Comparison of the superagonist complex, ALT-803, to IL15 as cancer immunotherapeutics in animal models

Peter R. Rhode, Jack O. Egan, Wenxin Xu, Hao Hong, Gabriela M. Webb, Xiaoyue Chen, Bai Liu, Xiaoyun Zhu, Jinghai Wen, Lijing You, Lin Kong, Ana C. Edwards, Kaiping Han, Sixiang Shi, Sarah Alter, Jonah Sacha, Emily K. Jeng, Weibo Cai, Hing C. Wong

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)49-60
Number of pages12
JournalCancer immunology research
Volume4
Issue number1
DOIs
StatePublished - Jan 1 2016

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Interleukin-15
Animal Models
Neoplasms
Cytokines
ALT-803
Macaca fascicularis
Fc Receptors
Lymphocyte Count
T-Lymphocyte Subsets
Multiple Myeloma
Inbred C57BL Mouse
Natural Killer Cells
Half-Life
Monocytes
Melanoma
Colon
Neutrophils
Cell Proliferation
Lymphocytes
Neoplasm Metastasis

ASJC Scopus subject areas

  • Cancer Research
  • Immunology

Cite this

Comparison of the superagonist complex, ALT-803, to IL15 as cancer immunotherapeutics in animal models. / 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; Jeng, Emily K.; Cai, Weibo; Wong, Hing C.

In: Cancer immunology research, Vol. 4, No. 1, 01.01.2016, p. 49-60.

Research output: Contribution to journalArticle

Rhode, PR, Egan, JO, Xu, W, Hong, H, Webb, GM, Chen, X, Liu, B, Zhu, X, Wen, J, You, L, Kong, L, Edwards, AC, Han, K, Shi, S, Alter, S, Sacha, J, Jeng, EK, Cai, W & Wong, HC 2016, 'Comparison of the superagonist complex, ALT-803, to IL15 as cancer immunotherapeutics in animal models', Cancer immunology research, vol. 4, no. 1, pp. 49-60. https://doi.org/10.1158/2326-6066.CIR-15-0093-T
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 ; Jeng, Emily K. ; Cai, Weibo ; Wong, Hing C. / Comparison of the superagonist complex, ALT-803, to IL15 as cancer immunotherapeutics in animal models. In: Cancer immunology research. 2016 ; Vol. 4, No. 1. pp. 49-60.
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AU - You, Lijing

AU - Kong, Lin

AU - Edwards, Ana C.

AU - Han, Kaiping

AU - Shi, Sixiang

AU - Alter, Sarah

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