Effect of modified vaccinia Ankara–5T4 and low-dose cyclophosphamide on antitumor immunity in metastatic colorectal cancer: A randomized clinical trial

Scurr, Martin ORCID: https://orcid.org/0000-0002-4120-0688, Pembroke, Tom ORCID: https://orcid.org/0000-0002-2600-2034, Bloom, Anja, Roberts, David, Thomson, Amanda, Smart, Kathryn, Bridgeman, Hayley, Adams, Richard ORCID: https://orcid.org/0000-0003-3915-7243, Brewster, Alison, Jones, Robert ORCID: https://orcid.org/0000-0003-3576-9496, Gwynne, Sarah, Blount, Daniel, Harrop, Richard, Wright, Melissa ORCID: https://orcid.org/0000-0002-1011-4795, 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. Effect of modified vaccinia Ankara–5T4 and low-dose cyclophosphamide on antitumor immunity in metastatic colorectal cancer: A randomized clinical trial. JAMA Oncology 3 (10) , e172579. 10.1001/jamaoncol.2017.2579

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Abstract

Importance The success of immunotherapy with checkpoint inhibitors is not replicated in most cases of colorectal cancer; therefore, different strategies are urgently required. The oncofetal antigen 5T4 is expressed in more than 90% of cases of metastatic colorectal cancer (mCRC). Preliminary data using modified vaccinia Ankara–5T4 (MVA-5T4) in mCRC demonstrated that it safely induced serologic and T-cell responses. Objective To determine whether antitumor immunity in mCRC could be increased using MVA-5T4, metronomic low-dose cyclophosphamide, or a combination of both treatments. Design, Setting, and Participants In this randomized clinical trial, 55 patients with inoperable mCRC and prior stable disease after standard chemotherapy were enrolled at a single center and randomized to watch and wait (n = 9), cyclophosphamide treatment only (n = 9), MVA-5T4 only (n = 19), and a combination of MVA-5T4 and cyclophosphamide (n = 18). Patients were enrolled and treated from July 9, 2012, through February 8, 2016, and follow-up was completed on December 13, 2016. Data were analyzed based on intention to treat. Interventions Patients randomized to a cyclophosphamide group received 50 mg twice daily on treatment days 1 to 7 and 15 to 21. Patients randomized to a MVA-5T4 group received an intramuscular injection at a dose of 1 × 109 50% tissue culture infectious dose on treatment days 22, 36, 50, 64, 78, and 106. Main Outcomes and Measures The predefined primary end point was the magnitude of anti-5T4 immune responses (5T4-specific T-cell and antibody levels) generated at treatment week 7. Secondary end points included analysis of the kinetics of anti-5T4 responses, progression-free survival (PFS), and overall survival (OS). Results Fifty-two patients (38 men and 14 women; mean [SD] age, 64.2 [10.1] years) were included in the study analysis. The 5T4-specific antibody immune responses were significantly increased in the MVA-5T4 (83.41 [36.09] relative units [RU]; P = .02) and combination treatment (65.81 [16.68] RU; P = .002) groups compared with no treatment (20.09 [7.20] RU). Cyclophosphamide depleted regulatory T cells in 24 of 27 patients receiving MVA-5T4, independently prolonging PFS (5.0 vs 2.5 months; hazard ratio [HR], 0.48; 95% CI, 0.21-1.11; P = .09). MVA-5T4 doubled baseline anti-5T4 responses in 16 of 35 patients, resulting in significantly prolonged PFS (5.6 vs 2.4 months; HR, 0.21; 95% CI, 0.09-0.47; P < .001) and OS (20.0 vs 10.3 months; HR, 0.32; 95% CI, 0.14-0.74; P = .008). No grade 3 or 4 adverse events were observed. Conclusions and Relevance This initial randomized clinical immunotherapy study demonstrates a significant survival benefit in mCRC. Prior depletion of regulatory T cells by cyclophosphamide did not increase immune responses generated by MVA-5T4 vaccination; however, cyclophosphamide and MVA-5T4 each independently induced beneficial antitumor immune responses, resulting in prolonged survival without toxic effects. Larger clinical trials are planned to further validate these data.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Centre for Trials Research (CNTRR) Medicine European Cancer Stem Cell Research Institute (ECSCRI)
Subjects:	R Medicine > R Medicine (General)
Additional Information:	This is an open access article distributed under the terms of the CC-BY license, which permits unrestricted use, distribution, and reproduction in any medium. You are not required to obtain permission to reuse this article content, provided that you credit the author and journal.
Publisher:	American Medical Association (AMA)
ISSN:	2374-2437
Funders:	Wellcome Trust
Date of First Compliant Deposit:	11 September 2017
Date of Acceptance:	14 June 2017
Last Modified:	11 Oct 2023 18:47
URI:	https://orca.cardiff.ac.uk/id/eprint/104525

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