Abstract
Cellular therapies are engineered using foreign and synthetic protein sequences, such as chimeric antigen receptors (CARs). The frequently observed humoral responses to CAR T cells result in rapid clearance, especially after re-infusions. There is an unmet need to protect engineered cells from host-versus-graft rejection, particularly for the advancement of allogeneic cell therapies. Here, utilizing the immunoglobulin G (IgG) protease “IdeS,” we programmed CAR T cells to defeat humoral immune attacks. IdeS cleavage of host IgG averted Fc-dependent phagocytosis and lysis, and the residual F(ab′)2 fragments remained on the surface, providing cells with an inert shield from additional IgG deposition. “Shield” CAR T cells efficiently cleaved cytotoxic IgG, including anti-CAR antibodies, detected in patient samples and provided effective anti-tumor activity in the presence of anti-cell IgG in vivo. This technology may be useful for repeated human infusions of engineered cells, more complex engineered cells, and expanding widespread use of “off-the-shelf” allogeneic cellular therapies.
Original language | English (US) |
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Pages (from-to) | 3398-3409 |
Number of pages | 12 |
Journal | Molecular Therapy |
Volume | 29 |
Issue number | 12 |
DOIs | |
State | Published - Dec 1 2021 |
Keywords
- CAR T cells
- IdeS
- anti-CAR IgG
- cell therapies
- humoral response
- immunogenicity
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Genetics
- Pharmacology
- Drug Discovery