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MVA-5T4 immunotherapy and low-dose cyclophosphamide for advanced colorectal cancer (TaCTiCC): An open-label, randomized phase I/II trial.

Scurr, Martin ORCID: https://orcid.org/0000-0002-4120-0688, Pembroke, Tom, Adams, Richard ORCID: https://orcid.org/0000-0003-3915-7243, Blount, Daniel, Brewster, Alison, Gwynne, Sarah, Harrop, Richard, Jones, Robert ORCID: https://orcid.org/0000-0003-3576-9496, 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. MVA-5T4 immunotherapy and low-dose cyclophosphamide for advanced colorectal cancer (TaCTiCC): An open-label, randomized phase I/II trial. Journal of Clinical Oncology 35 (7) , p. 154. 10.1200/JCO.2017.35.7_suppl.154

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License Start date: 7 September 2017

Abstract

Background: Current immunotherapies including checkpoint inhibitors and vaccines for advanced colorectal cancer (CRC) have been largely ineffective. We hypothesized that combining an MVA-based vaccine targeting the tumor-associated antigen 5T4 (TroVax) with low-dose cyclophosphamide to deplete Foxp3+regulatory T-cells (Tregs), could improve immunological responses and patient outcomes. Methods: In this open-label phase I/II clinical trial, TaCTiCC (TroVax and Cyclophosphamide Treatment in Colorectal Cancer) 53 patients with inoperable metastatic CRC were randomized to receive either no treatment (group 1, n=8), metronomic low-dose CPM (50mg B.D. during treatment weeks 1&3; group 2, n=9), TroVax only (6 i.m. injections weeks 4 to 16, group 3, n=18), or low-dose CPM followed by TroVax (group 4, n=18). The primary endpoint was boosted anti-5T4 responses at week 7, as measured by increased T-cell and antibody responses; secondary endpoints included progression-free (PFS)/overall survival (OS), and anti-5T4 responses over the trial period. Results: CPM depleted Tregs in 21/27 patients during treatment week 3 (p=0.0045), resulting in significantly prolonged PFS amongst groups 2&4 over group 1 (5.0 vs. 2.5 months, HR=0.17 95% CI 0.048-0.62, p=0.0072). TroVax induced a >2-fold increase in anti-5T4 immune responses in 15/36 group 3&4 patients; these patients experienced significantly prolonged median PFS (6.5 vs. 2.4 months, HR 0.31 95% CI 0.14-0.65, p=0.0022) and OS (20 vs. 12 months, HR=0.37 95% CI 0.17-0.82, p=0.014). Combination of CPM & TroVax was not significantly superior. The primary endpoint at a single timepoint was not met since CPM-induced responses declined by week 7, and TroVax-induced responses were greatest at weeks 10-16. No serious adverse events were reported. Conclusions: Both CPM and TroVax induced highly beneficial anti-tumor immune responses resulting in significantly prolonged survival of end-stage CRC patients without toxicity. This is the first study to show a clear benefit of immunotherapy in advanced CRC, and suggests this approach may be superior (and less toxic) to continuous palliative chemotherapy in these patients.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
European Cancer Stem Cell Research Institute (ECSCRI)
Subjects: R Medicine > R Medicine (General)
Publisher: American Society of Clinical Oncology
ISSN: 0732-183X
Date of First Compliant Deposit: 25 August 2017
Date of Acceptance: 19 June 2017
Last Modified: 29 Mar 2024 01:50
URI: https://orca.cardiff.ac.uk/id/eprint/102722

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