AUTHOR=Lum Lawrence G. , Thakur Archana , Elhakiem Abdalla , Alameer Lena , Dinning Emily , Huang Manley 

TITLE=Anti-CS1 × Anti-CD3 Bispecific Antibody (BiAb)-Armed Anti-CD3 Activated T Cells (CS1-BATs) Kill CS1+ Myeloma Cells and Release Type-1 Cytokines

JOURNAL=Frontiers in Oncology

VOLUME=10

YEAR=2020

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2020.00544

DOI=10.3389/fonc.2020.00544

ISSN=2234-943X

ABSTRACT=<p><bold>Background:</bold> Multiple myeloma (MM) remains incurable despite <italic>significant</italic> advances in chemotherapy, targeted therapies, and immunotherapy. Bispecific antibody (BiAb)-armed activated T cells (BATs) have been developed for targeting and treatment of solid and hematologic malignancies. BATs are serial killers of tumor cells, secrete Th<sub>1</sub> cytokines, and induce adaptive cellular and humoral immune responses in patients (pts). This study provides preclinical data using bispecific anti-CS1 (elotuzumab) × anti-CD3 (OKT3) antibody (CS1Bi)-armed activated T cells (CS1- BATs) that provide a strong rationale for applying CS1-BATs to pts with MM.</p><p><bold>Methods:</bold> CS1-BATs and unarmed activated T cells (ATC) were incubated with MM cell targets at various effector to target ratios (E:T) in a quantitative flow cytometry-based assay to determine the degree of cell loss relative to target cells incubated without ATC. ATC from up to 8 normal donors were armed with various concentrations of CS1 BiAb and tested against 5 myeloma cells lines for CS1-BATs-mediated killing and release of Th<sub>1</sub> cytokines, chemokines and granzyme B.</p><p><bold>Results:</bold> CS1-BATs from normal donors killed each of 5 MM cell lines proportional to E:T ratios ranging between 1:1 and 10:1 and arming concentrations of 12.5 to 50 ng/million ATC, which was accompanied by release of Th<sub>1</sub> cytokines, chemokines and granzyme B. CS1-BATs prepared from MM pts' peripheral blood mononuclear cells (PBMC) showed increasing cytotoxicity and T cell expansion over time against ARH77 MM cells. The optimal arming dose of CS1Bi is 50 ng/10<sup>6</sup> ATC.</p><p><bold>Conclusions:</bold> These data demonstrate the therapeutic potential of CS1-BATs-mediated cytotoxicity and Th<sub>1</sub> cytokines release at low E:T and support advancing their clinical development in pts with MM.</p>