Improved survival with adjuvant immunotherapy after surgical resection in a murine model

Background: Adoptive immunotherapy has met with limited success in the treatment of bulky metastatic disease. The purpose of this study was to determine whether lymphocytes stimulated in vitro could improve survival when given as an adjuvant to surgical resection in animals harboring microscopic metastatic disease. Methods: Lymphocytes from nodes draining the primary tumor (DLN lymphocytes) were stimulated in vitro with phorbol 12,13-dibutyrate and ionomycin and used as adjuvant immunotherapy after surgical resection of the primary tumor. Mice with advanced P-815 footpad tumors and disseminated microscopic metastases underwent amputation of the tumor-bearing extremity and were randomized to various adjuvant treatments. Results: Mice treated with adjuvant immunotherapy using stimulated DLN lymphocytes demonstrated significantly improved survival, showing that DLN lymphocytes stimulated in vitro can abrogate metastases that are invading multiple organs simultaneously. Mice successfully treated with adjuvant immunotherapy demonstrated long-term (80 days) in vivo antitumor activity by rejecting subsequent tumor challenge. In addition, stimulated DLN lymphocytes provided in vivo antitumor activity to naive mice. Conclusions: Adjuvant immunotherapy after resection in the face of residual microscopic tumor burden may prove to be a useful application of adoptive immunotherapy.