Ultrasound-Augmented CAR T-Cell Therapy for CNS Tumors: A Scoping Review of Emerging Strategies and Preclinical Evidence

Purpose: The coincidence of ultrasound bioengineering and (chimeric antigen receptor) CAR T-cell immunotherapy depicts a promising prototype for treating CNS tumors especially glioblastoma. However, the available evidence encompasses distinct strategies, from ultrasound as a delivery enhancer to its use as a remote controller of cellular activity. This scoping review has aimed to map the available preclinical evidence, identify the key technological approaches being investigated and synthesise the techniques used to evaluate the efficacy and safety of ultrasound-augmented CAR T-cell therapies for glioblastoma. Methods: A scoping review of the preclinical evidence is conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews. The protocol has been registered on Open Science Framework.Results: Initial search strategy identified 77 articles across databases. After primary screening 7 articles were left for full text screening with 5 being excluded in full text screening. The included 2 studies investigated the combination of ultrasound techniques with CAR T-cell therapy for glioblastoma. Two primary ultrasound methodologies, ultrasound-mediated blood brain barrier disruption and magnetic resonance guided focused ultrasound, were used. The majority of findings were related to CAR T-cell trafficking and therapeutic efficacy. The themes of tumour microenvironment modulation and safety/toxicity were also discussed. Both preclinical studies signify that ultrasound enhanced the intracranial delivery and activity of CAR T cells, making it efficacious for intracranial tumours. Conclusion: Preclinical studies identified in this scoping review suggests that CAR T-cell therapy enhancement by the use of ultrasound mediated blood brain barrier disruption is efficacious against glioblastoma in animals models. The review also indicates that there are no permanent long term safety hazards and toxic effects associated with this technique. A more comprehensive and disciplined approach across diverse tumor models is needed to determine the assertive efficacy and safety profile of ultrasound mediated blood brain barrier for CAR T-cell therapy. Keywords: Glioblastoma, CAR T-cell therapy, ultrasound, blood brain barrier disruption (BBBD), MRI guided focused ultrasound (MRgFUS)