Innovative platforms for development of TCR-T cell therapies against novel tumor targets: Triple negative breast cancer.

Abstract

e14536 Background: Adoptive T cells therapies have shown great potential over the past decade, particularly with the use of CAR-T cells to treat haematological tumors. However, their effect in the treatment of solid cancers is limited, due to a lack of relevant therapeutic targets and suppressive mechanisms of the tumor microenvironment. To counteract these challenges, we have developed Pan Cancer T (PCT) platforms to yield novel TCR-T cell therapies against untapped (intracellular) tumor targets exclusively expressed in 10 hard-to-treat solid tumors (including breast, melanoma, colorectal, glioma, lung cancer). Furthermore, we are developing engineering strategies aiming to improve the longevity of T cells within the inhibitory solid tumor microenvironment. Methods: The platforms we have developed to enable generation of genetically engineered TCR-T cells to recognize tumor-specific (intracellular) antigens include: 1) PCT Target Discovery (identifying and selecting safe, immunogenic tumor targets by combining advanced in silico and laboratory techniques); 2) PCT TCR Discovery (identifying, selecting, and validating potent TCR-T cells binding with high specificity and avidity); 3) PCT Next Gen Engineering (identifying drivers of immune evasion and implementing TCR-T cell-based gene-engineering approaches to overcome suppression and/or improve durability). Results: Using our PCT Target Discovery platform, we have validated a set of 30 unique tumor targets which are safe, immunogenic and highly shared. Our first showcase target is PCT-1, which is of particular interest in triple negative breast cancer (TNBC), where it is expressed by >85% of patients, with high homogeneity in >80% of all tumor cells. PCT-1 is also expressed in other tumor types, including >90% melanoma and >45% multiple myeloma patients. The PCT TCR Discovery platform has enabled development of a highly specific and active TCR against PCT-1, which outperformed standard of care TNBC treatments (ie, cis-platinum and sacituzumab govitecan) in advanced preclinical efficacy models, including in vitro killing of patient-derived 3D organoids and an in vivo model in NSG mice. Conclusions: The PCT platforms have enabled development of a promising TCR-T against a novel target antigen expressed in TNBC, an aggressive form of breast cancer that affects younger women with limited treatment options. A portfolio of 29 additional untapped targets has also been identified, providing potential to generate TCR-based therapies for treatment against a much larger range of solid tumors. Furthermore, we are developing next generation technologies, aiming to enhance the durability of responses within the hostile tumor microenvironment, which should be broadly applicable to TCR-T therapies.