Masterarbeit

Nonclinic for TCR-transgenic T cells for adoptive T cell therapy of cancer - current requirements for applicants to EMA and FDA

Dr. Vivian Scheuplein (2022)

Summary
Language: English
In light of the rapid development of new ex vivo modified cell products such as chimeric antigen receptor (CAR)-transgenic and T cell receptor (TCR)-transgenic T cells, EMA and FDA published guidelines explicitly tailored for such products recently in 2020 and 2022. They fit the needs of developers of such therapies well and the EMA guideline gives explicit guidance on safety testing on TCR-transgenic T cell products depending on TCR source and cell properties.
These guidelines encourage the use of appropriate animal models, but at the same time, the use of studies conducted in non-relevant species are discouraged. However, there are difficulties to find an animal model in which TCR-transgenic T cell products are active. Additionally, available animal models (mice or non-human primates) have poor predictive value of safety due to the incomplete overlap of human and animal proteome and expression pattern of target and off-target antigens.
In line with the recommendation of FDA and EMA also developers of TCR-transgenic T cell therapies and CAR-transgenic T cell therapies did not claim to gain safety and toxicity data from the conducted animal experiments.
Nevertheless, proof-of-concept (PoC) studies were confirmedly conducted for several TCR-transgenic T cell products presented for clinical trial applications (CTA) or investigational new drug (IND) applications and also done for all transgenic T cells products (here assessed by CAR-transgenic T cells) presented for market authorization application (MAA) and biologic license application (BLA). Even more, the amount of nonclinical PoC testing in vivo increased from the early developed products to the more recently developed products.
This development contradicts the scientific rational that these animal models are not directly/easily transferrable to the human situation. The trend in conducting more nonclinical studies can only be explained that either, regulators request (or developers anticipate the request) to see in vivo PoC or, developers feel the efficacy of their TCR-transgenic T cell product not proven sufficiently by in vitro testing alone.
Pages: 69
Annexes: 2, Pages: 11