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

Michela Consonni,Claudia De Lalla,Giulia Casorati,Fabio Ciceri,Lucia Mori,Andrea Grilli,Claudio Garavaglia,Gennaro De Libero,Silvio Bicciato,Sara Mastaglio,Monica Casucci,Paolo Dellabona,Daniel Häussinger,Massimo Bernardi,Marta Serafini,Alessandra Mancino,Daniela Montagna,Chiara Bonini

doi:10.1038/s41467-021-25223-0

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.

Highlights

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
We have shown that targeting T cells against tumor-related lipid antigens presented by CD1c are a viable immunotherapy strategy for hematological malignancies, which are driven by the pathological counterpart of the cells that normally express CD1 group 1 molecules
This strategy is importantly different from adoptive immunotherapy with T cells engineered to express T cell receptors (TCR) specific for MHC-presented peptides; rather, the approach we propose is comparable with chimeric antigen receptor (CAR)-T cell therapy because it has no histocompatibility barriers, owing to the lack of CD1c polymorphism[6]

Summary

Introduction

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. 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. Because of the high polymorphism of MHC, this approach requires the isolation of many different tumor-specific TCRs restricted to the most frequent HLA alleles

Methods

Results

Conclusion