 100 to 500 U/mL, and that cytotoxicity increased significantly even at a low concentration such as 4 U/mL. IL-2 induced significantly higher levels of cytotoxicity against renal carcinoma cells than did gamma-interferon. The influence of IL-2 on lymphocyte subpopulations was then examined using flow cytometry with monoclonal antibodies OKT3, OKT4, OKT8, Leu 7, and Leu 11. The results showed that IL-2 increased the number of cells positive to Leu 11, the so-called active NK cells. We concluded that IL-2 has an important role in the treatment of renal carcinoma.     

多靶点药物治疗晚期肾癌肾功能改善的临床观察

目的 总结多靶点药物治疗1例晚期双肾癌患者肾功能改善的效果. 方法 晚期双肾癌患者1例,男,60岁.腰痛1个月.B超及CT检查提示双肾癌.左肾肿瘤11.0 cm×9.4 cm×8.5 cm,右肾肿瘤3.5 cm×4.3 cm×4.1 cm,肾穿刺活检诊断为肾透明细胞癌.X线检查示肝及右下肺转移灶.实验室检查:左肾肾小球滤过率(GFR)20.39 ml/min,右肾25.40 ml/min.予多靶点药物索拉非尼400 mg,1～2次/d口服,共治疗12周. 结果 经索拉非尼治疗12周后.CT检查示左肾肿瘤缩小至9.0 cm×8.5 cm×7.4 cm,右肾肿瘤缩小至3.0 cm×3.6 cm×4.0 cm,病灶内部见液化坏死,未见新的转移灶.总肾GFR由治疗前45.79 ml/min升至71.38 ml/min,左肾GFR 31.57ml/min,较治疗前提高11.18 ml/min,右肾GFR 39.81 ml/min,较治疗前提高14.41 ml/min. 结论 多靶点药物治疗晚期肾癌可使肿瘤缩小,并改善肾功能.     

Chemosensitivity of murine renal carcinoma

Summary A non-endocrine dependent, spontaneous carcinoma of the kidney in a Wistar-Lewis rat has been studied for sensitivity to chemotherapeutic agents. Two tumour models have been employed. Subcutaneously transplanted flank nodules were used to screen single agents for antitumour activity. A model of intraperitoneal metastatic disease was employed to test further agents which had demonstrated some effectiveness in the nodule model. Single agents that proved ineffective were streptozotocin, neocarzinostatin, chlorozotocin and carminomycin. 5-FU, bleomycin and hydroxyurea were also ineffective at the doses tested. Agents that were effective included cyclophosphamide, adriamycin, vinblastine, vindesin, and maytansine. The most effective combination therapy appeared to be cyclophosphamide with vindesin and cisplatin.Supported by VA Grant No. 821-103     

转移性肾细胞癌免疫治疗的研究进展

转移性肾细胞癌为化疗和激素治疗抵抗性肿瘤,目前仍缺乏有效的治疗手段.经过20多年的发展,随着分子免疫机制的研究深入,新型免疫治疗方法不断推陈出新,过继免疫疗法、树突状细胞疫苗、免疫基因治疗等治疗方法研究发展迅速,部分已经应用于临床治疗.相信在不久将来,免疫治疗将获得突破性进展,终将成为临床治疗进展期肾细胞癌的主要手段.本文就近年来转移性肾细胞癌免疫治疗最新进展作一综述.     

Anti-tumour activity of heat-shock protein 60-recognizing CD4+ T cells against syngeneic murine renal cell carcinoma

OBJECTIVES: To determine whether heat-shock protein (HSP) 60-recognizing CD4(+) T cells show antitumour activity against renal carcinoma (RENCA) cells, as HSP is highly expressed by tumour cells and induced in cells by various stresses, including transformation. MATERIALS AND METHODS: RENCA, a renal cortical adenocarcinoma cell line of BALB/c origin, was used. Expression of major histocompatibility complex (MHC) class I, class II and HSP-60 on RENCA tumour cells was analysed by flow cytometry. BASL1.1, an autoreactive T-helper type 1 type CD4(+) T cell clone established by us, and that recognises HSP-60, was also used for a tumour-neutralising assay. RESULTS: The RENCA cells were negative for MHC class II, but expressed intracellular HSP-60. In the tumour-neutralising assay, BASL1.1 cells significantly suppressed the in vivo growth of RENCA cells. Three of five mice rejected RENCA cells when co-inoculated with BASL1.1 cells. CONCLUSIONS: These results indicate that HSP-60-recognizing CD4(+) T cells have the potential to eliminate renal cell carcinoma in vivo and that the eliciting of an anti-self T cell response at the tumour site can lead to regression of renal cancer.     

Antiangiogenic effect of ZD1839 against murine renal cell carcinoma (RENCA) in an orthotopic mouse model

INTRODUCTION: ZD1839 (Iressa) is a selective epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). We evaluated the antitumor and antiangiogenesis activities of ZD1839 in a murine renal cell carcinoma (RENCA) model. MATERIALS AND METHODS: The effect of ZD1839 on the cellular proliferation of RENCA cells in vitro was measured by colorimetric assay. For the in vivo studies, RENCA cells were adsorbed in Gelfoam and implanted into BALB/cJ mouse parenchyma with an agarose bar. Mice were treated with ZD1839 (40 mg/kg/day s.c.), genistein or saline for 14 days. Western blot analysis was performed to observe EGFR expression in RENCA cells and tumor tissues. Microvessel density (MVD) was quantified by immunostaining for factor VIII-related antigens and VEGF level was assayed by ELISA. RESULTS: ZD1839 showed a dose-dependent inhibition of RENCA cellular proliferation. ZD1839 treatment resulted in a marked decrease in tumor growth compared with saline treatment. The MVD and VEGF in the RENCA tumors were decreased significantly by ZD1839 (p<0.01 and p>0.05, respectively). Genistein also suppressed tumor growth and decreased MVD and VEGF level, but the efficacies were less than with ZD1839. CONCLUSION: The suppressive activity of ZD1839 on RENCA tumor growth was accompanied by decreases in the MVD and VEGF production. These results suggest that the antitumor effect of ZD1839 in a RENCA model is mediated partially by the inhibition of tumor angiogenesis.     

Prognostic value of peripheral blood T lymphocyte subsets in clear cell renal cell carcinoma

BackgroundTo date, few studies have evaluated the role of peripheral blood T lymphocyte subsets in patients with clear cell renal cell carcinoma (ccRCC). Here we measured the levels of peripheral blood T lymphocyte subsets and evaluated its prognostic value in ccRCC.MethodsData from 122 patients with RCC from January 2018 to January 2020 were collected. Preoperative peripheral blood T lymphocyte subsets and medical records were analyzed. Kaplan-Meier cures and log rank test were used for analyzing overall survival (OS). Univariate and multivariate survival analyses were underwent by performing the Cox proportional hazards models. Correlations were tested by Pearson’s correlation analysis.ResultsOf 122 patients, a total of 80 ccRCC patients was enrolled. Patients with low CD3⁺ T cells and low CD4⁺/CD8⁺ ratio displayed a worse OS than patients with high CD3⁺ T cells and high CD4⁺/CD8⁺ ratio (P=0.029 and 0.002, respectively). Multivariate analyses showed CD3⁺ T cells and CD4⁺/CD8⁺ ratio were independent predictive factors for the OS (HR: 0.295, 95% CI, 0.091–0.956; P=0.042 and HR: 0.244, 95% CI, 0.065–0.920; P=0.037, respectively). Moreover, NLR negatively correlated with both levels of CD3⁺ T cells and CD4⁺/CD8⁺ ratio (P<0.001, r=−0.398 and P=0.012, r=−0.280, respectively).ConclusionsThe findings of our study suggest that preoperative CD3⁺ T cells and CD4⁺/CD8⁺ ratio in peripheral blood are independent predictors for patients with ccRCC.     

Chemoimmunotherapy of metastatic murine renal cell carcinoma using flavone acetic acid and interleukin 2.

Metastatic renal cell carcinoma (RCC) remains largely incurable. We used a murine RCC (Renca) in BALB/c mice to investigate the treatment possibilities with chemoimmunotherapy using in vivo boosters of natural killer (NK) activity. Diffuse pulmonary metastases were induced by intravenous (i.v.) inoculation with 100,000 Renca cells. All untreated control animals died within one month from pulmonary metastases. Chemoimmunotherapy using the NK immunostimulator flavonic-8-acetic acid (FAA) at 200 mg./kg. i.v. was given on the third day post tumor inoculation, followed by four consecutive days of twice daily intraperitoneal (i.p.) administration of 10,000 units human recombinant interleukin-2 (rIL-2). This chemoimmunotherapy regimen consistently cured 70% of tumor-bearing animals. Mice cured by this chemoimmunotherapy regimen did not reject subsequent reinoculation with Renca, indicating absence of specific antitumor immunity as a result of the treatment. While FAA and rIL-2 have no demonstrable in vitro cytotoxicity for Renca, they are excellent boosters of in vivo NK activity. These data suggest a potential alternative treatment method for metastatic RCC, a tumor type for which no efficient cytostatic drugs are available.     

Asymptomatic renal cell carcinoma and small renal cell carcinoma

Of 151 patients with renal cell carcinoma 12 were asymptomatic and 13 were small in size. The patients with asymptomatic renal cell carcinoma were incidentally discovered by B ultrasonography or IVP. Most of asymptomatic renal cell carcinomas were of lower stage than suspected, but a few were advanced. The patients with small renal cell carcinoma, which were all classified into stage One, Simple hematuria or pain is not only the manifestation of advanced carcinoma but also early stage. It is termed early diagnosis that the renal cell carcinoma without capsule invasion and metastases is detected. B ultrasonography should be the first choice for early diagnosis of renal cell carcinoma.     

Incidentally diagnosed renal cell carcinoma.

We analyzed the incidence, sex and age distribution, diagnostic methods and survival rate of incidentally detected renal cell carcinomas (RCCs) and compared these factors with those of symptomatic RCCs. Of 141 patients with RCC treated between 1980 and 1989, 44 cases (31.4%) were incidentally detected. Thirty-one of these 44 cases were diagnosed by abdominal ultrasonography. The age of the incidental cases was significantly higher than that of the symptomatic ones (p = 0.045), particularly in male patients (p = 0.049). The tumor size in incidental cases was smaller and tumor stage earlier (p less than 0.0001). Moreover, the grade of malignancy was significantly lower, and clear cell type tumors were more frequently detected in the incidental cases. No difference was observed between the survival rates of incidental and symptomatic cases with stage 1 or 2 tumors. Of the incidental cases with stage 1 or 2, however, no patient with a tumor 3 cm or less in diameter has died. In conclusion, abdominal ultrasonography is a useful tool to detect RCC at an early stage, and patients with a relatively small tumor tend to have a good prognosis.     

Epidemiology of renal cell carcinoma.

The increasing incidence of RCC in most populations may in part be due to increasing numbers of incidentally detected cancers with new imaging methods. Further, the increase is not only limited to small local tumours but also includes more advanced tumours, which may to some part explain the still high mortality rates. The variation in incidence between populations may have several other explanations. Traditionally the starting point has included thoughts of environmental exposures, which so far have only in part explained the causes of RCC, by means of cigarette smoking and obesity, which may account for approximately 40% of cases in high-risk countries (Table 2). Further, the genetic variations may be of importance as a cause of the difference between populations. Continued research in RCC is needed with the knowledge that nearly 50% of patients die within 5 years after diagnosis. The further search for environmental exposures should take in account the knowledge that RCC consists of different types with specific genetic molecular characteristics. These genetic alterations have in some cases been suggested to be associated with specific exposures. Furthermore, there might exist a modulating effect of genetic polymorphisms among metabolic activation and detoxification enzymes. Hence, a further understanding of the genetic and molecular processes involved in RCC will hopefully give us a better knowledge how to analyse and interpret exposure associations that have importance for both initiation and progression of RCC.     

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.