A phase 1b clinical trial optimizing regulatory T cell depletion in combination with platinum-based chemotherapy in thoracic cancers. Issue 5 (4th May 2021)

• Record Type: Journal Article
• Authors: Cook, Alistair M.; McDonnell, Alison; Millward, Michael J; Creaney, Jenette; Hasani, Arman; McMullen, Michelle; Meniawy, Tarek; Robinson, Bruce W.S.; Lake, Richard a; Nowak, Anna K.
• Is Part Of: Expert review of anticancer therapy. Volume 21:Issue 5(2021)
• Page Start: 465
• Page End: 474
• Publication Date: 2021-05-04
• Subjects: Malignant mesothelioma -- non-small cell lung cancer -- clinical trial -- phase I -- cyclophosphamide -- immunotherapy -- chemoimmunotherapy; Cancer -- Treatment -- Periodicals; 616.99406
• DOI: 10.1080/14737140.2021.1882308
• Languages: English
• ISSNs: 1473-7140

Abstract

ABSTRACT: Background : Single-agent cyclophosphamide can deplete regulatory T-cells (Treg). We aimed to determine optimal dosing and scheduling of oral cyclophosphamide, alongside pemetrexed-based chemotherapy, to deplete Treg in mesothelioma or non-small-cell lung cancer patients. Methods : 31 Patients received pemetrexed ± cisplatin or carboplatin on day 1 of a 21-day cycle (maximum 6 cycles). From cycle two, patients received cyclophosphamide, 50 mg/day, with intrapatient escalation to maximum 100/150 mg/day alternately. Immunological changes were examined by flow cytometry. Primary endpoint was Treg proportion of CD4 + T-cells, with doses tailored to target Treg nadir <4%. Results : Reduction in Treg proportion was observed on day 8 of all cycles, and was not augmented by cyclophosphamide. Few patients achieved the <4% Treg target. Treg proliferation reached nadir one week after chemotherapy, and peaked on day 1 of the subsequent cycle. Efficacy parameters were similar to chemotherapy alone. Seventeen percent of patients ceased cyclophosphamide due to toxicity. Conclusions : Specific Treg depletion to the degree seen with single-agent cyclophosphamide was not observed during pemetrexed-based chemotherapy. This study highlights the poor evidence basis for use of cyclophosphamide as an immunotherapeutic in combination with chemotherapy, and the importance of detailed flow cytometry studies. Trial registration : Clinical trial registration: www.anzctr.org.au identifier is ACTRN12609000260224.