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

Scurr, Martin J ORCID: https://orcid.org/0000-0002-4120-0688, Pembroke, Tom, Bloom, Anja, Roberts, David J, Thomson, Amanda, Smart, Kathryn, Bridgeman, Hayley, Adams, Richard A ORCID: https://orcid.org/0000-0003-3915-7243, Brewster, Alison E, Jones, Robert ORCID: https://orcid.org/0000-0003-3576-9496, Gwynne, Sarah, Blount, Daniel, Harrop, Richard, Hills, Robert ORCID: https://orcid.org/0000-0003-0166-0062, Gallimore, Awen ORCID: https://orcid.org/0000-0001-6675-7004 and Godkin, Andrew ORCID: https://orcid.org/0000-0002-1910-7567 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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Abstract

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) Medicine 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
URI:	https://orca.cardiff.ac.uk/id/eprint/104522

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