Translational barriers in 5-ala photodynamic therapy for gliomas: a systematic review of the in vivo landscape and future directions for clinical applicability

INTRODUCTION Photodynamic therapy (PDT) is an emerging investigational therapeutic for gliomas marked by variable success. Several strategies to increase its efficacy have been attempted, and although promising, challenges that have hindered translational progress persist. The objective of this study was to analyze translational barriers through a systematic review and appraisal of the in vivo literature. Method: PRISMA guidelines were utilized to identify studies that reported translational in vivo data of 5-aminolevulinic acid (5-ALA) PDT in murine glioma models. Databases were searched from inception to 2022, using the terms: “photodynamic therapy” AND (“5-ALA” OR “ALA” OR “PPIX”) AND “in vivo” AND (“glioma” OR “glioblastoma” OR astrocytoma”). Study design parameters were appraised, and mechanistic and translational outcomes across all studies were evaluated and compared. Result: Eight studies (2002-2019) were included. The most common animal model used was immunosuppressed rats orthotopically implanted with glioma cells. Only two studies used syngeneic models. No studies validated findings in external cohorts or patient-derived xenografts. Experimental light power densities ranged widely from 0.5-100mW/ cm2. Only three studies utilized a longitudinal delivery strategy, and all found significantly decreased tumor volume and increased survival compared to high-dose single-session PDT. For mechanistic endpoints, only one study investigated the impact of PDT on the immune response, finding increased TME CD8+ T-cell infiltration in the experimental group. Safety endpoints, including hemorrhage, elevated intracranial pressure (ICP), and off-target cortical damage, were measured in only three studies, in which high power densities were associated with increased hemorrhage and elevated ICP. CONCLUSION While in vivo evidence for 5-ALA PDT is compelling, this appraisal uncovers discrepancies in power densities, lack of validation in putative translational models, and limited understanding of PDT impact on the immune response and TME. Future preclinical investigations that address these barriers will offer distinct and necessary steps toward effective clinical translation.