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.

BACKGROUND AND AIMS: 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 tumors 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.

METHODS

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 in vitro and in vivo studies further characterized UC-MSCTRAIL properties.

RESULTS

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 40 mg) and rivaroxaban 20 mg, respectively. Exploratory analyses found no clear pro-coagulant or immunogenic mechanisms, though participants receiving UC-MSCTRAIL had elevated inflammatory markers.

CONCLUSION

This first-in-human study of UC-MSCTRAIL in advanced lung cancer was terminated early due to high prevelance of pulmonary embolism. 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 malignancy. Future MSC-based therapies should incorporate close monitoring for asymptomatic thrombosis and follow a dose escalation design for safety. Safety concerns underscore the need for further research.