Abstract Body (Do not enter title and authors here): Introduction/Background: Neurodevelopmental impairment is a challenge for many children with complex congenital heart disease who undergo surgical intervention with cardiopulmonary bypass during the early postnatal period.
Research Questions/Hypothesis: We hypothesized that bone marrow-derived mesenchymal stromal cell (BM-MSC) delivery through cardiopulmonary bypass (CPB) will improve neurodevelopmental outcome and post-operative course.
Goals/Aims: The primary goal of this single-center, dose-escalation phase 1 trial was to assess the safety/feasibility and determine the maximum tolerated dose (MTD) of BM-MSC treatment.
Methods/Approach: Inclusion criteria of the phase 1 trial were neonates/infants (ages ≤ 6 months) who underwent scheduled two-ventricle repair without arch reconstruction. Dose escalation was guided by a modified continual reassessment method at four dose levels (1-40x10^6 cells/kg). Dose limiting toxicity was assessed for 45 days after BM-MSC delivery. Secondary endpoints before discharge were compared with a historical cohort (n=222) by inverse probability of treatment weighting (IPTW) using the propensity score to balance the groups.
Results/Data: Seventeen patients were enrolled from July 2020 to June 2023 (ventricular septal defect, n=9; tetralogy of Fallot, n=7; transposition of the great arteries, n=1; male, n=10). There were 3 serious adverse events all of which were related to cardiac surgery and not the BM-MSC product (junctional ectopic tachycardia, n=2; diaphragm paresis, n=1). Among 50 total events, there were no adverse events related to BM-MSCs. The BM-MSC dose was successfully escalated to the planned MTD (40x10^6 cells/kg), demonstrating safety and feasibility of this therapeutic delivery strategy. Consistent with results indicating little interference on CPB functions, electron microscopy studies showed no BM-MSC adherence on the CPB filter mesh at the MTD. Multivariable analyses with IPTW identified a reduction of CO2 and lactate levels in MeDCaP cases. We observed differences in white blood cell, monocyte, and platelet numbers between the two groups, suggesting possible interaction between endogenous blood cells and applied BM-MSCs.
Conclusions: We confirmed the safety and feasibility of BM-MSC treatment during CPB at the proposed MTD level. Successful design and completion of a future phase 2 trial is needed to determine efficacy.