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Effect of Modified Vaccinia Ankara–5T4 and Low-Dose Cyclophosphamide on Antitumor Immunity in Metastatic Colorectal Cancer A Randomized Clinical Trial

Scurr, Martin, Pembroke, Thomas, Bloom, Anja, Roberts, David, Thomson, Amanda, Smart, Kathryn, Bridgeman, Hayley, Admas, Richard, Brewster, Alison, Jones, Robert, Gwynne, Sarah, Blount, Daniel, Harrop, Richard, Wright, Melissa, Hills, Robert, Gallimore, Awen and Godkin, Andrew 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

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
Subjects: R Medicine > R Medicine (General)
Publisher: American Medical Association (AMA)
ISSN: 2374-2437
Date of First Compliant Deposit: 25 August 2017
Date of Acceptance: 19 June 2017
Last Modified: 28 Jun 2019 16:07
URI: http://orca.cf.ac.uk/id/eprint/102722

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