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'NealJulie K RitcheyMatthew L CooperJessica NiswongerL Sofía GonzálezEmily StreetMichael P RettigSusan W GladneyLeah GehrsRamzi AbboudJulie L PriorGabriel J HaasReyka G JayasingheLi DingArmin GhobadiRavi VijJohn F DiPersioPublished in: Leukemia (2022)
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.
Keyphrases
- newly diagnosed
- multiple myeloma
- induced apoptosis
- cell cycle arrest
- end stage renal disease
- minimally invasive
- ejection fraction
- poor prognosis
- cancer therapy
- drug delivery
- mouse model
- mesenchymal stem cells
- signaling pathway
- cell proliferation
- oxidative stress
- small molecule
- long non coding rna
- electronic health record
- smoking cessation
- artificial intelligence
- patient reported