Simultaneous blockade of multiple immune system inhibitory checkpoints enhances antitumor activity mediated by interleukin-15 in a murine metastatic colon carcinoma model.

Abstract

PURPOSE:

Interleukin 15 (IL-15) is a promising cytokine for immunotherapy of cancer due to its ability to stimulate the immunity of natural killer, B, and T cells. Its effectiveness, however, may be limited by inhibitory checkpoints and pathways that can attenuate immune responses. Finding strategies to abrogate these negative regulators and enhance the efficacy of IL-15 is a critical challenge.

EXPERIMENTAL DESIGN:

In a preclinical study, we evaluated IL-15 combined with antibodies to block the negative immune regulators cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death ligand 1 (PD-L1) in a metastatic murine CT26 colon carcinoma model.

RESULTS:

IL-15 treatment resulted in a significant prolongation of survival in mice with metastatic tumor. Administration of IL-15, however, also increased expression of PD-1 on the surface of CD8(+) T cells including CD8(+)CD44(high) memory phenotype T cells. Moreover, IL-15 also increased the secretion of the immunosuppressive cytokine, IL-10. Combining IL-15 with anti-PD-L1 and anti-CTLA-4 (multiple immune checkpoint blockade) exhibited greater CTL killing and IFNγ secretion. Moreover, this combination resulted in a significant reduction in surface expression of PD-1 on CD8(+) T cells, a decrease in IL-10 secretion, and led to significantly longer survival of tumor-bearing animals compared with mice treated with IL-15 alone or combined singularly with anti-PD-L1 or anti-CTLA-4.

CONCLUSIONS:

Combining the immune stimulatory properties of IL-15 with the simultaneous removal of 2 critical immune system inhibitory checkpoints, we showed enhancement of immune responses leading to increased antitumor activity.

• Authors: Ping Yu, Jason C Steel, Meili Zhang, John C Morris, Thomas A Waldmann
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 16 Issue 24 Pg. 6019-28 (Dec 15 2010) ISSN: 1557-3265 [Electronic] United States
• PMID: 20924130 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)
• Copyright: ©2010 AACR.

Chemical References

• Antibodies, Neutralizing
• Antigens, CD
• Antigens, Differentiation
• CTLA-4 Antigen
• Ctla4 protein, mouse
• Interleukin-15
• Pdcd1 protein, mouse
• Programmed Cell Death 1 Receptor

Topics

• Animals
• Antibodies, Neutralizing (administration & dosage, pharmacology)
• Antigens, CD (immunology, metabolism, physiology)
• Antigens, Differentiation (immunology, metabolism, physiology)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• CTLA-4 Antigen
• Carcinoma (drug therapy, immunology, mortality, pathology)
• Cell Line, Tumor
• Colonic Neoplasms (drug therapy, immunology, mortality, pathology)
• Disease Models, Animal
• Drug Evaluation, Preclinical
• Drug Synergism
• Female
• Immune Tolerance (drug effects, immunology)
• Immunotherapy (methods)
• Interleukin-15 (therapeutic use)
• Mice
• Mice, Inbred BALB C
• Models, Biological
• Neoplasm Metastasis
• Programmed Cell Death 1 Receptor
• Signal Transduction (drug effects, immunology)
• Treatment Outcome