肾癌免疫治疗的研究进展CSCD

肾癌起源于肾小管上皮,恶性程度很高,患者就诊时大多已经发生转移。虽然VEGF和m TOR为主的靶向治疗大大改善了肾癌的治疗现状,但患者最终会出现耐药。幸运的是肾癌具有潜在的免疫原性,PD-1/PD-L1抑制剂、个体化疫苗和CAR-T疗法等免疫疗法显示了巨大的临床效益。而且PD-1/PD-L1抑制剂与抑制血管生成或CDK4/6抑制剂等药物联合使用可以发挥出更强的治疗效果。在肾细胞癌中针对免疫治疗靶点和肿瘤生物学的进一步研究有望提供更有效的治疗手段,改善患者预后。然而这些新的免疫疗法发挥作用的同时,随之也会带来很多毒副作用。因此探索预测治疗反应的生物标志物十分重要,可以帮助确定哪些肾细胞癌患者适合这类治疗,提高治疗效应并使毒副作用降到最低。本文就肾癌中新的免疫治疗通过不同的分子机制抑制肾癌的发展和用于治疗的靶点而展开综述。     

肾癌免疫治疗的研究进展

肾癌起源于肾小管上皮,恶性程度很高,患者就诊时大多已经发生转移。虽然VEGF和m TOR为主的靶向治疗大大改善了肾癌的治疗现状,但患者最终会出现耐药。幸运的是肾癌具有潜在的免疫原性,PD-1/PD-L1抑制剂、个体化疫苗和CAR-T疗法等免疫疗法显示了巨大的临床效益。而且PD-1/PD-L1抑制剂与抑制血管生成或CDK4/6抑制剂等药物联合使用可以发挥出更强的治疗效果。在肾细胞癌中针对免疫治疗靶点和肿瘤生物学的进一步研究有望提供更有效的治疗手段,改善患者预后。然而这些新的免疫疗法发挥作用的同时,随之也会带来很多毒副作用。因此探索预测治疗反应的生物标志物十分重要,可以帮助确定哪些肾细胞癌患者适合这类治疗,提高治疗效应并使毒副作用降到最低。本文就肾癌中新的免疫治疗通过不同的分子机制抑制肾癌的发展和用于治疗的靶点而展开综述。     

转移性肾癌生物治疗研究进展

转移性肾癌(mRCC)作为一种高度恶性的疾病,以进展快、病死率高为特点,且一直以来临床上对其治疗效果并不理想.联合化疗和(或)放疗也不能显著提高反应率或改善生存.在分子靶向药物诞生之前,临床上应用以细胞因子为基础的免疫治疗作为mRCC的一线治疗.分子靶向药物的问世,彻底打破了传统细胞因子免疫治疗mRCC的局面,使mRCC患者获得较好的临床治疗效果.本文将系统阐述mRCC的免疫治疗与靶向治疗的进展,详细介绍目前靶向治疗的临床应用情况,以期为mRCC治疗药物的合理选择提供参考.     

CAR-T联合疗法治疗实体瘤的研究进展

CAR-T疗法(chimeric antigen receptor T-cell immunotherapy)即嵌合抗原受体T细胞免疫疗法,是目前肿瘤免疫治疗中较有潜力的策略之一^[1],已成功应用于多种血液肿瘤的治疗。但CAR-T疗法在治疗实体瘤领域进展缓慢,存在肿瘤微环境的限制、细胞因子释放综合征以及严重的脱靶效应等诸多挑战^[2]。与单一靶向治疗相比,CAR-T联合疗法为改进肿瘤治疗方法提供了新的方向。综述目前常用的CAR-T联合治疗策略,针对CAR-T疗法在实体瘤治疗领域面临的主要挑战,探讨提高CAR-T疗效的潜在方案。     

犬肿瘤免疫疗法的研究进展

目前,犬肿瘤疾病已成为临床常见病。手术疗法、放射疗法及化学疗法作为传统治疗手段虽然在一定程度上能够改善病犬的生存及预后,但仍不能彻底改变病犬的生存质量。因此,新的肿瘤治疗方式的引入迫在眉睫。肿瘤免疫疗法的诞生为犬类肿瘤的预防和治疗提供了契机。该文综述了犬肿瘤免疫疗法的研究进展,包括免疫检查点如程序性死亡受体1(programmed cell death 1,PD-1)/程序性死亡受体配体1(programmed cell death ligand 1,PD-L1)及细胞毒性T淋巴细胞抗原-4(cytotoxic T lymphocyte antigen-4,CTLA-4)。同时,该文评述了过继细胞疗法(adoptive cell therapy,ACT)在犬肿瘤治疗中的前景,为未来犬肿瘤治疗的研究方向提供了理论基础。     

γIL-2和α-IFN治疗转移性肾癌

目前，转移性肾癌尚无理想的治疗方法，我们自１９９６～１９９７年８月，联合应用γＩＬ ２和α ＩＦＮ治疗转移性肾癌１１例，报告如下：对１１例转移性肾癌，男８例，女３例，年龄４６～７２岁，均经手术治疗病理诊断，４例手术前已发现转移，７例为手术后５～１４个...     

胰腺癌免疫治疗新进展

胰腺癌高发病率和低治疗率使其死亡率逐年上升,因此急需新的治疗方法改善胰腺癌患者预后。近年,免疫疗法在肿瘤治疗上取得的突破性进展,CAR-T疗法、免疫点抑制剂,如细胞毒性T淋巴细胞相关抗原4和程序性死亡1/程序性死亡受体1已经在治疗恶性肿瘤上取得了巨大成功,树突状细胞(dendritic cells, DCs)疫苗、溶瘤病毒等免疫疗法也在治疗肿瘤方面表现出一定疗效。基于胰腺癌的部分免疫发病及逃逸机制,免疫疗法已部分运用于胰腺癌研究和临床试验,且取得了一定的疗效。本文将对胰腺癌免疫疗法最新进展作一综述。     

免疫检查点阻断疗法:肿瘤治疗的新篇章

肿瘤免疫疗法是目前肿瘤治疗的研究热点,因其疗效显著而备受瞩目。免疫检查点阻断疗法是众多免疫疗法的有效策略之一,其中以PD-1/PD-L1和CTLA-4为代表的免疫检查点抑制剂在黑色素瘤等实体肿瘤治疗中取得了令人振奋的结果。本文对免疫检查点阻断疗法的进展及该领域中亟需解决的问题做一分析和展望。     

纳米材料在肿瘤免疫治疗中的应用

癌症免疫疗法已经成为继手术疗法、放疗、化疗和靶向治疗后的第五大主流疗法,取得了令人瞩目的成果.然而,鉴于临床疗效和安全性问题,免疫疗法仍面临着许多挑战.借助生物材料构建智能纳米递释系统用于研究新型疫苗和靶向药物,有效地减小了癌症免疫疗法的毒副作用并提高了疗效.本文概述了癌症免疫疗法的发展过程,综述了近年来纳米材料在癌症免疫疗法中的研究进展,并展望了纳米材料在癌症免疫治疗方面所面临的机遇和挑战.     

Sci Rep:免疫疗法组合能够有效治疗小鼠癌症

正横纹肌肉瘤是一类由骨骼肌癌变导致的肿瘤,是一类高发于儿童群体中的软组织癌症。目前最主流的治疗方法包括手术、放射以及化学疗法。然而,这些疗法具有较高的副作用,对于儿童来说尤其如此。而最近的一项研究则提出了一种新的疗法,能够利用患者体内的免疫系统进行癌细胞的杀伤。在过去十年来,免疫疗法逐渐成为癌症治疗的主流治疗手段之一,它相比传统疗法副作用更低。在这一新研究中,来自Nationwide儿童医院     

Recent advancements in the treatment of renal cell carcinoma--focus on international guidelines

Recent advances in understanding the fundamental biology underlying clear-cell RCC have opened the door to a series of targeted agents, such as tyrosine kinase inhibitors (TKIs) or mTOR inhibitors. These new agents have become the standard of care in managing advanced clear-cell RCC. Choice of initial medical management in patients with metastatic clear-cell RCC should be guided by randomised studies. On the evidence available, the first-line therapy in patients with good- or intermediate-risk mRCC should be either sunitinib or pazopanib, or bevacizumab plus interferon. In selected patients sorafenib is an option, as is high-dose interleukin-2 if performance status is good. In patients with poor prognosis, temsirolimus is recommended. In cytokine refractory patients, sorafenib, when patients have progressed on a tyrosine kinase inhibitor everolimus is the agent of choice. Biró K, Küronya Z. Recent advancements in the treatment of renal cell carcinoma - focus on international guidelines.     

Single-cell analysis reveals metastatic cell heterogeneity in clear cell renal cell carcinoma

Renal cell carcinoma (RCC) is one of the leading causes of cancer-related death worldwide. Tumour metastasis and heterogeneity lead to poor survival outcomes and drug resistance in patients with metastatic RCC (mRCC). In this study, we aimed to assess intratumoural heterogeneity (ITH) in mRCC cells by performing a combined analysis of bulk data and single-cell RNA-sequencing data, and develop novel biomarkers for prognosis prediction on the basis of the potential molecular mechanisms underlying tumorigenesis. Eligible single-cell cohorts related to mRCC were acquired using the Gene Expression Omnibus (GEO) dataset to identify potential mRCC subpopulations. We then performed gene set variation analysis to understand the differential function in primary RCC and mRCC samples. Subsequently, we applied weighted correlation network analysis to identify coexpressing gene modules that were related to the external trait of metastasis. Protein-protein interactions were used to screen hub subpopulation-difference (sub-dif) markers (ACTG1, IL6, CASP3, ACTB and RAP1B) that might be involved in the regulation of RCC metastasis and progression. Cox regression analysis revealed that ACTG1 was a protective factor (HR < 1), whereas the other four genes (IL6, CASP3, ACTB and RAP1B) were risk factors (HR > 1). Kaplan-Meier survival analysis suggested the potential prognostic value of these sub-dif markers. The expression of sub-dif markers in mRCC was further evaluated in clinical samples by immunohistochemistry (IHC). Additionally, the genetic features of sub-dif marker expression patterns, such as genetic variation profiles, correlations with tumour-infiltrating lymphocytes (TILs), and targeted signalling pathway activities, were assessed in bulk RNA-seq datasets. In conclusion, we established novel subpopulation markers as key prognostic factors affecting EMT-related signalling pathway activation in mRCC, which could facilitate the implementation of a treatment for mRCC patients.     

Sunitinib treatment promotes metastasis of drug-resistant renal cell carcinoma via TFE3 signaling pathway

Receptor tyrosine kinase (RTK) inhibitors, such as sunitinib and sorafenib, remain the first-line drugs for the treatment of mRCC. Acquired drug resistance and metastasis are the main causes of treatment failure. However, in the case of metastasis Renal Cell Cancer (mRCC), which showed a good response to sunitinib, we found that long-term treatment with sunitinib could promote lysosome biosynthesis and exocytosis, thereby triggering the metastasis of RCC. By constructing sunitinib-resistant cell lines in vivo, we confirmed that TFE3 plays a key role in the acquired resistance to sunitinib in RCC. Under the stimulation of sunitinib, TFE3 continued to enter the nucleus, promoting the expression of endoplasmic reticulum (ER) protein E-Syt1. E-Syt1 and the lysosomal membrane protein Syt7 form a heterodimer, which induces ER fragmentation, Ca2⁺ release, and lysosomal exocytosis. Lysosomal exocytosis has two functions: pumping sunitinib out from the cytoplasm, which promotes resistance to sunitinib in RCC, releasing cathepsin B (CTSB) into the extracellular matrix (ECM), which can degrade the ECM to enhance the invasion and metastasis ability of RCC. Our study found that although sunitinib is an effective drug for the treatment of mRCC, once RCC has acquired resistance to sunitinib, sunitinib treatment will promote metastasis.Subject terms: Renal cell carcinoma, Cell invasion, Prognostic markers     

Gene Expression Profile of Peripheral Blood Lymphocytes from Renal Cell Carcinoma Patients Treated with IL-2, Interferon-�� and Dendritic Cell Vaccine

Lymphocytes are a key component of the immune system and their differentiation and function are directly influenced by cancer. We examined peripheral blood lymphocyte (PBL) gene expression as a biomarker of illness and treatment effect using the Affymetrix Human Gene ST1 platform in patients with metastatic renal cell carcinoma (mRCC) who received combined treatment with IL-2, interferon-?-2a and dendritic cell vaccine. We examined gene expression, cytokine levels in patient serum and lymphocyte subsets as determined by flow cytometry (FCM). Pre-treatment PBLs from patients with mRCC exhibit a gene expression profile and serum cytokine profile consistent with inflammation and proliferation not found in healthy donors (HD). PBL gene expression from patients with mRCC showed increased mRNA of genes involved with T-cell and T_REG-cell activation pathways, which was also reflected in lymphocyte subset distribution. Overall, PBL gene expression post-treatment (POST) was not significantly different than pre-treatment (PRE). Nevertheless, treatment related changes in gene expression (post-treatment minus pre-treatment) revealed an increased expression of T-cell and B-cell receptor signaling pathways in responding (R) patients compared to non-responding (NR) patients. In addition, we observed down-regulation of T_REG-cell pathways post-treatment in R vs. NR patients. While exploratory in nature, this study supports the hypothesis that enhanced inflammatory cytotoxic pathways coupled with blunting of the regulatory pathways is necessary for effective anti-cancer activity associated with immune therapy. This type of analysis can potentially identify additional immune therapeutic targets in patients with mRCC.     

Association of Angiopoietin-2 and Ki-67 Expression with Vascular Density and Sunitinib Response in Metastatic Renal Cell Carcinoma

The Angiopoietin-2 (Ang2, Angpt2) growth factor is a context-dependent antagonist/agonist ligand of the endothelial Tie2 receptor tyrosine kinase and known to promote tumour angiogenesis and metastasis. Angiopoietin antagonists have been tested in clinical cancer trials in combination with VEGF-based anti-angiogenic therapy, including sunitinib, which is widely used as a first-line therapy for metastatic renal cell carcinoma (mRCC). However, little is known about Ang2 protein expression in human tumours and the correlation of tumour Ang2 expression with tumour vascularization, tumour cell proliferation and response to anti-angiogenic therapies. Here, we evaluated, using immunohistochemistry, the expression of Ang2, CD31 and the cell proliferation marker Ki-67 in the primary kidney cancer from 136 mRCC patients, who received first-line sunitinib after nephrectomy. Ang2 protein expression was restrained to RCC tumour vessels, and correlated with tumour vascularization and response to sunitinib. High pre-therapeutic Ang2 expression, and more strongly, combined high expression of both Ang2 and CD31, were associated with a high clinical benefit rate (CBR). Low cancer Ki-67 expression, but not Ang2 or CD31 expression, was associated with favourable progression-free (PFS) and overall survival (OS) as compared to patients with high Ki-67 expression (PFS 6.5 vs. 10.6 months, P = 0.009; OS, 15.7 vs. 28.5 months, P = 0.015). In summary, in this study to investigate endothelial Ang2 in mRCC patients treated with first-line sunitinib, high cancer Ang2 expression was associated with the CBR, but not PFS or OS, whereas low Ki-67 expression was significantly associated with long PFS and OS.     

The Role of Angiopoietins as Potential Therapeutic Targets in Renal Cell Carcinoma

Angiopoietin 2 (Ang2) is a secreted glycoprotein upregulated at sites of angiogenesis and has been implicated in cancer neovascularization. Recent studies have suggested efficacy of combined Ang and vascular endothelial growth factor receptor (VEGFR) inhibition for patients with metastatic renal cell carcinoma (mRCC). We measured Ang2 expression in human tissue and plasma, and tested the effect of dual Ang1/2 (trebananib; AMG386) or Ang2 alone (L1-7) inhibition with VEGFR inhibition on murine RCC growth and blood flow. Ang2 levels were higher in human tumors than normal tissues with RCC ranking highest for Ang2 expression across all tumor types tested. Plasma Ang2 was significantly higher in patients with mRCC compared to controls or patients with stage I disease. Plasma Ang2 decreased with sunitinib treatment and increased at time of disease progression. In the RCC mouse, dual Ang1/2 and Ang2 inhibition improved the activity of sunitinib. Combined Ang1/2 and VEGFR inhibition prevented the resumption of blood flow associated with sunitinib resistance. Thus, Ang2 inhibition, independent of Ang1 inhibition, improves the activity of sunitinib and plasma Ang2 increases in the setting of progression on sunitinib possibly contributing to resistance. Further, arterial spin-labeled perfusion magnetic resonance imaging might be a non-invasive marker of the antiangiogenic activity of Ang inhibitors.     

A phase II study of the cancer vaccine TG4010 alone and in combination with cytokines in patients with metastatic renal clear-cell carcinoma: clinical and immunological findings

MUC1 over-expression in renal clear-cell carcinoma (RCC) is associated with poor prognosis. This phase II study determined the efficacy and tolerability of TG4010, a cancer vaccine based on a modified vaccinia virus expressing MUC1 and interleukin-2, in combination with cytokines, as first-line therapy in metastatic RCC. Thirty-seven patients with progressive, MUC1-positive RCC received TG4010 10(8) pfu/inj weekly for 6 weeks, then every 3 weeks until progression, when TG4010 was continued in combination with interferon-α2a and interleukin-2. Assessments included clinical response (primary endpoint), safety, time to treatment failure (TTF), overall survival (OS), and immune response. No objective clinical responses occurred. Five of the 27 evaluable patients (18%) had stable disease for >6 months with TG4010 alone and six of 20 patients (30%) had stable disease for >6 months with TG4010 plus cytokines. Median TTF was 4.1, 3.6, and 9.3 months for monotherapy, combination therapy, and overall, respectively. Median OS was 19.3 months for all patients and 22.4 months combination therapy recipients. The most frequent TG4010-related adverse events were minor-to-moderate injection-site reactions, fatigue, and flu-like symptoms. Six of 28 patients showed a MUC1 CD4+ T cell proliferative response during therapy. Anti-MUC1 CD8+ T cells were detected before and after therapy in 3 and 4 patients, respectively. MUC1-specific CD8+ T cell responses were associated with longer survival. Therapy with TG4010 plus cytokines appears to be feasible and well tolerated in patients with metastatic RCC. However, these data should be interpreted with caution, as additional prospective studies are necessary to clarify the clinical efficacy of this therapy.     

YB-1 suppression induces STAT3 proteolysis and sensitizes renal cancer to interferon-α

Renal cell carcinoma (RCC) accounts for 80–95 % of kidney tumors, and approximately 30 % of RCC patients have metastatic disease at diagnosis. Conventional chemotherapy is not effective in patients with metastatic RCC (MRCC); therefore, immunotherapy with interferon-α (IFN-α) has been employed to improve survival. However, the response rate of MRCC to IFN-α therapy is low. We previously reported that a signal transducer and activator 3 (STAT3) polymorphism was a useful diagnostic marker to predict the response to IFN-α therapy in patients with MRCC. Therefore, we hypothesized the inhibition of STAT3 in the addition of IFN-α therapy might be useful. Moreover, the blockage of STAT3 itself has been reported to enhance the antitumor effects. However, because IFN-α is thought to elicit its therapeutic effect via enhancement of an antitumor immune response mediated by lymphocytes that can be activated by IFN-α administrations, it is probable that the suppression of STAT3 in vivo relates to autoimmune disorders. In the present study, we found Y-box binding protein-1 (YB-1) was poorly expressed in T lymphocytes, as compared with cancer tissues. YB-1 was reported to have an important effect on the STAT3 pathway. Suppression of STAT3 by YB-1 inhibition did not seem to enhance the potential risk for autoimmune disorders. Moreover, we found sensitivity to IFN-α was increased by YB-1 suppression, and this suppression did not down-regulate IFN-α activation of T lymphocytes.     

IL-4 inhibits the TNF-α induced proliferation of renal cell carcinoma (RCC) and cooperates with TNF-α to induce apoptotic and cytokine responses by RCC: implications for antitumor immune responses

Objective: While previous reports clearly demonstrated antiproliferative effects of IL-4 on renal cell carcinoma (RCC) in vitro, the administration of IL-4 to patients with metastatic RCC in clinical trials could not recapitulate the promising preclinical results. In the present study we wanted to examine the context of IL-4 action and to establish conditions of enhanced IL-4 efficacy. Methods: Primary and permanent human RCC cells were cultured in either serum-supplemented or chemically defined, serum-free culture medium in the presence or absence of cytokines. Cell proliferation was assessed as [³H]-thymidine incorporation. Cell apoptosis was measured using the fluorescent DNA intercalator 7-aminoactinomycin D and flow cytometry. In addition, culture media conditioned by RCC were subjected to cytokine antibody array and cytokine multiplex analysis. Results: Our results indicate that the previously reported antiproliferative effects of IL-4 are serum-dependent. Under serum-free conditions, IL-4 failed to exhibit growth-inhibitory effects or was even growth-stimulatory. In a chemically defined, serum-free medium (AIM-V), however, IL-4 inhibited the TNF-α induced proliferation of RCC. IL-4 and TNF-α synergistically induced apoptosis of RCC as well as a complex cytokine response by RCC, which included the synergistic upregulation of RANTES and MCP-1. Conclusions: IL-4 alone has little effect on the spontaneous proliferation of RCC but can prevent the enhancement of proliferation induced by growth promoters like FBS and TNF-α. The concomitant growth inhibitory, apoptosis-inducing, and cytokine-enhancing effects of IL-4 in combination with TNF-α on RCC support the view that Th2 cytokines may be required for productive immune responses against RCC.