Effective vaccination against cancer, either for prophylaxis or therapy, has been an elusive goal for years. Cytokine gene therapy offers a novel approach to generate immunogenic tumor cell vaccines. To examine the feasibility of cytokine gene transfer into human renal cancer (RC) cells, we introduced the cDNAs for human interleukin-2 (IL-2) or interferon-γ (IFN-γ) into various RC cell lines with retroviral vectors. Using the NIH3T3 amplification assay, no replication competent retroviral particles were detectable in cell culture supernatants taken from gene-modified RC cell lines. Efficient expression of both lymphokines was achieved. Depending on the cell line and the vector construct used, lymphokine gene-modified human RC cell lines released 4 to 29 units/106 cells of IL-2, or up to 10 units/106 cells of IFN-γ within 48 h. Fluorescence-activated cell sorter analysis of SK-RC-29 cells releasing IFN-γ showed increased expression of major histocompatibility complex class I antigen, β2-microglobulin, and ICAM-1, as well as induction of major histocompatibility complex class II antigen expression [human leukocyte antigen(HLA)-DR, -DP], but no changes in these cell surface markers were observed with SK-RC-29 cells releasing IL-2. Following in vitro γ-irradiation with 5,000 or 10,000 rad, growth of lymphokine gene-modified RC cells was abrogated, but their capability to release lymphokine and express lymphokine-induced antigenic determinants, such as HLA-DR, was retained. Tumor formation by the human RC cell line SK-RC-29 in BALB/c nude mice was not affected by IFN-γ secretion, but was inhibited by in vivo release of IL-2 from s.c. injected tumor cells. These studies demonstrate the feasibility of retroviral mediated lymphokine-gene transfer into human RC cells and suggest a means for generating autologous or HLA-matched allogeneic tumor cell vaccines for the treatment of patients with renal cell carcinoma.
This work was supported in part by NIH Grants CA-08748 and CA-33049 from the National Cancer Institute; an award from the Special Projects Committee of The Society of Memorial Sloan-Kettering Cancer Center; grants from the Schultz Foundation and the Kleberg Foundation; and gifts from Cornell Medical Center Urologic Oncology Research Fund, Robert and Iris Chernok Fund, The Fred Housman Family Fund, and The Alissa Beth Bander Memorial Foundation.