| Popis: |
Renal cancer cell lines exhibit deficient expression of MHC class I antigens required for appropriate CTL stimulation. Nabel et al. (Proc. Natl. Acad. Sci. USA, 90: 11307-11311, 1993) demonstrated that direct gene transfer of the deficient class I MHC molecule into melanoma cells would stimulate their immune destruction. Stopeck et al. (J. Clin. Oncol., 15: 341-349, 1997) demonstrated the clinical use of this approach in melanoma patients. We investigated the safety and ability to bestow gene expression via intratumoral transfer of escalating amounts of lipid-formulated plasmid DNA encoding for the MHC HLA-B7 gene product Allovectin-7 into metastatic renal cancer lesions. Fifteen patients with histologically confirmed, HLA-B7-negative metastatic renal cancer received intratumoral injection of Allovectin-7 on an escalating dose schedule. Tumors were evaluated serially by computed tomography scan, ultrasound, and physical examination. Presence of the HLA-B7 gene and protein was determined via PCR, flow cytometry, and immunohistochemical staining in serial biopsy specimens. HLA-B7 gene, mRNA, or protein expression could be conclusively demonstrated in 8 of 14 patients (57%). Three patients had tumor biopsy to assess the presence of tumor-infiltrating lymphocytes, and all three had higher posttreatment levels of tumor-infiltrating lymphocytes. There were no significant clinical responses or toxicity at the site of injection or at other, noninjected tumor sites. This study demonstrated that intratumoral injection of Allovectin-7 is safe, feasible, and associated with minimal toxicity. This approach was capable of bestowing gene expression, possible resulting in antitumor CTL response. Despite lack of tumor regression in this series of renal cancer patients, the simplicity and low toxicity of this approach commend it for Phase II studies in renal and other cancers, as well as for transfection with other genes. |
