CS1 CAR-T targeting the distal domain of CS1 (SLAMF7) shows efficacy in high tumor burden myeloma model despite fratricide of CD8+CS1 expressing CAR-T cells

Julie O’Neal, Julie K. Ritchey, Matthew L. Cooper, Jessica Niswonger, L. Sofía González, Emily Street, Michael P. Rettig, Susan W. Gladney, Leah Gehrs, Ramzi Abboud, Julie L. Prior, Gabriel J. Haas, Reyka G. Jayasinghe, Li Ding, Armin Ghobadi, Ravi Vij, John F. DiPersio

Research output: Contribution to journalArticlepeer-review

Abstract

Despite improvement in treatment options for myeloma patients, including targeted immunotherapies, multiple myeloma remains a mostly incurable malignancy. High CS1 (SLAMF7) expression on myeloma cells and limited expression on normal cells makes it a promising target for CAR-T therapy. The CS1 protein has two extracellular domains – the distal Variable (V) domain and the proximal Constant 2 (C2) domain. We generated and tested CS1-CAR-T targeting the V domain of CS1 (Luc90-CS1-CAR-T) and demonstrated anti-myeloma killing in vitro and in vivo using two mouse models. Since fratricide of CD8 + cells occurred during production, we generated fratricide resistant CS1 deficient Luc90- CS1- CAR-T (ΔCS1-Luc90- CS1- CAR-T). This led to protection of CD8 + cells in the CAR-T cultures, but had no impact on efficacy. Our data demonstrate targeting the distal V domain of CS1 could be an effective CAR-T treatment for myeloma patients and deletion of CS1 in clinical production did not provide an added benefit using in vivo immunodeficient NSG preclinical models.

Original languageEnglish
Pages (from-to)1625-1634
Number of pages10
JournalLeukemia
Volume36
Issue number6
DOIs
StatePublished - Jun 2022

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