tailieunhanh - Báo cáo hóa học: " Three agonist antibodies in combination with high-dose IL-2 eradicate orthotopic kidney cancer in mice"

Three agonist antibodies in combination with high-dose IL-2 eradicate orthotopic kidney cancer in mice | Westwood et al. Journal of Translational Medicine 2010 8 42 http content 8 1 42 RESEARCH JOURNAL OF TRANSLATIONAL MEDICINE Open Access Three agonist antibodies in combination with high-dose IL-2 eradicate orthotopic kidney cancer in mice Jennifer A Westwood 1 3 Phillip K Darcy1 2 3 Preethi Mayura Guru1 3 Janelie Sharkey1 3 Hollie J Pegram1 3 Sally M Amos1 3 Mark J Smyth1 2 3 and Michael H Kershaw 1 2 3 Abstract Background Combination immunotherapies can be effective against subcutaneous tumors in mice but the effect against orthotopic malignant disease is less well characterized. In particular a combination of three agonist antibodies termed Tri-mAb consisting of anti-DR5 anti-CD40 and anti-CD137 has previously been demonstrated to eradicate a large proportion of subcutaneous renal cell carcinoma Renca tumors 75 long-term survival but the effect against orthotopic disease is not known. Purpose To determine the relative response of orthotopic tumors we inoculated Renca into the kidney followed by treatment with Tri-mAb. Results We found that orthotopic tumors responded much less to treatment 13 survival but a significant improvement in survival was achieved through the addition of IL-2 to the treatment regimen 55 survival . All three agonist antibodies and high dose IL-2 100 000 IU for up to six doses were required. CD8 T cells were also required for optimal anti-tumor responses. Coadministration of IL-2 led to enhanced T cell activity as demonstrated by an increased frequency of IFN-gamma-producing T cells in tumor-draining lymph nodes which may have contributed to the observed improvement of therapy against kidney tumors. Implications Responses of subcutaneous tumors to immunotherapy do not necessarily reflect how orthotopic tumors respond. The use of combination immunotherapy stimulating multiple facets of immunity and including cytokine support for T cells can induce effective anti-tumor responses against orthotopic and metastatic