A first-in-human phase I clinical trial investigating the safety and efficacy of repeat dosing MSCTRAIL cell therapy in addition to chemotherapy and immunotherapy in patients with advanced lung cancer

<h2>ABSTRACT</h2><h3>Introduction</h3> Despite recent progress, advanced non-small cell lung cancer (NSCLC) has poor survival outcomes, necessitating the development of novel therapies. TNF-related apoptosis-inducing ligand (TRAIL) selectively induces cancer cell death and can be delivered to tumours by mesenchymal stromal cells (MSCs) due to the cells' migratory properties. This first-in-human phase I trial assessed safety and dose of umbilical cord-derived MSCs expressing TRAIL (UC-MSCTRAIL) alongside standard NSCLC therapy. <h3>Methods</h3> Participants performance status 0-1 with treatment-naïve, inoperable stage IIIB/IV NSCLC received UC-MSCTRAIL infusions with each cycle of chemotherapy and immunotherapy, up to 3 cycles. A dose de-escalation design was used. Exploratory <i>in vitro</i> and <i>in vivo</i> studies further characterised UC-MSCTRAIL properties. <h3>Results</h3> Six participants enrolled; four received 4×10⁸ cells/infusion (median 5.4×10⁶ cells/kg), and two received 2×10⁸ cells/infusion (median 2.4×10⁶ cells/kg). Early termination occurred due to asymptomatic pulmonary emboli (N=5), which included two patients that were anticoagulated as a protocol amendment with prophylactic low molecular weight heparin (enoxaparin 40mg) and rivaroxaban 20mg, respectively. Exploratory analyses found no clear pro-coagulant or immunogenic mechanisms, though participants receiving UC-MSCTRAIL had elevated inflammatory markers. <h3>Conclusion</h3> This first-in-human study was terminated due to a high incidence of pulmonary emboli. Though exact mechanism remains unclear, UC-MSCTRAIL may have contributed to a pro-inflammatory environment in participants already at elevated risk of thrombosis due to their malignancy. Future MSC-based therapies should incorporate close monitoring for asymptomatic thrombosis and follow a dose escalation design for safety. <h3>Significance</h3> First-in-human study of UC-MSCTRAIL in advanced lung cancer was terminated early due to high prevalence of pulmonary embolism. Safety concerns underscore the need for further research which might include dose-escalation design.