Sustained Persistence of IL2 Signaling Enhances the Antitumor Effect of Peptide Vaccines through T-cell Expansion and Preventing PD-1 Inhibition

Hussein Sultan; Takumi Kumai; Valentyna I Fesenkova; Aaron E Fan; Juan Wu; Hyun-Il Cho; Hiroya Kobayashi; Yasuaki Harabuchi; Esteban Celis

doi:10.1158/2326-6066.CIR-17-0549

Sustained Persistence of IL2 Signaling Enhances the Antitumor Effect of Peptide Vaccines through T-cell Expansion and Preventing PD-1 Inhibition

Cancer Immunol Res. 2018 May;6(5):617-627. doi: 10.1158/2326-6066.CIR-17-0549. Epub 2018 Feb 26.

Authors

Hussein Sultan^#¹, Takumi Kumai^#^{2

3

4}, Valentyna I Fesenkova^#¹, Aaron E Fan¹, Juan Wu¹, Hyun-Il Cho⁵, Hiroya Kobayashi², Yasuaki Harabuchi³, Esteban Celis⁶

Affiliations

¹ Cancer Immunology, Inflammation and Tolerance Program, Augusta University Georgia Cancer Center, Augusta, Georgia.
² Department of Pathology, Asahikawa Medical University, Asahikawa, Japan.
³ Department of Otolaryngology, Head and Neck Surgery, Asahikawa Medical University, Asahikawa, Japan.
⁴ Department of Innovative Research for Diagnosis and Treatment of Head and Neck Cancer, Asahikawa Medical University, Asahikawa, Japan.
⁵ Catholic Hematopoietic Stem Cell Bank, College of Medicine, The Catholic University of Korea, Seoul, Korea.
⁶ Cancer Immunology, Inflammation and Tolerance Program, Augusta University Georgia Cancer Center, Augusta, Georgia. ecelis@augusta.edu.

^# Contributed equally.

Abstract

Peptide vaccines can be a successful and cost-effective way of generating T-cell responses against defined tumor antigens, especially when combined with immune adjuvants such as poly-IC. However, strong immune adjuvants can induce a collateral increase in numbers of irrelevant, nonspecific T cells, which limits the effectiveness of the peptide vaccines. Here, we report that providing prolonged IL2 signaling in the form of either IL2/anti-IL2 complexes or pegylated IL2 overcomes the competitive suppressive effect of irrelevant T cells, allowing the preferential expansion of antigen-specific T cells. In addition to increasing the number of tumor-reactive T cells, sustained IL2 enhanced the ability of T cells to resist PD-1-induced negative signals, increasing the therapeutic effectiveness of the vaccines against established tumors. This vaccination strategy using peptides and sustained IL2 could be taken into the clinic for the treatment of cancer. Cancer Immunol Res; 6(5); 617-27. ©2018 AACR.

Publication types

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

MeSH terms

Adjuvants, Immunologic / administration & dosage
Animals
Antigens, Neoplasm / immunology
Cancer Vaccines / therapeutic use*
Cell Proliferation / drug effects*
Combined Modality Therapy
Cytotoxicity, Immunologic / drug effects
Drug Administration Schedule
Drug Synergism
Female
Immunotherapy, Adoptive / methods*
Interleukin-2 / administration & dosage*
Interleukin-2 / pharmacology
Lymphocyte Activation / drug effects
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Transgenic
Neoplasms / immunology
Neoplasms / pathology
Neoplasms / therapy*
Poly I-C / administration & dosage
Programmed Cell Death 1 Receptor / antagonists & inhibitors
Programmed Cell Death 1 Receptor / immunology
Rats
Signal Transduction / drug effects
T-Lymphocytes / drug effects*
T-Lymphocytes / physiology
Tumor Cells, Cultured
Vaccines, Subunit / therapeutic use

Substances

Adjuvants, Immunologic
Antigens, Neoplasm
Cancer Vaccines
Interleukin-2
Programmed Cell Death 1 Receptor
Vaccines, Subunit
Poly I-C

Grants and funding

R01 CA157303/CA/NCI NIH HHS/United States