Immunotherapy and gene therapy for renal cell carcinoma (original) (raw)
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Gene Therapy, 2011
Despite novel targeted agents, prognosis of metastatic renal cell cancer (RCC) remains poor, and experimental therapeutic strategies are warranted. Transfection of tumor cells with co-stimulatory molecules and/or cytokines is able to increase immunogenicity. Therefore, in our clinical study, 10 human leukocyte antigen (HLA)-A*0201 + patients with histologicallyconfirmed progressive metastatic clear cell RCC were immunized repetitively over 22 weeks with 2.5-40Â10 6 interleukin (IL)-7/CD80 cotransfected allogeneic HLA-A*0201 + tumor cells (RCC26/IL-7/CD80). Endpoints of the study were feasibility, safety, immunological and clinical responses. Vaccination was feasible and safe. In all, 50% of the patients showed stable disease throughout the study; the median time to progression was 18 weeks. However, vaccination with allogeneic RCC26/IL-7/ CD80 tumor cells was not able to induce TH1-polarized immune responses. A TH2 cytokine profile with increasing amounts of antigen-specific IL-10 secretion was observed in most of the responding patients. Interferon-g secretion by patient lymphocytes upon antigen-specific and non-specific stimulation was substantially impaired, both before and during vaccination, as compared with healthy controls. This is possibly due to profound tumor-induced immunosuppression, which may prevent induction of antitumor immune responses by the gene-modified vaccine. Vaccination in minimal residual disease with concurrent depletion of regulatory cells might be one strategy to overcome this limitation.
Gene Modification Strategies to Induce Tumor Immunity
2005
strategies to correct deficiencies in the response against cancer. The following provides a review of ge-Cancer Immunology Program Peter MacCallum Cancer Center netic intervention strategies to overcome existing limitations of immune defenses at five crucial stages of East Melbourne, Victoria 3002 Australia the adaptive immune response ) and discusses how these might be integrated to develop improved therapies for cancer.
Suppression of Renal Cell Carcinoma Growth and Metastasis with Sustained Antiangiogenic Gene Therapy
Human Gene Therapy, 2008
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 dualphoton optical imaging of the tumor vasculature to ascertain angiogenic changes. All animals underwent postmortem histopathogical 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.
Allogeneic gene-modified tumour cells in metastatic kidney cancer. Preliminary report
Folia biologica, 2003
An allogeneic irradiated RCC cell line, engineered to produce IL-2 (ACHN-IL-2), admixed with autologous metastatic formalin-treated tumour cells, was used to vaccinate ten MRCC patients in progression of disease in spite of IL-2 immunotherapy. The cells were administered subcutaneously and/or intra-tumourally. Sixty-four MRCC patients in progressive disease, not treated by vaccination but receiving similar IL-2 immunotherapy, were considered as the control group. Patients received 4-16 injections (mean 9 +/- 4), containing an average of 10.6 x 10(7) +/- 7.7 x 10(7) ACHN-IL-2-transfected cells (a minimum of 4 x 10(7), and a maximum of 31 x 10(7)). Four patients also received intra-tumour injections. Vaccination was administered during 30-418 days, and the follow-up continued for 649 +/- 353 days (190-1342). Throughout this period, the patients continued receiving the previously set immunotherapy treatment. No adverse side effects related to the treatment were observed. One complete a...
Gene cancer immunogene therapy
Journal of Cancer Science & Therapy, 2017
A ntibodies to an oncoptrotein Alpha-fetoprotein, AFP, have constituted the first generation tool for cancer diagnostic and cancer therapy, especially of hepatocarcinoma. In the case of brain malignant tumor, glioblastoma, AFP being present as well in glial as in neuronal cells, another oncoprotein-IGF-I, specific for glial cells was selected. For therapy purpose, the second generation tool was created: the arrest of oncoprotein synthesis in cancer cells was performed on translation and transcription level in vitro using anti-gene anti IGF-I strategy (IGF-I antisense/triple helix, AS/TH). The created AS/TH cells, presented the following characteristics: absence of IGF-I; presence of IGF-I receptor; presence of MHC-I, B71 and B72 antigens; and presence of IL-6. The observed phenotypical characteristics became the standardized criteria for IGF-I AS/TH cell vaccines: while injected in cancer patients, the vaccines induced the antitumor immune response and stopped the progression of tumor development. In glioblastoma patients, the survival reached 2 years, and in some cases, up to 3-4 years.