The major unmet clinical need of acute leukemia and Non-Hodgkin lymphoma (NHL) remains the frequent recurrence after the frontline treatment. For these reasons there is pressing need for alternative strategies to target T cell responses selectively against malignant cells. We have shown that primary acute myelogenous (AML) and B-lymphoblastic (B-ALL) leukemia blasts express the CD1c molecule, and that a group of human CD1c-restricted, self-reactive T cell clones kills acute leukemia blasts by recognizing the leukemia-associated lipid antigen methyl-lysophosphatidic acid (mLPA). More recently we observed that also the majority of B-cell NHL express CD1c. Because CD1c is monomorphic and expressed only by healthy mature leukocytes, we can envisage a donor-unrestricted adoptive immunotherapy approach with reduced risk of GvHD induction using iNKT cells redirected against CD1c+ tumor cells. iNKT cells promote GvL reaction without eliciting GvHD and modulate immunosuppressive myeloid cells in the tumor microenvironment (TME) through their TCR. Hence, we envision to generate bi-specific iNKT cells armed with a universal mLPA-specific TCR to dual target leukemia cells and the immunosuppressive myeloid TME. Furthermore, CD1d can be also expressed by cancer cells, implying the possibility for combinatorial recognition of CD1d- and CD1c-restricted antigens on the malignant target by mLPA-specific TCR engineered iNKT cells. iNKT cells from any donor can be efficiently engineered with our lead CD1c-restricted TCR DN4.99 and can kill CD1c-expressing leukemia and lymphoma cell in vitro. Our results highlight a novel approach for ACT of acute leukemia with T or iNKT cells engineered to recognize malignant cells by the transfer of a lipid-specific TCR that works across MHC-barriers like a CAR