To ensure patients have timely access to innovative products, regulators must respond to evolving technologies by building up their expertise before reviewing the products with cutting-edge technology. Notably, new classes of therapeutics of unprecedented modality represent a regulatory challenge owing to the gaps in our knowledge. To accommodate emerging technologies, the Pharmaceuticals and Medical Devices Agency (PMDA) introduced “horizon scanning,” which involves systematic information gathering followed by activity prioritization (1). For the high-impact technologies that are difficult to assess under the existing regulatory standards, the PMDA Science Board, a committee of external experts, sheds light on significant points for the relevant area to ensure an optimal review and appropriate regulation (2). Herein, we would like to discuss the latest issue of the PMDA Science Board, “In vivo chimeric antigen receptor (CAR) T cells generation: An assessment of targeted gene delivery” (3). This is a regulatory effort not only to catch up with technological advancements but also to facilitate rational drug development. The purpose of this report is to inform the general readers about the regulatory challenges in the development of in vivo generated CAR T products and to assist foreign regulators and developers in following up discussions by the PMDA Science Board to support efficient development.

CAR T cell therapy is a cancer immunotherapy that has brought substantial benefits to patients with B cell malignancies (4). In addition to hematological malignancies, many efforts are ongoing to extend the CAR T cell approach to solid tumors and viral infections (5). However, personalized CAR T cell production is a bottleneck due to its complexity and resource requirements: T cells are extracted from patients via leukapheresis, and then these cells are genetically modified and expanded ex vivo at any eligible facility under current good manufacturing practices (6). Patient-derived starting materials may have intrinsic properties that affect CAR T cell manufacturing because of the disease state and prior treatment, leading to uncertainty in product completion. In addition, the production process normally takes several weeks, which is not feasible for rapidly progressing cancer patients who need immediate treatment. Another challenge for patients is to receive the standard preconditioning chemotherapy, which depletes endogenous lymphocytes before the infusion of the ex vivo-expanded CAR T cells. To overcome the barriers of the current ex vivo CAR T cell therapy, intensive research efforts are in place to generate CAR T cells in vivo through direct injection of the gene vector (7–9). In vivo CAR T cell generation could make this treatment immediately accessible to patients. However, efficient and highly selective gene delivery to target cells in vivo is challenging. Given that this issue is suitable for drug review and regulation, the PMDA Science Board selected this issue for the next technical subcommittee.

Intensive efforts have been focused on engineering CAR T cells directly in vivo to bypass ex vivo manipulation. While these innovative products offer clinical opportunities, they also present regulatory challenges that the Science Board is going to address.

The elaborate assessment of targeted gene delivery by the Science Board would apply not only to CAR T cell generation but also to genome editing, which is conventionally manipulated ex vivo. Figure 1 shows the literature landscape of gene therapy pertinent to the field. TCR T and CAR T articles form peaks, and the peak of genome editing literature is found in the vicinity. These fields are within the scope of the discussion by the Science Board, which will present points to consider for entering the first-in human clinical study. The outcome report will streamline the review process and the overall development of these fields.

From an international point of view, global regulators cooperate in the International Coalition of Medicines Regulatory Authorities (ICMRA), where horizon scanning is one of the focuses in which the PMDA is participating (30). In a recent publication on horizon scanning by the European Medicines Agency, a subset of 25 technological trends has been identified, many of which overlap with what the PMDA is also paying attention to (31). Using the ICMRA network, reports from the PMDA Science Board will help facilitate safe and timely access to innovative medicines globally.

RW conceived the idea and wrote the manuscript. AF-S performed the analysis of the available evidence. All authors contributed to manuscript revision, read, and approved the submitted version.