Treatment of microscopic pulmonary metastases with recombinant autologous tumor vaccine expressing interleukin 6 and Escherichia coli cytosine deaminase suicide genes.
Poorly immunogenic tumor cells genetically transduced to simultaneously express the cytokine interleukin 6 (IL-6) and the bacterial metabolic suicide gene cytosine deaminase (205-IL6-CD) become highly immunogenic. They are rejected by normal mice without 5-fluorocytosine prodrug treatment. Mice with preexisting wild-type pulmonary micrometastases exhibit prolonged survival and an increased rate of cure when treated with live 205-IL6-CD cells as a therapeutic vaccine. Treatment with these autologous tumor cells producing both the cytokine and the bacterial protein was more effective than treatment with exogenous IL-6 and/or irradiated wild-type tumor cells. Irradiation of the 205-IL6-CD cells significantly reduced their therapeutic efficacy. Therapeutic vaccination with 205-IL6-CD was more effective in animals with wild-type 205 tumor than in animals bearing an unrelated syngeneic tumor. Vaccine efficacy was significantly reduced in animals pretreated with high-dose cyclophosphamide. The results indicate that genetically engineered autologous tumor vaccines may be capable of inducing significant antitumor immunity in hosts of preexisting micrometastatic disease.
Mullen
C A
CA
Department of Experimental Pediatrics, University of Texas M.D. Anderson Cancer Center, Houston, 77030, USA.
Petropoulos
D
D
Lowe
R M
RM
D000230:Adenocarcinoma / Q000139:chemically induced / Q000276:immunology / Q000628:therapy; D000818:Animals; D002273:Carcinogens; D003110:Colonic Neoplasms / Q000139:chemically induced; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000494:pharmacology; D043525:Cytosine Deaminase; D004127:Dimethylhydrazines; D018450:Disease Progression; D005260:Female; D005354:Fibrosarcoma / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism / Q000401:mortality / Q000556:secondary* / Q000628:therapy*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism / Q000401:mortality / Q000556:secondary* / Q000628:therapy*; D008748:Methylcholanthrene; D051379:Mice; D008810:Mice, Inbred C57BL; D009700:Nucleoside Deaminases / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D014614:Vaccines, Synthetic / Q000276:immunology / Q000528:radiation effects / Q000627:therapeutic use*
D002273:Carcinogens; D004127:Dimethylhydrazines; D007166:Immunosuppressive Agents; D015850:Interleukin-6; D014614:Vaccines, Synthetic; D008748:Methylcholanthrene; D003520:Cyclophosphamide; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase