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Purpose: Anticancer T-cell responses can control tumors, but immunosuppressive mechanisms in vivo prevent their function. The role of regulatory T cells (Tregs) in metastatic colorectal cancer is unclear. We have previously shown depletion of Tregs enhances colorectal cancer-specific effector T-cell responses. Low-dose cyclophosphamide targets Tregs in animal models and some human studies; however, the effect of cyclophosphamide in metastatic colorectal cancer is unknown.Experimental Design: Fifty-five patients with metastatic colorectal cancer were enrolled in a phase I/II trial and randomly assigned to receive 2-week-long courses of low-dose (50 mg twice a day) cyclophosphamide or not. The absolute number, phenotype, and antitumor function of peripheral blood-derived lymphocyte subsets were monitored throughout treatment, as well as during 18-month follow-up.Results: Initially, cyclophosphamide reduced proliferation in all lymphocyte subsets; however, a rapid mobilization of effector T cells overcame this decrease, leading to increased absolute T-cell numbers. In contrast, a reduction in proportional and absolute Treg, B-cell, and NK-cell numbers occurred. The expansion and subsequent activation of effector T cells was focused on tumor-specific T cells, producing both granzyme B and IFNγ. Cyclophosphamide-treated patients demonstrating the most enhanced IFNγ+ tumor-specific T-cell responses exhibited a significant delay in tumor progression [HR = 0.29; 95% confidence interval (CI), 0.12-0.69; P = 0.0047), compared with nonresponders and no-treatment controls.Conclusions: Cyclophosphamide-induced Treg depletion is mirrored by a striking boost in antitumor immunity. This study provides the first direct evidence of the benefit of naturally primed T cells in patients with metastatic colorectal cancer. Our results also support the concept that nonmutated self-antigens may act as useful targets for immunotherapies. Clin Cancer Res; 23(22); 6771-80. ©2017 AACR.

Original publication

DOI

10.1158/1078-0432.CCR-17-0895

Type

Journal article

Journal

Clin Cancer Res

Publication Date

15/11/2017

Volume

23

Pages

6771 - 6780

Keywords

Antineoplastic Agents, Alkylating, Antineoplastic Combined Chemotherapy Protocols, Colorectal Neoplasms, Cyclophosphamide, Disease Progression, Female, Humans, Immunomodulation, Male, Neoplasm Metastasis, Neoplasm Staging, Retreatment, T-Lymphocytes, Treatment Outcome