BIOACTIVITY OF AUTOLOGOUS IRRADIATED RENAL-CELL CARCINOMA VACCINES GENERATED BY EX-VIVO GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR GENE-TRANSFER

Granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transdu ced, irradiated tumor vaccines induce potent, T-cell-mediated antitumo r immune responses in preclinical models. We report the initial result s of a phase I trial evaluating this strategy for safety and the induc tion of immune responses in patients with metastatic renal cell carcin oma (RCC). Patients were treated in a randomized, double-blind dose-es calation study with equivalent doses of autologous, irradiated RCC vac cine cells with or without ex vivo human GM-CSF gene transfer, The rep lication-defective retroviral vector MFG was used for GM-CSF gene tran sfer, No dose-limiting toxicities were encountered in 16 fully evaluab le patients, GM-CSF gene-transduced vaccines were equivalent in toxici ty to nontransduced vaccines up to the feasible limits of autologous t umor vaccine yield, No evidence of autoimmune disease was observed, Bi opsies of intradermal sites of injection with GM-CSF gene-transduced v accines contained distinctive macrophage, dendritic cell, eosinophil, neutrophil, and T-cell infiltrates similar to those observed in precli nical models of efficacy, Histological analysis of delayed-type hypers ensitivity responses in patients vaccinated with GM-CSF-transduced vac cines demonstrated an intense eosinophil infiltrate that was not obser ved in patients who received nontransduced vaccines. An objective part ial response was observed in a patient treated with GM-CSF gene-transd uced vaccine who displayed the largest delayed-type hypersensitivity c onversion, No replication-competent retrovirus was detected in vaccina ted patients, This Phase I study demonstrated the feasibility, safety, and bioactivity of an autologous GM-CSF gene-transduced tumor vaccine for RCC patients.