Efficient suppression of effector T cells isolated from multiple sclerosis patients by autologous, UniCAR-engrafted Tregs

In multiple sclerosis (MS) patients pathogenic, autoreactive effector T cells (Teffs) provoke demyelination and central nerve system damage. To impede those harmful immune reactions, the adoptive transfer of regulatory T cells (Tregs) emerged as a promising therapeutic strategy. Several preclinical mouse models confirm an inferior functionality of polyclonal compared to antigen-specific Treg cells. However, isolation and expansion of Tregs with a desired antigen-specificity proves to be highly time-consuming and labor-intensive.
To overcome these hurdles, we armed polyclonal Tregs isolated from MS patients with a universal chimeric antigen receptor (UniCAR) construct. This innovative technology allows a site-specific redirection of cells against any desired surface structure, as cross-linkage to target cells is mediated by a separate, antigen-binding targeting module (TM).
Highly pure CD4+CD25highCD127dimCD45RA+ MS-Tregs could be genetically modified to stably express the UniCAR 4-1BB/ζ construct. UniCAR-endowed Tregs strongly expand and show phenotypic stability also upon pro-inflammatory challenge. By adding a TM in the presence of target cells, UniCAR-engrafted Tregs are antigen-specifically activated demonstrated by CD69 and LAP upregulation. Most importantly, upon TM-stimulation UniCAR-armed Tregs efficiently suppress pre-activated, patient-derived Teffs.
Taken together, the UniCAR system holds an enormous therapeutic potential for MS, as it not only allows a site-specific and precisely regulated Treg activation but also confers strong suppressive capacity to Tregs from MS patients. Thereby, this innovate technology might broaden current treatment strategies to overcome impaired functionality of Tregs as well as resistance of pathogenic Teffs to Treg suppression reported for MS patients.