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VEGF neutralizing antibody increases the therapeutic efficacy of vinorelbine for renal cell carcinoma.

ABSTRACT: Renal cell carcinoma (RCC) is currently one of the most treatment-resistant malignancies and affects approximately three in 10,000 people. The impact of this disease produces about 31,000 new cases in the United States per year; and 12,000 people in the United States alone die from RCC annually. Although several treatment strategies have been investigated for RCC, this cancer continues to be a therapeutic challenge. For this reason, the aim of our study is to develop a more effective combinational therapy to treat advanced RCC. We examined the effect of vinorelbine on the signalling pathways of two human renal cancer cell lines (A498 and 786-O) and also examined the in vivo effect of vinorelbine treatment alone and vinorelbine in combination with the anti-VEGF antibody 2C3 on A498 and 786-O tumour growth in nude mice. Tumour angiogenesis was measured by vWF staining, and apoptosis was determined by the TUNEL assay. We observed a significant tumour growth inhibition when using a combinational therapy of anti-VEGF antibody 2C3 and vinorelbine in both A498 and 786-O tumour-bearing mice. The results suggest a breakthrough treatment for advanced RCC.

SUBMITTER: Sinha S

PROVIDER: S-EPMC2992850 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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VEGF neutralizing antibody increases the therapeutic efficacy of vinorelbine for renal cell carcinoma.

Sinha Sutapa S Cao Ying Y Dutta Shamit S Wang Enfeng E Mukhopadhyay Debabrata D

Journal of cellular and molecular medicine 20081107 3

Renal cell carcinoma (RCC) is currently one of the most treatment-resistant malignancies and affects approximately three in 10,000 people. The impact of this disease produces about 31,000 new cases in the United States per year; and 12,000 people in the United States alone die from RCC annually. Although several treatment strategies have been investigated for RCC, this cancer continues to be a therapeutic challenge. For this reason, the aim of our study is to develop a more effective combination ...[more]

PMID: 19017359

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Project description:The efficacy of anti-angiogenic treatment by targeting VEGF/VEGF receptors in metastatic clear cell renal cell carcinoma (ccRCC) varies from patient to patient. Discovering the reasons behind this variability could lead to the identification of relevant therapeutic targets. Thus, we investigated the novel splice variants of VEGF that are less efficiently inhibited by anti-VEGF/VEGFR targeting than the conventional isoforms. By in silico analysis, we identified a novel splice acceptor in the last intron of the VEGF gene resulting in an insertion of 23 bp in VEGF mRNA. Such an insertion can shift the open-reading frame in previously described splice variants of VEGF (VEGFXXX ), leading to a change in the C-terminal part of the VEGF protein. Next, we analysed the expression of these alternatively spliced VEGF new isoforms (VEGFXXX/NF ) in normal tissues and in RCC cell lines by qPCR and ELISA, and we investigated the role of VEGF222/NF (equivalent to VEGF165 ) in physiological and pathological angiogenesis. Our in vitro data demonstrated that recombinant VEGF222/NF stimulated endothelial cell proliferation and vascular permeability by activating VEGFR2. In addition, VEGF222/NF overexpression enhanced proliferation and metastatic properties of RCC cells, whereas downregulation of VEGF222/NF resulted in cell death. We also generated an in vivo model of RCC by implanting RCC cells overexpressing VEGF222/NF in mice, which we treated with polyclonal anti-VEGFXXX/NF antibodies. VEGF222/NF overexpression enhanced tumour formation with aggressive properties and a fully functional vasculature, while treatment with anti-VEGFXXX/NF antibodies slowed tumour growth by inhibiting tumour cell proliferation and angiogenesis. In a patient cohort from the NCT00943839 clinical trial, we investigated the relationship between plasmatic VEGFXXX/NF levels, resistance to anti-VEGFR therapy and survival. High plasmatic VEGFXXX/NF levels correlated with shorter survival and lower efficacy of anti-angiogenic drugs. Our data confirmed the existence of new VEGF isoforms that could serve as novel therapeutic targets in patients with RCC that are resistant to anti-VEGFR therapy.

Project description:BackgroundChimeric antigen receptor (CAR) T cells have demonstrated remarkable breakthroughs in treating hematologic malignancies, yet their efficacy in solid tumors is limited by the immunosuppressive microenvironment. Sympathetic nerves significantly contribute to this immunosuppressive milieu in solid tumors. However, the impact of tumor sympathetic denervation on enhancing CAR T-cell antitumor efficacy remains unclear.MethodsWe screened for sympathetic gene sets in various types of cancers and investigated the association of sympathetic nerves with immunosuppression in renal clear cell carcinoma. Using antibodies to block the nerve growth factor (NGF) pathway, we explored sympathetic nerve distribution in tumor tissues and tumor progression. Additionally, we engineered CAR T cells to secrete NGF single chain fragment variable (scFv) to achieve tumor immunosympathectomy and assessed their antitumor efficacy. Bulk RNA sequencing and single-cell RNA sequencing analyses were conducted to evaluate changes in immune cell phenotypes within the tumor microenvironment.ResultsBlocking the NGF pathway with antibodies effectively reduced sympathetic nerve distribution in tumor tissues and delayed tumor progression. CAR T cells engineered to secrete NGF scFv achieved a similar tumor immunosympathectomy and exhibited enhanced tumor suppression. RNA sequencing analyses revealed that this augmented effect was primarily due to the inhibition of the terminal exhaustion phenotype in tumor-infiltrating CD8 T cells and the prevention of macrophage polarization from M1 to M2. This approach maintained a stronger antitumor immune state at the tumor site. Additionally, splenic T cells also exhibited a more potent immune effector phenotype following the infusion of NGF scFv-secreting CAR T cells.ConclusionsOur results suggest that immunosympathectomy is a novel approach to weaken tumor microenvironment immunosuppression and synergistically enhance CAR T-cell efficacy against solid tumors.

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VEGF neutralizing antibody increases the therapeutic efficacy of vinorelbine for renal cell carcinoma.

Publications

VEGF neutralizing antibody increases the therapeutic efficacy of vinorelbine for renal cell carcinoma.

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