Human T cells engineered with a leukemia lipid-specific TCR enables donor-unrestricted recognition of CD1c-expressing leukemia

• Published in: Nature communications 2021-08, Vol.12 (1), p.4844-4844, Article 4844
• Main Authors: Consonni, Michela, Garavaglia, Claudio, Grilli, Andrea, de Lalla, Claudia, Mancino, Alessandra, Mori, Lucia, De Libero, Gennaro, Montagna, Daniela, Casucci, Monica, Serafini, Marta, Bonini, Chiara, Häussinger, Daniel, Ciceri, Fabio, Bernardi, Massimo, Mastaglio, Sara, Bicciato, Silvio, Dellabona, Paolo, Casorati, Giulia
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/106; 13/107; 13/21; 13/44; 42/109; 49/31; 631/250/21/1566; 631/250/2152/1566/1618; 631/250/2152/1566/20; 631/67/1059/2325; 64/60; 692/4028/67/1990/283/1897; Animal models; Antigens; CD1c antigen; Chemotherapy; Graft versus host disease; Graft-versus-host reaction; Hematopoietic stem cells; Humanities and Social Sciences; Immunization; Leukemia; Leukocytes; Lipids; Lymphocytes; Lymphocytes T; Lysophosphatidic acid; Major histocompatibility complex; multidisciplinary; Risk management; Science; Science (multidisciplinary); Stem cell transplantation; Stem cells; T cell receptors; Xenografts; Xenotransplantation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-25223-0

Acute leukemia relapsing after chemotherapy plus allogeneic hematopoietic stem cell transplantation can be treated with donor-derived T cells, but this is hampered by the need for donor/recipient MHC-matching and often results in graft-versus-host disease, prompting the search for new donor-unrestricted strategies targeting malignant cells. Leukemia blasts express CD1c antigen-presenting molecules, which are identical in all individuals and expressed only by mature leukocytes, and are recognized by T cell clones specific for the CD1c-restricted leukemia-associated methyl-lysophosphatidic acid (mLPA) lipid antigen. Here, we show that human T cells engineered to express an mLPA-specific TCR, target diverse CD1c-expressing leukemia blasts in vitro and significantly delay the progression of three models of leukemia xenograft in NSG mice, an effect that is boosted by mLPA-cellular immunization. These results highlight a strategy to redirect T cells against leukemia via transfer of a lipid-specific TCR that could be used across MHC barriers with reduced risk of graft-versus-host disease. Leukaemia therapy may benefit from the use of antigens that are less restricted to individual donors. Here the authors engineered T cells with a TCR specific for a CD1c restricted lipid leukaemia antigen and show that they can protect against disease progression in mouse leukaemia xenograft models.