Biological and gene therapy of
cancer have become important components of clinical
cancer research. Advances in this area are based on evidence for the presence of
tumor antigens, antitumor immune responses, evasion of host control by
tumors, and the recognition of host defense failure in
cancer patients. These mechanisms are being corrected or exploited in the development of
biological and gene therapy. Over the last decade, 9
biological therapies have received Food and Drug Administration approval, and another 12 appear promising and will likely be approved in the next few years. Our approach to gene therapy has been to allogenize
tumors by the direct intratumoral injection of HLA-B7/beta2-microglobulin genes as plasmid
DNA in a cationic
lipid into patients with
malignant melanoma. In four Phase I studies, we found a 36% response by the local injected
tumor and
a 19% systemic antitumor response. In other
cancers, gene transfer, expression, and an intratumoral T-cell response were seen, but no clinical response was seen. A variety of follow-up studies with
HLA-B7 and other genes are planned. Evasion of host control is now a major target of gene therapy. Strategies to overcome this include up-regulation of MHC and introduction of
cell adhesion molecules into
tumor cells, suppression of
transforming growth factor and
interleukin 10 production by
tumor cells, and blockade of the
fas ligand-fas interaction between
tumor cells and attacking lymphocytes. With these approaches, it seems likely that gene therapy may become the fifth major modality of
cancer treatment in the next decade.