Bioactivity of Autologous Irradiated Renal Cell Carcinoma Vaccines Generated by Ex Vivo Granulocyte-Macrophage Colony-Stimulating Factor Gene Transfer

Abstract

Granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transduced, irradiated tumor vaccines induce potent, T-cell-mediated antitumor immune responses in preclinical models. We report the initial results of a Phase I trial evaluating this strategy for safety and the induction of immune responses in patients with metastatic renal cell carcinoma (RCC). Patients were treated in a randomized, double-blind dose-escalation study with equivalent doses of autologous, irradiated RCC vaccine cells with or without ex vivo human GM-CSF gene transfer. The replicationdefective retroviral vector MFG was used for GM-CSF gene transfer. No dose-limiting toxicities were encountered in 16 fully evaluable patients. GM-CSF gene-transduced vaccines were equivalent in toxicity to nontransduced vaccines up to the feasible limits of autologous tumor vaccine yield. No evidence of autoimmune disease was observed. Biopsies of intradermal sites of injection with GM-CSF gene-transduced vaccines contained distinctive macrophage, dendritic cell, eosinophil, neutrophil, and T-cell infiltrates similar to those observed in preclinical models of efficacy. Histological analysis of delayed-type hypersensitivity responses in patients vaccinated 1 This work was supported by the NIH GCRC at Johns Hopkins, the Kirby Award of the Cancer Research Institute, the Longrifles Endowment, the Burroughs Wellcome Experimental Therapeutics Award, and the CaPCURE Foundation. Partial funding for this study was provided by Somatix Corporation. Under an agreement between Somatix and the Johns Hopkins University, D. P. is entitled to a share of sales royalty received by the University from Somatix. The terms of this arrangement are being managed by the University in accordance with its conflict of interest policies.

Allogeneic gene-modified tumor cells (RCC-26/IL-7/CD80) as a vaccine in patients with metastatic renal cell cancer: a clinical phase-I study

“…Use of granulocyte-macrophage colony stimulating factor-secreting autologous tumor cells was feasible and safe; after vaccination of RCC patients with advanced disease strong DTH reactions of the skin were observed, together with cellular infiltrates at the injection site as well as occasional immunological and clinical responses. 30,31 Two other clinical studies used CD80-transfected autologous tumor cells in RCC patients. 32,33 Both studies confirmed the feasibility of the approach and clinical responses were reported in a few patients; however, assessment of clinical efficacy was hampered by coadministration of s.c. IL-2 in these trials.…”

Replication-defective recombinant Semliki Forest virus encoding GM-CSF as a vector system for rapid and facile generation of autologous human tumor cell vaccines

“…Expression levels at 24 h after transduction were higher or comparable to hGM-CSF expression levels found after transduction of RCC samples using recombinant retrovirus. 1,8 In most cases expression levels were higher in the RCC samples than in the healthy tissue of the same patient, however, the opposite was found as well (patient D). When MOIs were increased higher expression levels could be measured.…”

“…When MOIs were increased higher expression levels could be measured. In none of the untransduced samples was mGM-CSF expression measured indicating that the ELISA is specific for mGM-CSF (in Simons et al 1 it was described that human RCC cells produce autologous hGM-CSF). The different samples produced GM-CSF for up to 4 days after transduction.…”

“…Possibilities that are already explored in the clinic involve immunization with autologous tumor cells, genetically modified with recombinant viral vectors to produce interferon-gamma, IL-4, IL-12, and GM-CSF. [1][2][3][4][5][6] At present, GM-CSF appears to be the most efficient cytokine for obtaining optimal immune responses. 7 Within the context of the use of cytokine gene-modified autologous tumor cell vaccines, currently, in the clinic retrovirus vectors are applied most widely for delivery of the cytokine gene to the tumor cells, [7][8][9][10][11] although other viral delivery systems are also under investigation.…”

Gene transfer approaches in cancer immunotherapy

“…Thus, a combination of these cytokines is a powerful tool, as it was reported. 65 The main cause of such amplifications of the immune GM-CSF Mouse models and clinical trial of autologous irradiated tumor cells generated by ex vivo transfection [23,63] Gene transfer approaches in cancer immunotherapy SS Larin et al system response is the involvement of different and independent mechanisms of adoptive immune response.…”