Engineering Immune Cells for in vivo Secretion of Tumor-Specific T Cell-Redirecting Bispecific Antibodies

Abstract

Immunotherapeutic approaches based on the redirection of T cell activity toward tumor cells are actively being investigated. The impressive clinical success of the continuously intravenously infused T cell-redirecting bispecific antibody (T-bsAb) blinatumomab (anti-CD19 x anti-CD3), and of engineered T cells expressing anti-CD19 chimeric antigen receptors (CAR-T cells) in hematological malignancies, has led to renewed interest in a novel cancer immunotherapy strategy that combines features of antibody- and cell-based therapies. This emerging approach is based on the endogenous secretion of T-bsAbs by engineered T cells (STAb-T cells). Adoptive transfer of genetically modified STAb-T cells has demonstrated potent anti-tumor activity in both solid tumor and hematologic preclinical xenograft models. We review here the potential benefits of the STAb-T strategy over similar approaches currently being used in clinic, and we discuss the potential combination of this promising strategy with the well-established CAR-T cell approach.

Keywords: T cell-redirection; bispecific antibodies; cancer immunotherapy; chimeric antigen receptors; in situ secretion.

Figure 1

Schematic diagram depicting cell-based T cell-redirecting strategies for cancer immunotherapy. Engineered T cells (orange cells) expressing second-generation scFv-based chimeric antigen receptors (CAR-T cells), and engineered T cells secreting T cell-redirecting bispecific antibodies (STAb-T cells) in BiTE format. The tumor-associated antigen (TAA)-specific scFv is displayed in light green and the anti-CD3ζ scFv in magenta. Red arrows and dots represent delivery of the “lethal hit” to tumor cells (green cells) by CAR- or BiTE-activated T cells: engineered and/o bystander non-engineered tumor infiltrating T lymphocytes (TILs, gray cells). In engineered T cells expressing second generation CARs, a single molecular interaction provides both signals 1 and 2, whereas TAA-specific BiTEs do not provide co-stimulatory signaling to T cells. Topology observed in CAR-mediated and BiTE-mediated immunological synapse (IS): the CAR-mediated IS shows a rather disordered structure whereas the BiTE-mediated IS displays a well-organized canonical “bull's eye” structure.