A phase 1b clinical trial optimizing regulatory T cell depletion in combination with platinum-based chemotherapy in thoracic cancers.
Alistair M CookAlison McDonnellMichael J MillwardJenette CreaneyArman HasaniMichelle McMullenTarek M MeniawyBruce W S RobinsonRichard A LakeAnna K NowakPublished in: Expert review of anticancer therapy (2021)
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.
Keyphrases
- end stage renal disease
- clinical trial
- low dose
- newly diagnosed
- high dose
- ejection fraction
- chronic kidney disease
- flow cytometry
- small cell lung cancer
- prognostic factors
- regulatory t cells
- locally advanced
- peritoneal dialysis
- open label
- squamous cell carcinoma
- stem cells
- randomized controlled trial
- transcription factor
- young adults
- signaling pathway
- sensitive detection
- placebo controlled