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

Systemic T cell adoptive immunotherapy of malignant gliomas

“…It is currently under inves-tigation as an adjuvant for many clinical applications and has demonstrated great promise in promoting tumor immune responses. 2,9,13,14,24,26,43,46 In patients with malignant glioma, GM-CSF induced local erythema at the vaccine site; however, in contrast to bacillus Calmette-Guérin vaccine, which has been used in previous immunotherapy protocols, no local ulceration or infection was observed. 10 Additionally, tumor growth was never observed at the vaccination site, possibly because of irradiation of the vaccine and the poor metastatic capacity of gliomas.…”

Activated lymph node T cells for systemic adoptive immunotherapy of malignant glioma

“…It is currently under investigation as an adjuvant for many clinical applications and has demonstrated great promise in promoting tumor immune responses. [2,9,13,14,24,26,43,46] In patients with malignant glioma, GM-CSF induced local erythema at the vaccine site; however, in contrast to bacill Calmette-Guérin vaccine, which has been used in previous immunotherapy protocols, no local ulceration or infection was observed. [10] Additionally, tumor growth was never observed at the vaccination site, possibly because of irradiation of the vaccine and the poor metastatic capacity of gliomas.…”

Update on vaccine development for renal cell cancer

“…Furthermore, combinational therapy benefit was also suggested in a study by Simons et al83 who performed a randomized, double-blinded phase II study comparing the efficacy of vaccines composed of control or GM-CSF cDNA-engineered autologous, irradiated RCC cells. In this trial, the GM-CSF-engineered vaccine was well tolerated with no dose-limiting toxicities or autoimmunity reported.…”