We also develop approaches to improve T cell responses against cancer, focusing on the signaling domains of recombinant tumor-specific receptors. Our research shows that the identity and topology of TCR-derived signaling domains of these recombinant receptors determines their efficiency with respect to activating the T cells. These results have a direct implication for improving cellular cancer immunotherapy. They also provide new inroads into understanding the mechanisms underlying TCR function.
In a third, clinically-oriented project, we have generated CAR-T cells against Acute Myeloid Leukemia (AML). While CAR-T cells that can recognize various types of B cell lymphoma and leukemia have been very successful in the clinic, use of CAR-T cell therapy for AML treatment has been severely hampered by unacceptable toxicity against the patient’s myeloid precursors that express the same antigen as the ones targeted on the AMLs. As no better target antigens have been defined, we are generating CAR-T cells that use a logic gate formed by an activating CAR recognizing the shared antigen on precursors and AMLs and an inhibitory immune receptor that recognizes a ligand only expressed by the myeloid precursors. If successful, this concept can be applied to other type of cancers using appropriate combinations of activating and inhibiting receptors.