Stijn De Munter
Doctoral fellow, department of Diagnostic Sciences (Faculty of Medicine and Health)
Principal investigator: prof. Bart Vandekerckhove (MD, PhD)
Adoptive chimeric antigen receptor (CAR) T cell therapy seems to be remarkably effective for acute lymphoblastic leukemia (ALL). CD19 CAR T cells eradicate late stage leukemia in 70–90% of treated patients. This strategy uses synthetic chimeric receptors introduced in T cells consisting of a single chain variable fragment (scFv) derived from a monoclonal antibody to recognize specific antigens expressed on the surface of tumor cells and an intracellular part containing (co)stimulatory signals derived from CD3ζ, CD28 and/or 4_1BB. However, the success rate in patients with solid tumors remains disappointing. The limited therapeutic efficacy is the result of the typical tumor microenvironment and the presence of negative regulators of T cell response. These key hallmarks of solid tumors warrant the development of better CAR structures to induce a durable response.
We are studying the potential differences in T cell response in both solid and liquid malignancies and develop the most optimal CAR structure to target each malignancy. A first modification we have done to the standard CAR structure is the replacement of the scFv by a nanobody. These single antigen-binding domains are isolated from the heavy chain only antibodies from Camilidae. They can be cloned, easily expressed and retain the affinity for the specific antigen. Their strict monomeric behavior and their small size makes them ideal building blocks for multidomain constructs such as CARs. We are testing these nanoCARs in different in vitro and in vivo models of both solid as liquid malignancies.
- Safe eradication of large established tumors using neovasculature-targeted tumor necrosis factor-based therapies. EMBO Mol Med. 2020 Feb 7;12(2):e11223. doi: 10.15252/emmm.201911223.
- T-cells with a single tumor antigen-specific T-cell receptor can be generated in vitro from clinically relevant stem cell sources. Oncoimmunology. 2020 Feb 17;9(1):1727078. doi: 10.1080/2162402X.2020.1727078. eCollection 2020.
- Rapid and Effective Generation of Nanobody Based CARs using PCR and Gibson Assembly. Int J Mol Sci. 2020 Jan 30;21(3):883. doi: 10.3390/ijms21030883.
- Nanobody based dual specific CARs. International Journal of Molecular Sciences, 2018. (PMID: 29385713)
- Antigen receptor-redirected T cells derived from hematopoietic precursor cells lack expression of the endogenous TCR/CD3 receptor and exhibit specific antitumor capacities. Oncoimmunology, 2017. (PMID: 28405508)
Contact & links
- Lab address: campus UZ Gent, MRB2 (entrance 38), Corneel Heymanslaan 10, 9000 Ghent