P2.01-16 TACTICAL: A Phase I/II Trial to Assess the Safety and Efficacy of MSCTRAIL in Metastatic Lung Adenocarcinoma

Abstract

Mesenchymal stromal cells (MSCs) migrate to and incorporate into tumour stroma, acting as vehicles for delivering anti-cancer therapies. TNF-related apoptosis inducing ligand (TRAIL) selectively induces apoptosis in malignant cells, however its short biological half-life has limited therapeutic efficacy. We have transduced MSCs with a lentiviral vector to express TRAIL (MSCTRAIL), demonstrating efficacy in vitro using co-culture assays and in vivo in orthotopic lung metastasis murine model, showing regression of metastases following treatment with intravenous MSCTRAIL [1] and synergistic activity with other systemic anti-cancer therapies. Given their immune-privileged nature we are now delivering ex vivo MSCTRAIL from pooled third party umbilical cord donors without tissue matching or immunosuppression. TACTICAL is a phase I/II trial assessing safety and efficacy of MSCTRAIL in combination with first line standard of care (SOC); pemetrexed (500mg/m2) and cisplatin (75mg/m2) and/or pembrolizumab (200mg), in treatment-naive patients with stage IIIB/IV metastatic lung adenocarcinoma. Patients have no actionable driver mutations and ECOG performance status 0-1. Phase I is a dose de-escalation study; patients receive SOC on day 1 and 4x108 MSCTRAIL cells on day 2 of a 21-day cycle for 3 cycles, with a Bayesian adaptive design recommending dose reductions if severe toxicities occur (Fig.1A). Primary outcomes are recommended phase II dose (RP2D), safety and tolerability of MSCTRAIL. In phase II, 46 patients will be randomised (1:1) in a double-blind trial to receive SOC and either RP2D of MSCTRAIL or placebo (Fig.1B). Primary outcome is tumour response rate by RECIST (v1.1) at 12 weeks. Translational work will include measuring: biomarkers of response; T, B, NK cell function in reaction to allogeneic MSCs; tracking migration of MSCs radiolabelled with 89Zirconium-oxine through serial PET imaging. TACTICAL is the first clinical trial of this novel cell and gene therapy and if successful will pave the way for future allogeneic MSC cancer therapies. 1. Loebinger, M.R., et al., Mesenchymal stem cell delivery of TRAIL can eliminate metastatic cancer. Cancer Res, 2009. 69(10): p. 4134-42.