Adoptive immunotherapy of acute Leukemia with CD1c retargeted iNKT cells
Worldwide Cancer Research
Fondazione Centro San Raffaele
We have shown that a group of human T lymphocytes kills acute leukemia blasts by recognizing the leukemia-associated lipid antigen methyl-lysophosphatidic acid (mLPA) presented by the CD1c molecule, which is identical in all individuals, suggesting a donor-unrestricted adoptive immunotherapy approach. Indeed, we efficiently engineered total T lymphocytes from any donor with a selected mLPA-specific TCR to kill CD1c-expressing leukemia cell in vitro and in immunodeficient mouse xenografts. In this project, we aim at assessing whether the transfer of the mLPA-specific TCR into invariant Natural Killer T (iNKT) cells, a subset of lipid-specific lymphocytes expressing an invariant TCR restricted for CD1d molecules, may further improve efficacy and safety of this adoptive immunotherapy strategy. The advantages of using iNKT instead of T cells resides in their ability to: i. migrate into the bone marrow; ii. control graft versus host disease (GVHD) while promoting graft versus leukemia (GVL); iii. modulate/eliminate immunosuppressive cells in the tumor microenvironment (TME). We posit that iNKT cells may be harnessed to target, at the same time, leukemia cells with the mLPA-specific TCR, and therapeutically reprogram the TME with the endogenous one. The final aim of the project is to generate iNKT cells armed with a universal mLPA-specific TCR for off-the-shelf adoptive immunotherapy of human acute leukemia.
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