Nanobody-based CAR NK cells for possible immunotherapy of MICA + tumors

• Published in: PNAS nexus Vol. 3; no. 5; p. pgae184
• Main Authors: Verhaar, Elisha R, van Keizerswaard, Willemijn J C, Knoflook, Anouk, Balligand, Thomas, Ploegh, Hidde L
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.05.2024
• Subjects: Biological, Health, and Medical Sciences; CAR NK cells; nanobodies; PET imaging; MICA; immunotherapy
• ISSN: 2752-6542; 2752-6542
• DOI: 10.1093/pnasnexus/pgae184

The glycoproteins MICA and MICB are upregulated on the surface of cells undergoing stress, for instance due to (viral) infection or malignant transformation. MICA/B are the ligands for the activating receptor NKG2D, found on cytotoxic immune cells like NK cells, CD8 T cells, and γδ T cells. Upon engagement of NKG2D, these cells are activated to eradicate the MICA/B-positive targets, assisted by the secretion of cytokines. Nanobodies, or VHHs, are derived from the variable regions of camelid heavy-chain only immunoglobulins. Nanobodies are characterized by their small size, ease of production, stability, and specificity of recognition. We generated nanobodies that recognize membrane-bound MICA with high affinity. Here, we use these nanobodies as building blocks for a chimeric antigen receptor (CAR) to establish VHH-based CAR NK cells. These anti-MICA nanobody-based CAR NK cells recognize and selectively kill MICA-positive tumor cells in vitro and in vivo. We track localization of the VHH-based CAR NK cells to MICA-positive lung metastases by immuno-positron emission tomography imaging.