Advancing RNA-based T-cell receptor redirection of lymphocytes to improve antitumor responses in adoptive T-cell immunotherapy for acute myeloid leukemia

Genetic engineering of T cells for adoptive cell transfer has marked a turning point in personalized immunotherapy, especially in the treatment of cancer. This strategy focuses on specifically targeting tumor-associated antigens (TAAs) by modifying T cells with immune receptors, such as T-cell receptors (TCRs), to improve T-cell ability to detect and eradicate tumor cells. T cells express TCRs that recognize short peptides derived from the intracellular processing of proteins. These peptides are bound to molecules of the major histocompatibility complex (MHC) and presented on the cell surface as peptide-MHC complexes. Thus, in TCR-engineered T (TCR-T)-cell therapy, T cells are engineered with nucleic acids containing the genetic information of TCRs derived from tumor-specific T-cell clones that specifically target peptides of TAAs. TCR-T-cell therapy has achieved extraordinary results in solid cancers like melanoma; however, the development and use of TCR-T cells in the clinic for the treatment of hematological malignancies has been challenging and it is still unsatisfactory. In particular, acute myeloid leukemia (AML) is an aggressive type of blood cancer and one of the most common types of leukemia in adults, especially in those older than 65. Relapse rate in AML patients after standard of care is 80% and current rate of survival for relapsed patients is no higher than 10%, warranting the development of improved and safe therapies for this malignancy. This thesis explores the use of RNA electroporation as a non-genotoxic strategy to redirect T-cell specificity towards an AML antigen named Wilms’ tumor 1 (WT1), as well as the parameters involved in increasing TCR-engineered T-cell-mediated tumor cell recognition.

Jaar van publicatie:2021

Trefwoorden:Doctoral thesis

Toegankelijkheid:Open