The evolving role of monoclonal antibodies in the treatment of patients with advanced renal cell carcinoma: a systematic review

ABSTRACT

Introduction: While the majority of the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) inhibitors currently used for the therapy of metastatic renal cell carcinoma (mRCC) are small molecule agents inhibiting multiple targets, monoclonal antibodies are inhibitors of specific targets, which may decrease off-target effects while preserving on-target activity. A few monoclonal antibodies have already been approved for mRCC (bevacizumab, nivolumab), while many others may play an important role in the therapeutic scenario of mRCC.

Areas covered: This review describes emerging monoclonal antibodies for treating RCC. Currently, bevacizumab, a VEGF monoclonal antibody, is approved in combination with interferon for the therapy of metastatic RCC, while nivolumab, a Programmed Death (PD)-1 inhibitor, is approved following prior VEGF inhibitor treatment. Other PD-1 and PD-ligand (L)-1 inhibitors are undergoing clinical development.

Expert opinion: Combinations of inhibitors of the PD1/PD-L1 axis with VEGF inhibitors or cytotoxic T-lymphocyte antigen (CTLA)-4 inhibitors have shown promising efficacy in mRCC. The development of biomarkers predictive for benefit and rational tolerable combinations are both important pillars of research to improve outcomes in RCC.     

Molecular targeted therapy for renal cell carcinoma and other urological cancers

In Japan, therapeutic strategy for metastatic renal cell carcinoma(RCC) has been markedly changed since the recent introduction of multiple tyrosine kinase inhibitors, including sorafenib and sunitinib, into the clinical practice. In addition to these agents, inhibitors of mTOR(mammalian target of rapamycin) are scheduled to be available in patients with metastatic RCC near future. In this review, we would like to summarize the current status of these molecular targeted agents for the treatment of RCC, and subsequently describe the important issues associated with the administration of these agents, such as the effects on quality of life and the possible use as neoadjuvant setting. Finally, the prospects for the use of molecular targeted agents against urological cancers other than RCC are mentioned.     

Suppression of renal cell carcinoma growth and metastasis with sustained antiangiogenic gene therapy

Renal cell carcinoma (RCC) is the third most common urologic neoplasm. This aggressive malignancy has proven refractory to conventional treatment options. Antiangiogenic agents have shown early success in treating metastatic disease. The highly vascular nature of RCC appears particularly susceptible to this approach. This study investigates the potential of sustained expression of an endostatin-angiostatin fusion protein in an early-stage model of RCC to inhibit tumor growth and metastasis. Subcutaneous RCC-29 tumors were induced in athymic nude mice. Once tumors reached volumes of 10 and 25 mm(3), subjects received intratumoral injections of a nonreplicating adenoviral vector every 20 days until the conclusion of the trial. The mice were randomly assigned to three treatment groups: saline control, viral Ad-GFP control, and Ad-EndoAngio. Tumor volumes were measured twice weekly for 80 days. During days 40-50 of the trial, subjects underwent dual-photon optical imaging of the tumor vasculature to ascertain angiogenic changes. All animals underwent postmortem histopathological analysis to assess for metastatic disease in the kidney, lung, liver, brain, and spleen. Results indicate that tumors treated with Ad-EndoAngio displayed 97% growth reduction compared with controls (p < 0.001). Further, in vivo tumor vascular imaging illustrated a reduction in blood vessel number and lumen diameter size. Kaplan-Meier analysis suggested dramatic survival advantage with Ad-EndoAngio treatment. Importantly, histopathological examination demonstrated marked lung and liver metastasis suppression in the treatment arms. These results suggest that sustained EndoAngio gene therapy has effective antiangiogenic action against human RCC tumors and possesses potential as a novel treatment for metastatic renal cell carcinoma.     

LyP-1-conjugated PEGylated liposomes: A carrier system for targeted therapy of lymphatic metastatic tumor

The application of liposomes in targeted therapy of lymphatic metastatic tumors has been hampered by the low uptake rate of liposome by metastatic lymph nodes. In this report, LyP-1, a peptide that can specifically bind tumor cells, tumor lymphatics and tumor-associated macrophages, was conjugated to liposomes for targeting and treating lymphatic metastatic tumors. Firstly, LyP-1-conjugated PEGylated liposomes loaded with fluorescein or doxorubicin (DOX) were prepared and showed satisfactory vesicle size and size distribution. The in vitro cellular uptake and in vivo near-infrared fluorescence imaging results showed that LyP-1 modification increased liposome uptake by tumor cells and metastatic lymph nodes, but did not increase uptake by normal lymph nodes. The immunofluorescence analysis evidenced that LyP-1-conjugated liposomes were distributed adjacent to tumor lymphatics and tumor-associated macrophages in metastatic lymph nodes. The pharmacodynamic study suggested that compared with unmodified liposomes, LyP-1-conjugated DOX-loaded liposomes exhibited enhanced inhibition effect on tumor cells in vitro and lymphatic metastatic tumors in vivo. Pathological examination showed that liposomal DOX caused reduced tissue damage to injection site compared with DOX solution. In summary, LyP-1-conjugated PEGylated liposomes could be targeted to metastatic lymph nodes based on their specific binding to tumor cells, tumor lymphatics and tumor-associated macrophages. They are a safe and effective drug delivery system of antineoplastic agents for targeted therapy of lymphatic metastatic tumors.     

Vascular disruption in combination with mTOR inhibition in renal cell carcinoma

Renal cell carcinoma (RCC) is an angiogenesis-dependent and hypoxia-driven malignancy. As a result, there has been an increased interest in the use of antiangiogenic agents for the management of RCC in patients. However, the activity of tumor-vascular disrupting agents (tumor-VDA) has not been extensively examined against RCC. In this study, we investigated the therapeutic efficacy of the tumor-VDA ASA404 (DMXAA, 5,6-dimethylxanthenone-4-acetic acid, or vadimezan) in combination with the mTOR inhibitor everolimus (RAD001) against RCC. In vitro studies were carried out using human umbilical vein endothelial cells and in vivo studies using orthotopic RENCA tumors and immunohistochemical patient tumor-derived RCC xenografts. MRI was used to characterize the vascular response of orthotopic RENCA xenografts to combination treatment. Therapeutic efficacy was determined by tumor growth measurements and histopathologic evaluation. ASA404/everolimus combination resulted in enhanced inhibition of endothelial cell sprouting in the 3-dimensional spheroid assay. MRI of orthotopic RENCA xenografts revealed an early increase in permeability 4 hours posttreatment with ASA404, but not with everolimus. Twenty-four hours after treatment, a significant reduction in blood volume was observed with combination treatment. Correlative CD31/NG2 staining of tumor sections confirmed marked vascular damage following combination therapy. Histologic sections showed extensive necrosis and a reduction in the viable rim following combination treatment compared with VDA treatment alone. These results show the potential of combining tumor-VDAs with mTOR inhibitors in RCC. Further investigation into this novel combination strategy is warranted.     

Neuroblastoma: the impact of biology and cooperation leading to personalized treatments

Neuroblastoma is the most common extra-cranial solid tumor in children. It is a heterogeneous disease, consisting of neural crest-derived tumors with remarkably different clinical behaviors. It can present in a wide variety of ways, including lesions which have the potential to spontaneously regress, or as an extremely aggressive form of metastatic cancer which is resistant to all forms of modern therapy. They can arise anywhere along the sympathetic nervous system. The median age of presentation is approximately 18 months of age. Urinary catecholamines (HVA and VMA) are extremely sensitive and specific tumor markers and are used in diagnosis, treatment response assessment and post-treatment surveillance. The largest national treatment groups from North America, Europe and Japan have formed the International Neuroblastoma Risk Group Task Force (INRG) to identify prognostic factors, to understand the mechanisms of tumorigenesis in this rare disease and to develop multi-modality therapies to improve outcomes and decrease treatment-related toxicities. This international cooperation has resulted in a significant leap in our understanding of the molecular pathogenesis of neuroblastoma. Lower staged disease can be cured if the lesion is resectable. Treatment of unresectable disease (loco-regional and metastatic) is stratified depending on clinical features (age at presentation, staging investigations) and specific tumor biological markers that include histopathological analyses, chromosomal abnormalities and the quantification of expression of an oncogene (MYCN). Modern treatment of high-risk neuroblastoma is the paradigm for the evolution of therapy in pediatric oncology. Outcomes have improved substantially with multi-modality therapy, including chemotherapy, surgery, radiation therapy, myeloablative therapy with stem cell transplant, immunotherapy and differentiation therapy; these comprise the standard of care worldwide. In addition, newer targeted therapies are being tested in phase I/II trials. If successful these agents will be incorporated into mainstream treatment programs.     

Functional MR imaging as a new paradigm for image guidance

Guidance and monitoring of locoregional minimally invasive treatment for primary or secondary liver tumor are critical to ensuring success and efficacy of therapy. In this article, we review advanced MR imaging techniques, including MR spectroscopy, diffusion and perfusion MR imaging, which can provide essential in vivo physiologic and metabolic information. These innovative imaging techniques can provide potential additional criteria to assess tumor response in addition to the accepted yet often limited Response Evaluation Criteria in Solid Tumors (RECIST) and the European Association for the Study of the Liver (EASL) criteria, which are based on decrease of tumor size and lesion enhancement, respectively. In this article, we also discuss the role of tumor size and enhancement in addition to apparent diffusion coefficient (ADC) findings after radiofrequency ablation (RFA), transarterial chemoembolization (TACE), and radioembolization.     

PET/CT用于肾细胞癌进展

肾细胞癌（RCC）是泌尿系统最常见的恶性肿瘤之一,约占肾癌的90%。PET/CT已广泛用于RCC的诊断、分级、疗效评价及预后评估等。¹⁸F-FDG为PET最常用显像剂之一,其他新型显像剂也在不断研发中。本文对PET/CT在RCC的应用进展进行综述。     

Mitogen-activated protein kinase kinase 1/2 inhibitors and 17-allylamino-17-demethoxygeldanamycin synergize to kill human gastrointestinal tumor cells in vitro via suppression of c-FLIP-s levels and activation of CD95

Prior studies have noted that inhibitors of mitogen-activated protein kinase (MAPK) kinase 1/2 (MEK1/2) enhanced geldanamycin lethality in malignant hematopoietic cells by promoting mitochondrial dysfunction. The present studies focused on defining the mechanism(s) by which these agents altered survival in carcinoma cells. MEK1/2 inhibitors [PD184352; AZD6244 (ARRY-142886)] interacted in a synergistic manner with geldanamycins [17-allylamino-17-demethoxygeldanamycin (17AAG) and 17-dimethylaminoethylamino-17-demethoxy-geldanamycin] to kill hepatoma and pancreatic carcinoma cells that correlated with inactivation of extracellular signal-regulated kinase 1/2 and AKT and with activation of p38 MAPK; p38 MAPK activation was reactive oxygen species dependent. Treatment of cells with MEK1/2 inhibitors and 17AAG reduced expression of c-FLIP-s that was mechanistically connected to loss of MEK1/2 and AKT function; inhibition of caspase-8 or overexpression of c-FLIP-s abolished cell killing by MEK1/2 inhibitors and 17AAG. Treatment of cells with MEK1/2 inhibitors and 17AAG caused a p38 MAPK-dependent plasma membrane clustering of CD95 without altering the levels or cleavage of FAS ligand. In parallel, treatment of cells with MEK1/2 inhibitors and 17AAG caused a p38 MAPK-dependent association of caspase-8 with CD95. Inhibition of p38 MAPK or knockdown of BID, FAS-associated death domain, or CD95 expression suppressed MEK1/2 inhibitor and 17AAG lethality. Similar correlative data were obtained using a xenograft flank tumor model system. Our data show that treatment of tumor cells with MEK1/2 inhibitors and 17AAG induces activation of the extrinsic pathway and that suppression of c-FLIP-s expression is crucial in transduction of the apoptotic signal from CD95 to promote cell death. [Mol Cancer Ther 2008;7(9):2633-48].     

Assessment of response to therapy in hepatocellular carcinoma

Abstract

The appropriate use of conventional or potential treatments for hepatocellular carcinoma requires that benefit can be shown. Therefore, the accurate assessment of response is both critical and essential. Demonstration of benefit observed will be determined by the criteria used. However, the use of conventional criteria based on anatomical imaging to assess response and progression is inadequate. Limitations occur due to the unique nature, presentation, and course of hepatocellular cancer, any underlying concomitant disease, the multiplicity of treatment options, and the challenges in assessing viable tumor. Locoregional therapies or cytostatic therapies can have beneficial effects and induce tumor necrosis without appreciable changes in tumor size. In recognition of the inherent limitations in conventional imaging criteria, various modifications have been proposed. In this review, the goals of assessing tumor response in clinical practice and in clinical trials are outlined. The varying patterns of response to different therapeutic modalities such as locoregional therapy and molecularly targeted therapy are reviewed, and an approach to the assessment of response based on clinical, biochemical, morphological, and functional criteria has been outlined. The implications of current and proposed approaches of assessing response for clinical practice or design of clinical trials are reviewed.     

Dual nano‐sized contrast agents in PET/MRI: a systematic review

Nowadays molecular imaging plays a vital role in achieving a successful targeted and personalized treatment. Hence, the approach of combining two or more medical imaging modalities was developed. The objective of this review is to systematically compare recent dual contrast agents in Positron Emission Tomography (PET)/Magnetic Resonance Imaging (MRI) and in some cases Single photon emission computed tomography (SPECT)/MRI in terms of some their characteristics, such as tumor uptake, and reticuloendothelial system uptake (especially liver) and their relaxivity rates for early detection of primary cancer tumor. To the best of our knowledge, this is the first systematic and integrated overview of this field. Two reviewers individually directed the systematic review search using PubMed, MEDLINE and Google Scholar. Two other reviewers directed quality assessment, using the criteria checklist from the CAMARADES (Collaborative Approach to Meta‐Analysis and Review of Animal Data from Experimental Studies) tool, and differences were resolved by consensus. After reviewing all 49 studies, we concluded that a size range of 20–200 nm can be used for molecular imaging, although it is better to try to achieve as small a size as it is possible. Also, small nanoparticles with a hydrophilic coating and positive charge are suitable as a T₂ contrast agent. According to our selected data, the most successful dual probes in terms of high targeting were with an average size of 40 nm, PEGylated using peptides as a biomarker and radiolabeled with copper 64 and gallium 68. Copyright © 2017 John Wiley & Sons, Ltd.     

Application of the indocyanine green fluorescence imaging method in laparoscopic resection of a solitary retroperitoneal metastasis of renal cell carcinoma: A case report

Fluorescence image-guided surgery has improved intraoperative identification of anatomic structures including visualization of vascular anatomy. Herein, indocyanine green (ICG) fluorescence imaging was applied to identify of a recurrent small tumor of renal cell carcinoma (RCC) during laparoscopic surgery. The patient underwent left laparoscopic radical nephrectomy via the retroperitoneal approach for RCC (clear cell carcinoma, pT1bN0M0) at the age of 39 years. A solitary retroperitoneal mass (14 mm in diameter) was identified in a computed tomography scan 6 years after surgery. We performed laparoscopic resection with the application of the ICG angiography, because RCC is recognized as one of the most hypervascular cancers. The tumor was clearly visualized by fluorescence. Histopathological diagnosis of the resected tumor was recurrent RCC (low grade, G1). The patient remained free of disease at 2 years after surgery. The ICG fluorescence imaging would be a useful method for identification of metastatic small lesions of RCC during laparoscopic surgery.     

Imaging tumor response following liver-directed intra-arterial therapy

Liver-directed intra-arterial therapies are palliative treatment options for patients with unresectable liver cancer; their use has also resulted in patients being downstaged leading to curative resection and transplantation. These intra-arterial therapies include transarterial embolization, conventional transarterial chemoembolization (TACE), drug-eluting bead TACE and radioembolization. Assessment of imaging response following these liver-directed intra-arterial therapies is challenging but pivotal for patient management. Size measurements based on computed tomography or magnetic resonance imaging (MRI) have been traditionally used to assess tumor response to therapy. However, these anatomic changes lag behind functional changes and may require months to occur. Further, these intra-arterial therapies cause acute tumor necrosis, which may result in a paradoxical increase in tumor size on early follow-up imaging despite complete cell death or necrosis. This concept is unique comparing to changes seen following systemic chemotherapy. The recent development of functional imaging techniques including diffusion-weighted MRI (DW MRI) and positron emission tomography (PET) allow for early assessment of treatment response and even prediction of overall tumor response to intra-arterial therapies. Although the results of DW MRI and PET studies are promising, the impact of these imaging modalities to assess treatment response has been limited without standardized protocols. The aim of this review article is to delineate the best practice for assessing tumor response in patients with primary or secondary hepatic malignancies undergoing intra-arterial therapies.     

Stereotactic body radiation therapy of liver tumors: post-treatment appearances and evaluation of treatment response: a pictorial review

Stereotactic body radiation therapy (SBRT) is a noninvasive treatment technique for selected patients with primary liver tumors and liver-confined oligometastatic disease. Recently, SBRT has emerged as an alternative treatment option in non-surgical candidates and in whom percutaneous treatment methods are not possible or contraindicated. The experience with SBRT continues to grow. There are currently no imaging guidelines for assessment of tumor response and follow-up schedule following SBRT. SBRT produces characteristic radiation-induced changes in the treated tumor and surrounding liver parenchyma. Knowledge of these changes is essential in the interpretation of follow-up imaging and assessment of treatment response. In this review, we will describe the CT, MRI, and PET imaging findings following SBRT of both the targeted liver tumor and surrounding hepatic parenchyma.     

Inverse relationship of expression between GM3 and globo-series ganglioside in human renal cell carcinoma

Renal cell carcinoma (RCC) is highly metastatic. We previously showed that expression of globo-series ganglioside is associated with the metastatic potential of RCC. However, the mechanism of metastasis remains largely unknown, and there is no effective therapy for metastasis. It was recently shown that induction of differentiation of colon cancer cells by brefeldin A was accompanied by an increase of GM3 with a concomitant decrease of neolacto-series gangliosides. To get a clue to a new method of therapy for RCC, we investigated whether the similar changes occur in RCC cells expressing globo-series ganglioside. Growth suppression and an increase of GM3 simultaneous with a decrease of monosialosyl galactosyl globoside, a member of globo-series gangliosides, were observed in human RCC cell line ACHN following brefeldin A treatment. The resultant change of the ganglioside profile is inversely related to the ganglioside pattern associated with the malignant potential of RCC and almost coincided with that representative of RCC cases showing favorable prognoses. It is suggested that the inverse relationship of expression between GM3 and globo-series ganglioside is reflected on the degree of malignancy of RCC, and may be useful as one of the indicators for exploiting treatment methods of RCC.     

Reduced intensity transplantation for metastatic renal cell cancer with 2-year follow-up

Metastatic renal cell carcinoma (RCC) is a disease that is resistant to conventional systemic therapy. Nonmyeloablative allogeneic stem cell transplant has activity in patients with metastatic RCC. This approach has been used in related donor transplantation but there are limited data on outcomes in the setting of unrelated donor (URD) transplantation. This phase II trial assessed the efficacy, safety, and responses in 16 patients, 10 related and 6 URD transplants after a reduced intensity conditioning regimen and stem cell transplant as a treatment for metastatic RCC. Sixteen patients received a conditioning consisting of either fludarabine, cyclophosphamide (n=11) or fludarabine, total body irradiation (n=5) followed by transplantation from an HLA-matched sibling donor or a unrelated HLA-donor. Cyclosporine and mycophenolate mofetil were administered as posttransplant immunosuppression. Patients were monitored for engraftment by short tandem repeat for myeloid and lymphoid lineages and clinical response was assessed by serial imaging. All patients achieved donor chimerism, 7 patients developed acute, grades 2 to 3, graft-versus-host disease. Chronic graft-versus-host disease occurred in 6 patients and transplant-related mortality was 12%. Of the 10 related donors, 1 obtained a complete response, 3 had a partial response, and 3 had stable disease. In the 6 patients who underwent URD transplant, 1 obtained a complete response and 1 patient had stable disease. These results suggest that similar outcomes are possible where either related or URD were used as the stem cell source in reduced intensity stem cell transplant for metastatic RCC.     

Breaking through a plateau in renal cell carcinoma therapeutics: development and incorporation of biomarkers

With the Food and Drug Administration approval of 6 novel targeted agents since December 2005 and limited comparative trials to discern relative efficacy, the treatment of metastatic renal cell carcinoma (RCC) has become immensely complex. The research community must look to novel ways in which to identify appropriate candidates for selected targeted therapies; one potential strategy is the use of clinical and molecular biomarkers. A growing body of knowledge-related von Hippel Lindau-driven pathways in this disease has highlighted the potential role of hypoxia-inducible factor subtypes in distinguishing RCC patients clinically. Techniques applied in other malignancies, such as gene expression and proteomic profiling, may also ultimately allow for clinical stratification. An emerging understanding of immunologic phenomena that may affect cancer progression (i.e., tumor infiltration by CD68 lymphocytes, memory T-cells, etc.) has unveiled a number of other potential biomarkers of response. Several vascular endothelial growth factor receptor-directed therapies classically thought to function as antiangiogenics may also have complex effects upon the tumor microenvironment including the associated immune cell milieu. As such, immunologic parameters could potentially predict response to current therapies. Finally, clinical biomarkers, such as hypertension, may predict the efficacy of several currently available targeted agents, although implementation of such biomarkers remains challenging. Herein, the clinical relevance of putative RCC biomarkers is examined in detail.     

Treatment of renal cell carcinoma with interferons

Renal cell carcinoma (RCC) is considered to be an immunogenic cancer. RCC is refractory to chemotherapy and radiation. Immunotherapy including interferon (IFN)-alpha, gamma and interleukin-2 are the treatment of choice for metastatic RCC. IFN-alpha is most widely used in Japan. The response rate of IFN-alpha is 10-20 %. Lung lesions and lymphnodes are the usual effective sites. The survival benefit of IFN-alpha in patients with metastatic RCC has been shown in prospective randomized studies. Nephrectomy is recommended before interferon therapy if the patients have good performance status. Adjuvant interferon therapy failed to show any survival benefit after curative excision of primary RCC. The place of IFN-alpha is going to be changed due to the recent use of molecular targeting drugs.     

18F-FDG PET/CT在肾脏肿瘤诊疗中的应用

目的评价18F-FDG PET/CT在肾脏肿瘤诊断和治疗中的价值。方法对30例CT或MRI确诊或怀疑肾脏肿瘤的患者行18F-FDG PET/CT显像,22例患者行延迟显像。所有肾脏肿瘤均经手术或穿刺活检后病理确诊。评价18F-FDG PET/CT对患者治疗方案的影响。结果 30例中,肾细胞癌(RCC)24例,肾神经内分泌肿瘤1例,淋巴瘤3例,肺癌肾转移1例,肾脏炎性病变1例。PET/CT诊断肾脏肿瘤的灵敏度为89.66%(26/29),特异度为100%(1/1),准确率为90.00%(27/30),阳性预测值为100%(26/26),阴性预测值为25.00%(1/4)。PET/CT检出肾癌伴肾门淋巴结转移2例,远处转移5例。8例(RCC 4例、肾淋巴瘤3例及肾转移癌1例)接受PET/CT后治疗方案发生改变。显像阳性肾癌患者Fuhrman分级高于阴性患者(P<0.05),显像阳性肾癌平均直径大于阴性者(P<0.05)。22例肾癌早期最大标准摄取(SUVmax)值与延迟显像SUVmax值差异无统计学意义(P>0.05)。结论 18F-FDG PET/CT可准确显示肾肿瘤患者局部病变及远处转移。对可疑肾淋巴瘤及肾转移瘤患者应行18F-FDG PET/CT显像,以明确分期并寻找原发灶。