Active immunotherapy with transiently transfected cytokine-secreting tumor cells inhibits breast cancer metastases in tumor-bearing animals.
BACKGROUND
Metastatic disease remains the most frequent cause of treatment failure in the management of patients with breast cancer. A novel method that allows delivery of a gene into primary tumor cells was used to generate tumor cell vaccines to inhibit metastasis formation in tumor-bearing hosts.


METHODS
Inoculation of 2.5 x 10(4) 4T1 murine breast cancer cells into the footpads of BALB/c mice reliably leads to tumor growth and pulmonary metastases. Interleukin-2 (IL-2)-secreting 4T1 cells (4T1-pMP6A/IL-2) and control transduced 4T1 cells (4T1-pMP6A) were generated by lipofection with a cationic liposome complexed to an adeno-associated viral plasmid bearing the IL-2 gene (pMP6A/IL-2). Unmodified 4T1 cells were inoculated into the footpads on day 0, and weekly immunization with phosphate-buffered saline solution or 2 x 10(6) irradiated 4T1, 4T1-pMP6A, or 4T1-pMP6A/IL-2 cells commenced on day 21. Hindlimb amputation was performed when tumors measured 6 mm in diameter. Mice were killed 24 days after amputation, and metastatic disease was determined by weighing lungs at time of harvest.


RESULTS
A significant reduction was seen in the pulmonary metastatic load of mice receiving IL-2 gene-modified tumor cell immunization (4T1-pMP6A/IL2) when compared with mice given control immunizations.


CONCLUSIONS
These results suggest that active immunization strategies with cytokine gene-modified tumor cells generated by clinically relevant gene delivery systems may prove useful in inhibiting the development of metastases from primary breast cancer.
Coveney
E
E
Department of Surgery, Duke University Medical Center, Durham, N.C. 27710, USA.
Clary
B
B
Iacobucci
M
M
Philip
R
R
Lyerly
K
K
D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D000229:Dependovirus / Q000235:genetics; D017930:Genes, Reporter / Q000276:immunology; D015316:Genetic Therapy; D007167:Immunotherapy; D007376:Interleukin-2 / Q000235:genetics; D008081:Liposomes; D008285:Major Histocompatibility Complex / Q000235:genetics; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000556:secondary / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D010957:Plasmids / Q000235:genetics; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000276:immunology; D014612:Vaccines / Q000235:genetics / Q000276:immunology
D016207:Cytokines; D007376:Interleukin-2; D008081:Liposomes; D014612:Vaccines