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.

Duke Scholars

Author Herbert Kim Lyerly Surgery, Surgical Sciences