GÉTICA 2021

22 VII FORO DE I nmunología Traslacional e INMUNOTERAPIA DEL CÁNCER Iñaki Etxeberria Úriz Memorial Sloan Kettering Cancer Center. New York, USA Substantial efforts have been placed on re-di- recting T-cell specificity and reducing toxicity of the ACT approaches. The use of gene engi- neering strategies to re-direct T-cell specificity towards tumor-associated antigens (TAA) led to the development of TCR-engineered T-cells and CAR-T Cells. Importantly, discovery of tu- mor exclusive TAAs, i.e. neoantigens (NeoAgs), and the development ACT approaches target- ing such antigens is a rapidly expanding field that may potentially be the next generation of re-directed T cells. In MSKCC, we have developed an active trans- lational pipeline to efficiently identify, collect, and screen viable TIL/PBMCs from cancer patients of defined HLA and driver oncogene mutational status. This pipeline seeks to dis- cover and characterize public NeoAgs and create a new TCR-based immunotherapy based on targeting public NeoAgs. ACT represents a cutting-edge immunother- apy approach in which gene engineering strategies provide tools to modulate desired specific functions of T cells. Nonetheless, cur- rent cell-therapy tools are far from perfect and offer room for improvement. Engineer- ing platforms can be used not only to confer antigen recognition specificity to T cells but also to build a better, stronger, and faster T A doptive T-cell therapy (ACT) based approaches have notably advanced in experimental cancer immunother- apy and are intensively being evaluated in the clinic. TIL therapy achieves impressive overall response rates in metastatic melano- ma patients and CAR-T cell-based therapies have revolutionized the treatment of hema- tological malignancies. In fact, CD19 target- ing CAR-T cells are currently being consoli- dated for the treatment of B cell lymphoma and leukemia. However, and despite the substantial im- provements experienced in the last decade, efficacy and safety challenges still need to be addressed to develop highly efficient ACT ap- proaches. Beyond the success in hematolog- ical malignancies and metastatic melanoma, efficacy in other malignancies has been rather limited. To broaden the treatment spectrum, in partic- ular for solid tumors, the functional features that a T cell in ACT must fulfill for successful outcomes include: (i) optimal trafficking to the tumor tissue, (ii) specific tumor cell recog- nition and killing, (iii) optimal T-cell prolifera- tion and persistence, (iv) resistance to the im- munosuppressive tumor microenvironment (TME), and (v) controlled activity. Intratumor T cell therapy