Gene therapy of cancer with interleukin-12.
IL-12 has demonstrated remarkable antitumor activity when used directly as a recombinant protein or when different viral or non-viral vectors transfer its genes. At enhancing tumor immunity, IL-12 acts as a bridge between innate and adaptive immune responses due to its ability to induce proliferation and activation of NK, NKT, and T cells. In addition, IL-12 inhibits tumor angiogenesis mainly through IFN gamma-dependent production of the chemokine IP10. As a result, IL-12 can eliminate several types of tumors developed in rodents. Pre-clinical experience forecasted a quick and successful clinical translation, but the encouraging results observed in animals were not reproduced in patients. Moreover, unacceptable toxicity resulting from IFN gamma overproduction was observed in 2 renal carcinoma patients included in a phase II clinical trial that consisted in systemic administration of rIL-12. As a consequence, development of IL-12 as an antitumor agent was temporarily halted while the high expectations raised among clinicians faded away. Gene transfer methods are designed to confine IL-12 production in the tumor environment preventing systemic toxicity. Tumor cells, dendritic cells, or autologous fibroblasts have been transfected with recombinant adenoviruses or retroviruses to secrete IL-12 locally, showing good efficacy and safety profiles. IL-12 combination with other immunotherapy approaches synergizes to achieve even better results. Encouraging pilot clinical results have been recently obtained from the first phase I trial studying adenovirus mediated in vivo gene transfer of IL-12 into lesions of advanced cancer patients. Further improvements will follow from: i) increases in the efficacy of gene transduction; ii) development of tumor specific promoters; iii) development of regulatable and long-term expression vectors and iv) combination with other immunological and non-immunological anticancer therapies.
Mazzolini
Guillermo
G
Division of Hepatology and Gene Therapy, Department of Medicine, Centro de Investigación Médica Aplicada (FIMA), School of Medicine and Clínica Universitaria, University of Navarra, Pamplona, Spain. gmazzolini@unav.es
Prieto
Jesús
J
Melero
Ignacio
I
D000818:Animals; D000938:Antigen-Presenting Cells / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D018664:Interleukin-12 / Q000235:genetics* / Q000276:immunology / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D011994:Recombinant Proteins / Q000627:therapeutic use
D000970:Antineoplastic Agents; D011994:Recombinant Proteins; D018664:Interleukin-12