Comparison of the Superagonist Complex, ALT-803, to IL15 as Cancer Immunotherapeutics in Animal Models

• Published in: Cancer immunology research Vol. 4; no. 1; p. 49
• Main Authors: Rhode, Peter R, Egan, Jack O, Xu, Wenxin, Hong, Hao, Webb, Gabriela M, Chen, Xiaoyue, Liu, Bai, Zhu, Xiaoyun, Wen, Jinghai, You, Lijing, Kong, Lin, Edwards, Ana C, Han, Kaiping, Shi, Sixiang, Alter, Sarah, Sacha, Jonah B, Jeng, Emily K, Cai, Weibo, Wong, Hing C
• Format: Journal Article
• Language: English
• Published: United States 01.01.2016
• Subjects: Adjuvants, Immunologic - pharmacokinetics; Adjuvants, Immunologic - therapeutic use; Adjuvants, Immunologic - toxicity; Animals; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Antineoplastic Agents - toxicity; Cell Line, Tumor; Cell Proliferation; Cytokines - metabolism; Female; Humans; Immunotherapy; Interleukin-15 - pharmacokinetics; Interleukin-15 - therapeutic use; Interleukin-15 - toxicity; Killer Cells, Natural - drug effects; Killer Cells, Natural - physiology; Macaca fascicularis; Melanoma, Experimental - drug therapy; Mice, Inbred BALB C; Mice, Inbred C57BL; Neoplasm Transplantation; Proteins - pharmacokinetics; Proteins - therapeutic use; Proteins - toxicity; Tissue Distribution; Tumor Burden - drug effects; Xenograft Model Antitumor Assays
• DOI: 10.1158/2326-6066.CIR-15-0093-T

IL15, a potent stimulant of CD8(+) T cells and natural killer (NK) cells, is a promising cancer immunotherapeutic. ALT-803 is a complex of an IL15 superagonist mutant and a dimeric IL15 receptor αSu/Fc fusion protein that was found to exhibit enhanced biologic activity in vivo, with a substantially longer serum half-life than recombinant IL15. A single intravenous dose of ALT-803, but not IL15, eliminated well-established tumors and prolonged survival of mice bearing multiple myeloma. In this study, we extended these findings to demonstrate the superior antitumor activity of ALT-803 over IL15 in mice bearing subcutaneous B16F10 melanoma tumors and CT26 colon carcinoma metastases. Tissue biodistribution studies in mice also showed much greater retention of ALT-803 in the lymphoid organs compared with IL15, consistent with its highly potent immunostimulatory and antitumor activities in vivo. Weekly dosing with 1 mg/kg ALT-803 in C57BL/6 mice was well tolerated, yet capable of increasing peripheral blood lymphocyte, neutrophil, and monocyte counts by >8-fold. ALT-803 dose-dependent stimulation of immune cell infiltration into the lymphoid organs was also observed. Similarly, cynomolgus monkeys treated weekly with ALT-803 showed dose-dependent increases of peripheral blood lymphocyte counts, including NK, CD4(+), and CD8(+) memory T-cell subsets. In vitro studies demonstrated ALT-803-mediated stimulation of mouse and human immune cell proliferation and IFNγ production without inducing a broad-based release of other proinflammatory cytokines (i.e., cytokine storm). Based on these results, a weekly dosing regimen of ALT-803 has been implemented in multiple clinical studies to evaluate the dose required for effective immune cell stimulation in humans.