Molecular genetic interventions for cancer

Genetic instability within malignant cells gives rise to mutant proteins which can be recognized by the immune system, and this recognition by T lymphocytes could contribute to the elimination of the neoplastic cells. We have developed a molecular genetic intervention for the treatment of malignancies based on the knowledge that foreign MHC proteins expressed on the cell surface are efficient at stimulating an immune response. Initially, in a murine model, foreign MHC genes were introduced directly into malignant tumors in vivo in an effort to stimulate an immune response and subsequent rejection of the tumor cells. Expression of this foreign MHC gene within the tumors did induce a cytotoxic T-cell response to the introduced gene. More importantly, the immune system recognized tumor-specific antigens on unmodified tumor cells as foreign. Growth of the tumors diminished, and in many cases there was complete regression. This evidence that direct gene transfer in vivo can induce cell-mediated immunity against specific gene products offers the potential for effective immunotherapy for the treatment of human cancer and infectious diseases. We have successfully conducted a human clinical study to determine the safety and efficacy of this treatment and are now conducting additional studies with improved vectors and liposomes. Since several studies have shown that the introduction of cytokines improves antitumor effect (Fearon et al. 1990; Gansbacher et al. 1990a,b; Dranoff et al. 1993), future modifications of gene therapy protocols against cancer could include the added expression of a cytokine gene, such as IL-2 or GM-CSF. Although combined vectors are not yet available, inclusion of a cytokine in the treatment protocol could further stimulate T-cell immunity against tumors locally and improve recognition of tumor-associated antigens. Immunotherapy has shown promise as a primary treatment for some forms of cancer, particularly melanoma and renal cell carcinoma, which are relatively more responsive to modulation of immune function. The development of more efficient vital and nonviral vectors has also enhanced the attractiveness of gene therapy for cancer and facilitates the application of molecular biology to clinical settings. Finally, progress in developing safe and effective methods of direct, in vivo gene transfer brings this approach to cancer therapy well within the constraints of clinical medicine. It is possible that within a few years gene therapy will provide alternative treatments for cancer.