Synergistic innate and adaptive immune response to combination immunotherapy with anti-tumor antigen antibodies and extended serum half-life IL-2

Eric F Zhu; Shuning A Gai; Cary F Opel; Byron H Kwan; Rishi Surana; Martin C Mihm; Monique J Kauke; Kelly D Moynihan; Alessandro Angelini; Robert T Williams; Matthias T Stephan; Jacob S Kim; Michael B Yaffe; Darrell J Irvine; Louis M Weiner; Glenn Dranoff; K Dane Wittrup

doi:10.1016/j.ccell.2015.03.004

Synergistic innate and adaptive immune response to combination immunotherapy with anti-tumor antigen antibodies and extended serum half-life IL-2

Cancer Cell. 2015 Apr 13;27(4):489-501. doi: 10.1016/j.ccell.2015.03.004.

Authors

Eric F Zhu¹, Shuning A Gai¹, Cary F Opel¹, Byron H Kwan², Rishi Surana³, Martin C Mihm⁴, Monique J Kauke¹, Kelly D Moynihan², Alessandro Angelini⁵, Robert T Williams⁶, Matthias T Stephan⁷, Jacob S Kim⁵, Michael B Yaffe⁸, Darrell J Irvine⁹, Louis M Weiner³, Glenn Dranoff¹⁰, K Dane Wittrup¹¹

Affiliations

¹ Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
² Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
³ Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA.
⁴ Department of Pathology, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02214, USA.
⁵ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁶ Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁷ Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁸ Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁹ Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, MA 02129, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
¹⁰ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
¹¹ Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: wittrup@mit.edu.

Abstract

Cancer immunotherapies under development have generally focused on either stimulating T cell immunity or driving antibody-directed effector functions of the innate immune system such as antibody-dependent cell-mediated cytotoxicity (ADCC). We find that a combination of an anti-tumor antigen antibody and an untargeted IL-2 fusion protein with delayed systemic clearance induces significant tumor control in aggressive isogenic tumor models via a concerted innate and adaptive response involving neutrophils, NK cells, macrophages, and CD8(+) T cells. This combination therapy induces an intratumoral "cytokine storm" and extensive lymphocyte infiltration. Adoptive transfer of anti-tumor T cells together with this combination therapy leads to robust cures of established tumors and development of immunological memory.

Publication types

Research Support, N.I.H., Intramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adaptive Immunity
Animals
CD8-Positive T-Lymphocytes / drug effects
CD8-Positive T-Lymphocytes / immunology
Drug Synergism
Half-Life
Immunity, Innate
Immunotherapy
Interleukin-2 / metabolism
Interleukin-2 / pharmacokinetics
Interleukin-2 / pharmacology
Killer Cells, Natural / drug effects
Killer Cells, Natural / immunology
Mice
Mice, Inbred C57BL
Neoplasms / immunology
Neoplasms / therapy*

Substances

Interleukin-2

Abstract

Publication types

MeSH terms

Substances

Grants and funding