TCR/HLA-I double knockout CAR-T cells maintain lytic ability with reduced allogenicity
K Pavlovic(1,2) M D Carmona(2) N Maldonado(1) M Cortijo(1) M Tristán(1) F J Molina(1) F Martín(1) I C Herrera(2,3) K Benabdellah(1)
1:GENyO- Centro de Genomica e Investigacion Oncologica: Pfizer / Universidad de Granada / Junta de Andalucia; 2:Instituto Maimónides de Investigación Biomédica de Córdoba; 3:Hospital Universitario Reina Sofía
Therapy based on T cells expressing chimeric antigen receptors (CAR) is a novel treatment for lymphoid neoplasms, with 5 medicaments already approved for liquid cancers. However, currently approved CAR therapies are based on autologous T cells, which increases the cost and reduces the efficacy of the treatment. On the other hand, several clinical trials involving CAR T cells have been impacted by T cell–intrinsic dependent factors, associated with their phenotypes, which could be overcome by the selection and combination of specific subsets of less-differentiated state for the final CAR production. In this project, we expect to generate off-the-shelf allogeneic CAR-CD19 T cells with a defined phenotype.
We generated universal antiCD19-CAR T cells, disrupting the B2M and TRAC genes in CAR T cells to avoid both graft versus host and host versus graft reactions, and then edited cells were isolated according to their phenotype, to obtain cells with a memory phenotype that increase the persistence, proliferation, and antitumor effect in vivo. Functionally, these cells are able to eliminate tumoral cells in vitro with the same efficacy as non-edited CAR T cells, and they do not seem to respond against allogeneic cells as cells with both HLA-I and TCR complexes do.
The combination of gene editing of CAR T lymphocytes by TCR and B2M loci disruption, with the isolation of specific less-differentiated T subsets is an in vitro procedure developed with the translational objective of improving the clinical results of CAR T cells infusions in patients with refractory or relapsing B neoplasms.