Direct gene transfer for treatment of human cancer.
Genetic instability within malignant cells gives rise to mutant proteins which can be recognized by the immune system. Recognition of tumor-associated antigens by T lymphocytes could thus contribute to the elimination of neoplastic cells. We have developed a molecular genetic intervention for the treatment of malignancies based upon the knowledge that foreign major histocompatibility complex (MHC) proteins expressed on the cell surface are efficient at stimulating an immune response. Expression of this foreign MHC gene within tumors induced 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 research provides evidence that direct gene transfer in vivo can induce cell-mediated immunity against specific gene products, and offers the potential for effective immunotherapy for the treatment of cancer and infectious diseases in man. Our laboratory conducted a phase I clinical trial to determine the safety and efficacy of this treatment in humans. These studies suggest that direct gene transfer provides a safe and feasible approach for the treatment of human cancer. More recent developments using combination gene therapy and the initiation of a second human trial with improvements on this technology have been implemented. Finally, we have begun to define mechanisms of resistance to immune recognition by established malignancies.
Nabel
G J
GJ
Howard Hughes Medical Institute, Ann Arbor, Michigan, USA.
Yang
Z Y
ZY
Nabel
E G
EG
Bishop
K
K
Marquet
M
M
Felgner
P L
PL
Gordon
D
D
Chang
A E
AE
D000818:Animals; D017321:Clinical Trials, Phase I as Topic; D004274:DNA, Recombinant / Q000008:administration & dosage; D004337:Drug Carriers; D015972:Gene Expression Regulation, Neoplastic; D018014:Gene Transfer Techniques; D005805:Genes, MHC Class I; D015793:HLA-B7 Antigen / Q000235:genetics* / Q000276:immunology; D006801:Humans; D015552:Injections, Intralesional; D008081:Liposomes; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D011993:Recombinant Fusion Proteins / Q000276:immunology*
D004274:DNA, Recombinant; D004337:Drug Carriers; D015793:HLA-B7 Antigen; D008081:Liposomes; D011993:Recombinant Fusion Proteins