MulTplex project: Development of a combinatorial multi-epitope T-cell receptor (TCR), non-signaling chimeric antigen receptor (NSCAR) and immunosuppressive immune checkpoint (IICP)-disrupted adoptive T-cell therapy against leukemia.

Acute myeloid leukemia (AML) is one of the most common leukemias in adults with a 5‐year overall survival rate of only 30%. Despite therapeutic advances in the last decade, novel adoptive T-cell immunotherapies using anti-tumor chimeric antigen receptors (CARs) and T-cell receptors (TCRs) are not fully developed for AML. Moreover, expression of immunosuppressive immune checkpoints (IICPs) hinder the success of these T-cell therapies. To address this issue, the aim of this project is to develop an innovative multi-epitope Wilms' tumor 1 (WT1)-specific TCR, CD200-specific non-signaling chimeric antigen receptor (NSCAR) and IICP-disrupted (mulTplex)-engineered adoptive T-cell therapy for AML. We will combine TCRs with different human leukocyte antigen (HLA) restrictions and specificities against diverse epitopes of WT1, a key intracellular antigen, in a multi-epitope strategy. To avoid the interaction between native and introduced TCRs, native TCRs will be disrupted by CRISPR-Cas9 technology. The NSCAR, which lacks the typical CAR's signaling domain, will act as an "anchor" for the T cells by locking onto AML cells through CD200, a novel extracellular AML antigen, and without triggering T-cell activation. By doing so, we expect to improve TCR-mediated anti-AML cytotoxic capacity of mulTplex-engineered T cells. To further harness the anti-leukemic activity of engineered T cells, AML-associated IICPs will also be disrupted using CRISPR-Cas9 methods. Both in vitro and in vivo evaluation of mulTplex-engineered T cells will ensure translation of our innovative combinatorial approach into clinical studies.

Keywords:MRNA ELECTROPORATION, CELL THERAPY, CANCER IMMUNOTHERAPY, LEUKEMIA

Disciplines:Cancer therapy, Hematology, Molecular and cell biology not elsewhere classified, Cell therapy