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


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Alice Davies1,Beth Sage2,Krishna Kolluri1,Rebecca Graham1,Ben Weil3,Rita Rego3,Owen Bain3,P. Stephen Patrick4,Kim Champion5,Alex Day5,Bilyana Popova5,Graham Wheeler5,Dan Fullen6,Tammy Kalber4,Martin Forster7,Mark Lowdell3,Sam Janes1
1Lungs for Living, UCL Respiratory, University College London,2Raigmore Hospital, NHS Highlans,3Centre for Cell, Gene and Tissue Therapeutics Royal Free Hospital, NHS Foundation Trust,4Centre for Advanced Biomedical Imaging, University College London,5Cancer Research UK & UCL Cancer Trials Centre, University College London,6Translational Research Office, University College London,7UCL Cancer Institute

Abstract

Background

Mesenchymal stromal cells (MSCs) migrate to and incorporate into tumour stroma allowing them to act as vehicles, delivering anti-cancer therapies. TNF-related apoptosis inducing ligand (TRAIL) selectively induces apoptosis in malignant cells however short biological half-life has limited its therapeutic efficacy.

We have transduced umbilical cord MSCs with a lentiviral vector to express TRAIL (MSCTRAIL). These cells trigger apoptosis selectively in cancer cells with evidence of synergistic activity with other systemic anti-cancer therapies. Given their immune-privileged nature we are delivering ex vivo pooled MSCTRAIL from third party donors without tissue matching or immunosuppression

Efficacy has been demonstrated using in vitro co-culture assays and in vivo in orthotopic lung metastasis murine model, showing regression of metastases following treatment with MSCTRAIL

Method

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 naïve patients with stage IIIB/IV metastatic lung adenocarcinoma. Patients have no actionable driver mutations and ECOG performance status 0-1

Patients currently enrolling in a dose de-escalation phase I study receive SOC day 1 and 4x108 MSCTRAIL cells day 2 of a 21 day cycle for 3 cycles. A Bayesian adaptive design will recommend dose reductions if excessive toxicities occur. Primary outcomes are to determine recommended phase II dose along with safety and tolerability of MSCTRAIL

46 patients will then be randomised in a phase II double blind, placebo-controlled trial receiving SOC and either MSCTRAIL or placebo (1:1). Primary outcome is tumour response rate by RECIST (v 1.1) criteria at 12weeks. Secondary outcomes include, best overall response, duration of response, progression free survival and overall survival

Results

Conclusion

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