Th133 - CAR T-Cell Therapy Targeting CD84 Alone or in Combination with CD19 for the Treatment of B-Cell Malignancies

Lorena Pérez-Amill – Fundació de Recerca Clínic Barcelona-Institut D’Investigacions Biomèdiques August Pi i Sunyer. Barcelona, Spain; Sergio Peña – Fundació de Recerca Clínic Barcelona-Institut D’Investigacions Biomèdiques August Pi i Sunyer. Barcelona, Spain; Mercedes Armand-Ugon – Fundació de Recerca Clínic Barcelona-Institut D’Investigacions Biomèdiques August Pi i Sunyer. Barcelona, Spain; Maria Val-Casals – Fundació de Recerca Clínic Barcelona-Institut D’Investigacions Biomèdiques August Pi i Sunyer. Barcelona, Spain; Julio Delgado – Hospital Clínic de Barcelona, Spain; Juan Gonzalo Correa – Hospital Clínic de Barcelona, Spain; Nela Klein-González – Fundació de Recerca Clínic Barcelona-Institut D’Investigacions Biomèdiques August Pi i Sunyer. Barcelona, Spain; Claudio Santos – Gyala Therapeutics S.L., Barcelona, Spain; Manel Juan – Hospital Clínic de Barcelona, Spain

Abstract Text: Most B-cell acute lymphoblastic leukaemia (B-ALL) patients (>80%) achieve complete remission with CD19-directed CART cell therapy, but negative or low-antigen expressing leukemic cells may lead to relapse. In contrast, chronic lymphocytic leukaemia (CLL) patients have significantly lower response rates with this type of treatment. CD84 (SLAMF5) is an immunoreceptor overexpressed in B-cell malignancies that emerges as a novel target for their treatment.
A CD84-directed second-generation CART cell (CART84) was engineered (anti-CD84scFv-CD8αTM-4-1BB-CD3) and proved to be cytotoxic towards aggressive B-cell lymphoma cell lines (Ramos) and B-ALL (NALM-6) in vitro. Moreover, CART84 controlled Ramos tumour progression and increased survival of CART84-treated NSG mice compared to the control group.
We designed a CD19 and CD84 dual CAR T cell (CD19/CD84-DUAL1) using an “AND” strategy. C164S and C181S mutations were introduced to prevent dimerization of the hinge domains (CD19/CD84-DUAL1m). Subsequently, two different CD19 and CD84 dual CART cells were engineered employing an “IF BETTER” strategy (CD19/CD84-DUAL2m: anti-CD19scFv-4-1BB-CD3/anti-CD84scFv-4-1BB; CD19/CD84-DUAL3m: anti-CD19scFv-4-1BB-CD3-anti-CD84scFv-CD28) in an attempt of improving the efficacy of CD19-directed CART cells for CD19low B-ALL relapses. CD19/CD84-DUAL1m, CD19/CD84-DUAL2m and CD19/CD84-DUAL3m specifically killed CD19+/CD84+ NALM-6, but not CD19-/CD84+ MOLM-13 (acute myeloid leukaemia) cells in vitro.
In conclusion, CART84 cells are highly cytotoxic towards aggressive B-cell lymphoma both in vitro and in vivo, thus supporting the t use of CD84-targeted CAR T cells to treat B-cell malignancies. Furthermore, CD19/CD84-directed dual CAR T cells could be used to rescue CD19low B-ALL relapses after CD19-directed CART cell therapy.