Successful combination immunotherapy for the generation in vivo of antitumor activity with anti-CD3, interleukin 2, and tumor necrosis factor alpha

S. C. Yang, K. D. Fry, E. A. Grimm and J. A. Roth
Department of Thoracic Surgery, University of Texas M.D. Anderson Cancer Center, Houston 77030.

The purpose of this study was to generate lymphokine-activated killer cells via alternative pathways using combinations of biologic agents. Immunotherapy with the mouse anti-CD3 analogue combined with low-dose interleukin 2 (IL-2) and tumor necrosis factor alpha (TNF-alpha) was tested for in vivo antitumor efficacy against established pulmonary metastases from a variety of mouse tumor-cell lines. Administration of a single dose of anti-CD3 followed by low-dose IL-2 and TNF-alpha potentiated reduction of metastases compared with higher doses of IL-2 alone or IL-2 plus TNF-alpha. Treatment with anti-CD3 plus IL-2 plus TNF-alpha significantly prolonged survival and resulted in 60% of the mice achieving long-term survival compared with no survival using single agents or other combinations. The lymphokine-activated killer and natural killer activities of mouse splenocytes increased following treatment with anti-CD3 plus IL-2 plus TNF-alpha. These results indicate that the sequential use of anti-CD3, IL-2, and TNF-alpha for the induction and maintenance of lymphokine-activated killer activity potentiates antitumor activity and provides novel strategies for combination immunotherapy.