Synergy of topical toll-like receptor 7 agonist with radiation and low-dose cyclophosphamide in a mouse model of cutaneous breast cancer.

Abstract

PURPOSE:

This study tested the hypothesis that topical Toll-like receptor (TLR) 7 agonist imiquimod promotes antitumor immunity and synergizes with other treatments in a model of skin-involving breast cancer.

EXPERIMENTAL DESIGN:

TSA mouse breast carcinoma cells were injected s.c. into syngeneic mice. Imiquimod 5% or placebo cream was applied topically on the shaved skin overlying tumors three times/wk. In some experiments, local ionizing radiation therapy (RT) was delivered to the tumor in three fractions of 8 Gy, given on consecutive days. Cyclophosphamide was given intraperitoneally (i.p.) in one dose of 2 mg/mouse. Mice were followed for tumor growth and survival.

RESULTS:

Treatment with imiquimod significantly inhibited tumor growth, an effect that was associated with increased tumor infiltration by CD11c(+), CD4(+), and CD8(+) cells, and abolished by depletion of CD8(+) cells. Administration of imiquimod in combination with RT enhanced significantly tumor response compared with either treatment alone (P < 0.005), and 11% to 66% of irradiated tumors completely regressed. Importantly, the addition of topical imiquimod also resulted in growth inhibition of a secondary tumor outside of the radiation field. Low-dose cyclophosphamide given before start of treatment with imiquimod and RT further improved tumor inhibition and reduced tumor recurrence. Mice that remained tumor-free rejected a tumorigenic inoculum of TSA cells, showing long-term immunologic memory.

CONCLUSIONS:

Topical imiquimod inhibits tumor growth and synergizes with RT. Addition of cyclophosphamide further increases the therapeutic effect and induces protective immunologic memory, suggesting that this combination is a promising strategy for cutaneous breast cancer metastases.

• Authors: M Zahidunnabi Dewan, Claire Vanpouille-Box, Noriko Kawashima, Sara DiNapoli, James S Babb, Silvia C Formenti, Sylvia Adams, Sandra Demaria
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 18 Issue 24 Pg. 6668-78 (Dec 15 2012) ISSN: 1557-3265 [Electronic] United States
• PMID: 23048078 (Publication Type: Journal Article)
• Copyright: 2012 AACR.

Chemical References

• Aminoquinolines
• Cytokines
• Histocompatibility Antigens Class I
• ICAM1 protein, human
• Membrane Glycoproteins
• Tlr7 protein, mouse
• Toll-Like Receptor 7
• Intercellular Adhesion Molecule-1
• Cyclophosphamide
• Imiquimod

Topics

• Administration, Topical
• Aminoquinolines (administration & dosage)
• Animals
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, pharmacology, therapeutic use)
• Cell Line, Tumor
• Chemoradiotherapy
• Cyclophosphamide (administration & dosage)
• Cytokines (metabolism)
• Dose Fractionation, Radiation
• Drug Synergism
• Histocompatibility Antigens Class I (genetics, metabolism)
• Humans
• Imiquimod
• Immunologic Memory
• Injections, Intraperitoneal
• Intercellular Adhesion Molecule-1 (genetics, metabolism)
• Lymph Nodes (drug effects, immunology)
• Mammary Neoplasms, Experimental (drug therapy, immunology, pathology, radiotherapy)
• Membrane Glycoproteins (agonists)
• Mice
• Mice, Inbred BALB C
• Neoplasm Recurrence, Local (prevention & control)
• Neoplasm Transplantation
• Skin Neoplasms (drug therapy, immunology, radiotherapy, secondary)
• T-Lymphocytes (drug effects, immunology, metabolism)
• Toll-Like Receptor 7 (agonists)
• Tumor Burden (drug effects, radiation effects)