Successful combination immunotherapy for the generation in vivo of antitumor activity with anti-CD3, interleukin 2, and tumor necrosis factor alpha.
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.
Yang
S C
SC
Department of Thoracic Surgery, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Fry
K D
KD
Grimm
E A
EA
Roth
J A
JA
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D017252:CD3 Complex; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007376:Interleukin-2 / Q000627:therapeutic use*; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D008175:Lung Neoplasms / Q000556:secondary / Q000628:therapy*; D008545:Melanoma / Q000556:secondary / Q000628:therapy; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D011994:Recombinant Proteins; D012513:Sarcoma, Experimental / Q000556:secondary / Q000628:therapy; D013601:T-Lymphocytes / Q000276:immunology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use*
D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha