Date

Tuesday 29 Sep 2026

Time

14:00 - 14:30

Location

BW007

Supervisor

Sander van Kasteren

Jury

Marco van Eijk

Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of hematological malignancies. However, its personalized, complex, costly and time-consuming ex vivo manufacturing process hinders its accessibility and broader application. In vivo CAR T-cell engineering aims to overcome these hurdles by generating therapeutic CAR T cells directly within the patient through systemic delivery of the CAR-encoding genetic material, potentially replacing individualized cell manufacturing with a standardized off-the-shelf delivery product. However, transferring CAR T-cell engineering into the systemic environment introduces new challenges regarding cellular specificity, delivery efficiency and safety control. This colloquium critically compares two prominent but contrasting in vivo delivery strategies that try to address these challenges: viral/gene-editing-based delivery, resulting in stable genomic integration, and mRNA-lipid nanoparticle (LNP) delivery, which achieves transient expression, using two recent preclinical studies as representative examples. Nyberg et al. (2026) developed a dual-viral vector, CRISPR-Cas9-based system achieving site-specific CAR integration at the T-cell receptor alpha constant (TRAC) locus, producing durable tumor control across three distinct mouse models. Hunter et al. (2025) engineered a CD8-targeted mRNA-LNP platform achieving efficient, dose-controllable, transient CAR expression, and rapid B-cell depletion followed by predominantly naïve B-cell recovery, across mice, nonhuman primates and patient-derived cell models. Both studies demonstrate that functional CAR T cells can be generated in vivo without ex vivo manipulation and address key challenges inherent to their respective delivery platforms. Each nonetheless retains its own trade-offs, the foremost being persistence versus reversibility of CAR expression, alongside differences in safety profile and manufacturing complexity. Neither strategy emerges as universally superior at this preclinical stage. Instead, their relative value appears to depend on the disease indication and the required balance between CAR durability and control. This distinction is increasingly reflected by early clinical studies, with integrating viral platforms primarily being investigated for malignancies and targeted mRNA-LNP approaches emerging for autoimmune diseases. Further translational and clinical evaluation will be required to establish long-term safety, reproducibility, scalability and therapeutic durability for both strategies. If successfully translated, both in vivo CAR T-cell engineering strategies could broaden access to CAR-based therapies and facilitate their application across malignancies, autoimmune disorders and potentially other diseases.