Functional activity of anti-GD2 CAR-T cells with different antigen-recognition module
https://doi.org/10.15789/1563-0625-FAO-3161
Abstract
Neuroblastoma (NB) is the most common extracranial solid tumor in children comprising, 8 to 10% of all pediatric tumors, with incidence of about 1-1.3 cases per 100,000 children under 15 years of age. Despite the use of intensive treatment with surgery, high-dose chemotherapy and radiotherapy, the 5-year event-free survival rate is 25-50% and 10-40% after relapse. Over the past decade, a new type of cell therapy with chimeric antigen receptor (CAR) modification of lymphocytes has been rapidly developed. Among the main promising antigens for development of CAR-T therapy against NB is the disialoganglioside GD2, the expression of which is shown in 100% of NB cases. Most clinical variants of anti-GD2 CAR-T cells are based on scFv 14.G2, originating from chimeric antibody 14.18 (denutuximab). In 2020, the FDA approved a new anti-GD2 humanized antibody, 3F8 (naxitamab) with a better safety profile. Despite partial success, the results of anti-GD2 CAR-T therapy remain modest. One option to increase receptor specificity is based on targeting O-acetyl-GD2, a disialoganglioside derivative in which the external sialic acid residue is modified with an O-acetyl ester. Acetylation of GD2 occurs only in tumor cells, and it is not detected in peripheral nerves. An 8B6 antibody is known to target O-acetyl-GD2. Thus, at least 3 therapeutic antibodies, 14G2a, hu3F8 and 8B6, compete with each other for targeting GD2 with CAR-T cells. In all these cases, the anti-GD2 CAR contains insertion domains in extracellular portion of the molecule. Results of separate clinical trials have been published for CAR-T based on 14G2a and hu3F8. So far, however, there are no data on the usage of 8B6 antibody in CARs. The aim of the present study is to obtain 2nd generation chimeric antigenic receptors based on three antibodies with different lengths of extracellular domain, and to evaluate their functional activity against a number of cell lines to justify further clinical trials.
About the Authors
D. V. Lutskovich
Belarusian Research Center for Pediatric Oncology, Hematology and Immunology
Belarus
Belarus
Lutskovich D.V., Researcher, Laboratory of Genetic Biotechnology
43 Frunzenskaya St Borovlyany village, Minsk Region 223053
M. A. Keraz
Belarusian Research Center for Pediatric Oncology, Hematology and Immunology
Belarus
Belarus
Keraz M.A., Junior Researcher, Laboratory of Genetic Biotechnology
43 Frunzenskaya St Borovlyany village, Minsk Region 223053
H. V. Klych
Belarusian Research Center for Pediatric Oncology, Hematology and Immunology
Belarus
Belarus
Klych H.V., Researcher, Laboratory of Genetic Biotechnology
43 Frunzenskaya St Borovlyany village, Minsk Region 223053
E. S. Lutskovich
Belarusian Research Center for Pediatric Oncology, Hematology and Immunology
Belarus
Belarus
Lutskovich E.S., Junior Researcher, Laboratory of Genetic Biotechnology
43 Frunzenskaya St Borovlyany village, Minsk Region 223053
A. N. Meleshko
Belarusian Research Center for Pediatric Oncology, Hematology and Immunology
Belarus
Belarus
Meleshko A.N., PhD (Biology), Leading Researcher, Laboratory of Genetic Biotechnology, Scientific Department
43 Frunzenskaya St Borovlyany village, Minsk Region 223053
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For citations:
Lutskovich D.V., Keraz M.A., Klych H.V., Lutskovich E.S., Meleshko A.N. Functional activity of anti-GD2 CAR-T cells with different antigen-recognition module. Medical Immunology (Russia). 2025;27(5):1001-1012. (In Russ.) https://doi.org/10.15789/1563-0625-FAO-3161
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