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

Michela Consonni, Claudio Garavaglia, Andrea Grilli, Claudia Lalla, Alessandra Mancino, Lucia Mori, Gennaro Libero, Daniela Montagna, Monica Casucci, Marta Serafini, Chiara Bonini, Daniel Häussinger, Fabio Ciceri, Massimo Bernardi, Sara Mastaglio, Silvio Bicciato, Paolo Dellabona () and Giulia Casorati ()
Additional contact information
Michela Consonni: IRCCS San Raffaele Scientific Institute
Claudio Garavaglia: IRCCS San Raffaele Scientific Institute
Andrea Grilli: University of Modena and Reggio Emilia
Claudia Lalla: IRCCS San Raffaele Scientific Institute
Alessandra Mancino: IRCCS San Raffaele Scientific Institute
Lucia Mori: University of Basel and University Hospital
Gennaro Libero: University of Basel and University Hospital
Daniela Montagna: University of Pavia
Monica Casucci: IRCCS San Raffaele Scientific Institute
Marta Serafini: University of Milano-Bicocca
Chiara Bonini: IRCCS San Raffaele Scientific Institute
Daniel Häussinger: University of Basel
Fabio Ciceri: IRCCS San Raffaele Scientific Institute
Massimo Bernardi: IRCCS San Raffaele Scientific Institute
Sara Mastaglio: IRCCS San Raffaele Scientific Institute
Silvio Bicciato: University of Modena and Reggio Emilia
Paolo Dellabona: IRCCS San Raffaele Scientific Institute
Giulia Casorati: IRCCS San Raffaele Scientific Institute

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-25223-0

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