An ROR1 bi-specific T-cell engager provides effective targeting and cytotoxicity against a range of solid tumors

Abstract

We have developed a humanized bi-specific T-cell engager (BiTE) targeting receptor tyrosine kinase-like orphan receptor 1 (ROR1), a cell surface antigen present on a range of malignancies and cancer-initiating cells. Focusing initially on pancreatic cancer, we demonstrated that our ROR1 BiTE results in T cell mediated and antigen-specific cytotoxicity against ROR1-expressing pancreatic cancer cell lines in vitro at exceedingly low concentrations (0.1 ng/mL) and low effector to target ratios. Our BiTE prevented engraftment of pancreatic tumor xenografts in murine models and reduced the size of established subcutaneous tumors by at least 3-fold. To validate its wider therapeutic potential, we next demonstrated significant cytotoxicity against ovarian cancer in an in vitro and in vivo setting and T-cell-mediated killing of a range of histologically distinct solid tumor cell lines. Overall, our ROR1 BiTE represents a promising immunotherapy approach, because of its ability to target a broad range of malignancies, many with significant unmet therapeutic needs.

Targeting Wnt signaling pseudokinases in hematological cancers

“…On the other hand, given the promising results in clinical trials of CD19 CAR‐T cells and Blinatumomab, a bi‐specific T‐cell engager (BiTE) targeting CD19 in B‐cell malignancies with poor prognosis, ROR1 targeted CAR‐T cells and BiTE have been developed, offering the advantage of low off‐target cytotoxicity due to restricted expression of ROR1 mainly on cancer cells. ROR1 CAR‐T cells were able to lyse primary ROR1 + CLL and MCL cells, but not normal mature B‐cells in vitro , whereas ROR1‐BiTE has shown efficient cytotoxicity in preclinical models by preventing the engraftment of pancreatic and ovarian cancer cells in xenograft models . This provides a new platform for T‐cell mediated targeting of ROR1‐positive tumors that warrants further clinical investigations.…”

“…ROR1 CAR-T cells were able to lyse primary ROR1 + CLL and MCL cells, but not normal mature B-cells in vitro, 47 whereas ROR1-BiTE has shown efficient cytotoxicity in preclinical models by preventing the engraftment of pancreatic and ovarian cancer cells in xenograft models. 48 This provides a new platform for T-cell mediated targeting of ROR1-positive tumors that warrants further clinical investigations.…”

Ibrutinib enhances the efficacy of ROR1 bispecific T cell engager mediated cytotoxicity in chronic lymphocytic leukaemia

“…We have generated a fully humanized ROR1 bispecific T cell engager (BiTE), which utilizes the inherent cytotoxic potential of polyclonal resident T cells without the need for ex vivo expansion or genetic manipulation. Efficacy has been demonstrated in a range of preclinical solid tumour models (Gohil et al, 2017) and herein we assess its potential to target CLL.BiTEs are small, 55 kDa immunotherapies composed of two antibody-derived single chain variable fragments (scFv) linked in tandem with a flexible linker. One scFv binds to the target antigen on tumour cells, while the second binds to CD3 on effector T cells, bringing both into close proximity γ α ª…”

Adoptive immunotherapy with CAR modified T cells in cancer current landscape and future perspectives

“…CLL, mantle cell lymphoma, B-cell ALL) and numerous types of solid tumors (37)(38)(39)(40). Due to its high-level surface expression as well as to its crucial role in tumor cell proliferation, survival, and metastasis, a number of pharmacological agents targeting ROR1 are under development, such as humanized monoclonal antibodies, small molecule inhibitors, bispecific T-cell engagers (BiTE) and anti-ROR1 CAR T cells (41)(42)(43). ROR1-targeted T cells have demonstrated to generate cytotoxicity against human ROR1 positive B cell malignancies in preclinical studies (39), without causing overt cytotoxicity in nonhuman primates (44).…”