Model-based Approaches in CAR-T Cell development and assessment:Bridging Scientific Research and Regulatory Applications

Introduction/Objectives<br/>Chimeric Antigen Receptor T-cell (CAR-T) therapies are genetically modified cell-based treatments for hematologic malignancies, leveraging engineered T-cells to target cancer antigens. Six CAR-T products have received EU approval, primarily as third- or fourth-line therapies in relapsed or refractory cases. Given the limited patient populations in these indications, model-informed drug development (MIDD) offers potential advantages in addressing data gaps and optimizing dose-response relationships. However, the extent to which modeling and simulation (M&amp;S) methodologies have been integrated into CAR-T regulatory submissions remains unclear. The present study aims to compare the model possibilities available in the literature with those employed in the regulatory assessment of the benefit-risk balance.<br/>Methods<br/>Two separate systematic reviews have been conducted on the role of modelling in the development of CAR-T cells. The first study was situated in the extant literature, focusing on computational models related to autologous for approved CAR-T cells. The second study reviewed the place of modelling and simulation as supporting evidence during regulatory submissions at the EMA. Regulatory questions addressed by M&amp;S were classified into efficacy, safety, pharmacokinetics (PK), and modality of use. M&amp;S methods were identified through targeted screening, and their credibility was evaluated using the structured framework from the ICH M15 guideline.<br/>Results<br/>A review of regulatory documents revealed that the mostly used models were dose-exposure-response (DER) and population PK (popPK) models. These models were utilised for PK characterisation, dose-response evaluations (including efficacy and safety components), and comparison with standard treatment. A review of the literature revealed the existence of more types of models including popPK, Pharmacokinetics/Pharmacodynamics (PK/PD), Physiologically-Based-PK/PD (PB-PK/PD), Exposure-Response (E-R) and two Quantitative Systems Pharmacology (QSP) models. These models were ultimately used to inform different several components of CART cells efficacy and safety, including patient survival. <br/>The analysis identified 117 regulatory questions across key categories (modality: 26, benefit-risk: 23, efficacy: 50, safety: 18). M&amp;S approaches were applied in only 11.0% of questions, primarily using dose-exposure-response and population PK (popPK) models for PK characterization, cytokine release syndrome (CRS) prediction, and dose-response evaluations. Model credibility assessments revealed variable regulatory acceptance. <br/>Conclusion<br/>Although M&amp;S methods have significant potential in CAR-T cell development, their use in regulatory submissions remains limited. Most models serve as supportive tools rather than primary evidence for decision-making.