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Low-dose cyclophosphamide induces anti-tumor T-cell responses which associate with survival in metastatic colorectal cancer

Scurr, Martin J ORCID:, Pembroke, Tom, Bloom, Anja, Roberts, David J, Thomson, Amanda, Smart, Kathryn, Bridgeman, Hayley, Adams, Richard A ORCID:, Brewster, Alison E, Jones, Robert ORCID:, Gwynne, Sarah, Blount, Daniel, Harrop, Richard, Hills, Robert ORCID:, Gallimore, Awen ORCID: and Godkin, Andrew ORCID: 2017. Low-dose cyclophosphamide induces anti-tumor T-cell responses which associate with survival in metastatic colorectal cancer. Clinical Cancer Research , clincanres.0895.2017. 10.1158/1078-0432.CCR-17-0895

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Purpose: Anti-cancer T-cell responses can control tumors, but immune-suppressive mechanisms in vivo prevent their function. The role of regulatory T-cells (Tregs) in metastatic colorectal cancer (mCRC) is unclear. We have previously shown depletion of Tregs enhances CRC-specific effector T-cell responses. Low dose cyclophosphamide (CPM) targets Tregs in animal models and some human studies, however the effect of CPM in mCRC is unknown. Experimental Design: Fifty-five mCRC patients were enrolled onto a phase I/II trial and randomized to receive two week-long courses of low-dose (50mg twice-a-day) CPM or not. The absolute number, phenotype and anti-tumor function of peripheral blood-derived lymphocyte subsets were monitored throughout treatment, along with 18-month follow-up. Results: Initially CPM 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 IFN-gamma. CPM-treated patients demonstrating the most enhanced IFN-gamma+ tumor-specific T-cell responses exhibited a significant delay in tumor progression (HR=0.29, 95% CI 0.12-0.69, P=0.0047), compared to non-responders and no-treatment controls. Conclusions: CPM-induced Treg-depletion is mirrored by a striking boost to anti-tumor immunity. This study provides the first direct evidence of the benefit of naturally primed T-cells in mCRC patients. Our results also support the concept that non-mutated self-antigens can act as useful targets for immunotherapies.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Centre for Trials Research (CNTRR)
European Cancer Stem Cell Research Institute (ECSCRI)
Subjects: R Medicine > R Medicine (General)
Publisher: American Association for Cancer Research
ISSN: 1078-0432
Date of First Compliant Deposit: 12 September 2017
Date of Acceptance: 8 August 2017
Last Modified: 11 Oct 2023 17:40

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