Aptamers and Peptides: Finding and Guiding CAR T Cells for Better Cancer Care

Abstract

Chimeric antigen receptor (CAR) T-cell therapy has prompted a new age of cancer treatments, in which a patient’s T cells are genetically programmed with a cancer-targeting receptor ex vivo and reinfused for immune-mediated clearance of the tumor. However, despite some success in treating CD19+ B-cell malignancies in pediatric and adult patients, commercial CAR T-cell therapies currently suffer from an expensive manufacturing process that limits access to care and an inflexible design that cannot prevent treatment-associated side-effects and cancer relapse from antigen escape. Accordingly, new strategies for making more cost-effective, safe, and versatile CAR T-cell therapies are urgently needed to broaden and increase their therapeutic impact on the cancer community. Synthetic DNA aptamer and peptide targeting ligands are uniquely positioned to address these issues, owing to their specificity, low cost, small size, and ease of modification for a variety of applications (Chapter 1). To this end, we developed aptamer selection reagents that inexpensively isolate label-free CD8+ T cells (Chapter 2) and efficiently deplete TfR1+ cancer cells (Chapter 3) for CAR T-cell manufacturing. We also generated aptamer and peptide targeting reagents that selectively bind integrins expressed on liquid and sold tumors (Chapter 4 and Chapter 5, respectively) and integrated them into heterobifunctional intermediates that direct the anti-cancer activity of a novel universal CAR T-cell platform via covalent SpyCatcher003-SpyTag003 chemistry (Chapter 6). At the end of each chapter, we discuss limitations and future directions of this work.