Journal Article

1037 Adoptive cell therapy with genetically engineered t-cells for epithelial ovarian cancer

Maffia, Maria Chiara, Bergamini, Alice, Pavone, Giacomo, Rabaiotti, Emanuela, Ruggiero, Eliana, Doglioni, Claudio, Prodeus, Aaron, Mangili, Giorgia, Schultes, Birgit, Sabini, Carlotta, Candotti, Giorgio, Candiani, Massimo, Tassi, Elena, Magnani, Zulma, Bocciolone, Luca, Sant’angelo, Miriam, Bonini, Chiara, Parretta, Mariangela, Cioffi, Raffaella

2024

Overview

Introduction/BackgroundThe observed clinical benefit of immunotherapy in EOC is limited. During cancer progression, tumor-specific T cells display increased expression of inhibitory receptors (IRs), causing their functional exhaustion. We hypothesize that protecting tumor-specific T cells from immunosuppression by gene editing approaches aimed at reducing IRs expression might maximize their therapeutic potential.MethodologyWe characterized by flow cytometry EOC cell lines and patients’ ascites-derived primary cultures (PC) to evaluate their expression of selected tumor-associated antigens and IR ligands. Considering antigen expression, we selected a HLA-A*02:01-restricted WT1-specific TCR from our library (HD1-TCR) and tested different T-cell products engineered to express HD1-TCR and also harboring gene disruption ( HD1-IRKO) of distinct IRs (2B4, TIM3, LAG3).To functionally characterize the putative advantage provided by IR disruption on the anti-tumor efficacy of engineered T cells, HD1-TCR and HD1-IRKO gene-edited T cells were challenged with WT-1pos HLA-A*02:01pos (or HLA-A*02:01neg, as control) cancer cell lines, PC and tumor derived organoids (PDOs). We evaluated cytokine secretion, T cell activation and apoptosis.ResultsWe observed high expression of WT-1 while IR ligands (IR-L) were expressed by a low percentage of tumor cells and increased by IFNγ exposure. After co-culture with tumor cells, the different T-cell products displayed similar killing of cell lines, while increased killing was observed with HD1-IRKO cells against EOC primary cultures expressing IR-Ls. In particular, TIM-3KO HD1-TCR edited T cells displayed more potent killing of PC expressing TIM-3 IR ligands compared to the other T cell products. Additionally, upon co-culture with HLA-matched PDOs, both TIM-3KO and LAG-3KO HD1-TCR T cells showed an increased induction of cancer cell apoptosis compared to IR-competent cells.ConclusionHD1-IRKO T-cell products appear superior to HD1-TCR IR-competent counterparts in killing WT-1pos HLA-A*02:01 cancer cells. The most consistent advantages were observed with TIM-3KO HD1-TCR.DisclosuresReceipt of grants/research supports from Intellia Therapeutics.Receipt of grants/research supports from GSK, MSD/Astrazeneca, Pharmamar

• Publisher: BMJ Publishing Group Ltd,Elsevier Inc,Elsevier Limited
• Subject: Apoptosis / Cancer / Ligands / Lymphocytes / Poster and E-Posters