Memory T Cells Masquerading as Naïve Cells: Implications on Adoptive T Cell Immunotherapy

Abstract 1471 Differentiation stage of adoptively transferred T cells has a critical impact on the success of immune-gene therapy. Ex vivo T cell manipulation often induces their terminal differentiation, resulting in poor persistence and activity of transferred cells. We previously showed that costimulation and culture with γ-chain cytokines generates gene modified T cells with a functional central memory (TCM) phenotype superior to effector/effector memory (TEM) counterparts for expansion potential and antitumor activity. Here we investigated the consequence of initial targeting of selected T cell subpopulations. We activated and efficiently transduced FACS-sorted T Naïve (TN), TCM and TEM cells by viral vectors. In contrast to TCM and TEM, TN had a greater expansion potential and more sustained expression of IL7-Rα. Strikingly, manipulation of TN resulted in a predominant population of post-mitotic lymphocytes expressing the CD45RA+CD62L+CCR7+ naïve phenotype. These cells expressed markers common to early differentiated cells (CD27, CD28, CD127 and Bcl2) and markers proper of memory lymphocytes (CD45RO, CD122 and CXCR3). Post-mitotic TN produced lower levels of IFNg and Granzyme A, expressed higher levels of c-Kit and CXCR4, and lower levels of HLA-DR, CCR5 and PD1 than memory counterparts. To verify their self-renewal and differentiation potential upon antigen stimulations, TN, TCM and TEM were transduced to express a WT1-specific TCR. Upon multiple stimulations TN expanded at higher numbers and were unique in the ability to generate a mixed population of CD127+/CD127- lymphocytes. When infused in immunodeficient mice, transduced TN proved higher engraftment and persistence potential than memory counterparts, reconstituted a mixed CD45RA±CD62L± phenotype and were significantly higher xenoreactive. These results suggest that gene transfer into TN lymphocytes might increase the efficacy of cancer immunotherapy. Disclosures: Bonini: MolMed: Consultancy.