界定 TIL（肿瘤浸润淋巴细胞）药品的质量属性

Tumor-infiltrating lymphocyte (TIL) medicinal products (MPs) show promise for treating solid tumors, especially metastatic melanoma, in the clinical trial setting. Through these studies, TIL developers have gained an immunological perspective into the mechanism of action (MoA) and infusion product characteristics that influence clinical response.

However, to reach marketing authorization for any of the TIL MPs, it will be beneficial to gain a pharmaceutical (process) development perspective as well, from which control of the TIL MPs manufacturing process can be demonstrated and a suitable control strategy can be developed. To do this, a well-defined TIL MP must be established.

Defining and optimizing MPs from a pharmaceutical perspective is done by identifying and improving product characteristics or quality attributes (QAs) thought to impact safety and efficacy. Through awareness of the QAs relevant to TIL MPs and considering them throughout pharmaceutical development, improvements and changes can be validated. This approach to pharmaceutical development is part of the quality-by-design workflow, of which this review tackles the first steps.

Here, the QAs are structured within a quality target product profile (QTPP), and the corresponding regulatory expectations are considered, spanning quantity, identity, purity, microbiological assays, and biological activity. Based on the regulatory expectations and available literature, the (critical) QAs and points of consideration are proposed when developing TIL MPs. The active pharmaceutical ingredient of the TIL MP is defined as the CD45+CD3+ cells. By analyzing identity attributes correlated to clinical efficacy, four broadly applicable in vivo functionalities associated with TIL MPs MoA and clinical effectiveness are described: tumor recognition, cytotoxic capacity, tumor homing, and persistence.

How these in vivo functionalities are quantified in potency assays and the limitations of their methods/readouts are also discussed. The QTPP is a foundation for developing a robust, substantiated control strategy for regulatory approval and increasing patient access. Harmonizing TIL MP development under a unified QTPP applicable in different settings could also facilitate comparisons and, therefore, the development of safer and more efficacious TIL MP variations.