In Vivo CAR-Based Immune Cell Engineering: Future Applications and Challenges in Malignant Glioma

Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable success in hematologic malignancies, and its development is being actively pursued across a broad range of cancer types. However, current CAR-T cell therapies rely on ex vivo engineering, which presents significant logistical, temporal, and biological limitations. In vivo CAR-T cell engineering is emerging as a new paradigm that may overcome these challenges by enabling the direct reprogramming of immune cells within the patient through the administration of CAR-encoding vectors. This approach represents an off-the-shelf form of autologous immune therapy. Advances in viral engineering and nanotechnology have enabled the development of diverse CAR delivery platforms that not only deliver CAR constructs but also facilitate the delivery of gene-editing components, such as Cas9, allowing for more sophisticated in vivo genetic modifications. Some of these approaches have already entered clinical evaluation and have shown promising early results in hematologic malignancies, with clinical trials in solid tumors now underway. However, the application of in vivo-engineered CAR-T cell therapies to malignant glioma remains largely unexplored, reflecting challenges distinct from those encountered in hematologic malignancies. In this review, we discuss these challenges and potential strategies to address them, while highlighting recent progress in in vivo CAR-T cell engineering.