Paredes Moscosso, Solange Rosa; (2017) ROR1 as a target for cancer immunotherapy. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Receptor tyrosine-kinase like orphan receptor (ROR1) is a member of the tyrosine kinase family. Importantly, ROR1 is absent in healthy, critical tissue but overexpressed in various solid and haematological malignancies, including Chronic Lymphocytic Leukaemia (CLL). Moreover, recent studies suggest ROR1 is expressed on cancer stem cell-like cells (CSCs). The overriding aim of this study was therefore to combine the unique features of ROR1 with the exquisite specificity/therapeutic potential of monoclonal antibodies (MAbs) and/or their derivatives. To this end, our group generated a rat hybridoma library and screened >150 anti-ROR1+ clones. I then cloned 16 of our novel antibodies to human IgG1, kappa constant regions, of which 12 recognised ROR1 on different cell types. Based on functional/characterisation data, it was identified that clone SA1 exhibited significant CDC activity on primary CLL cells, whilst clone F was the only MAb able to bind the Frizzled domain of ROR1. Further investigation, however, revealed clone SA1 bound non-specifically to ROR1- cells. Therefore, my investigation focused instead on clone F, which was developed in parallel as a bispecific T-cell engager (BiTE) within our group. Having shown F BiTE elicited potent and specific cytotoxicity of ROR1+ cells on various solid cancer cell lines, including pancreatic cancer (PaCa), ROR1 BiTE was tested on PaCa cell line-derived CSCs using an in vitro tumoursphere model. Immunocytochemistry data confirmed specific elimination of cells expressing both CSC biomarkers and ROR1. As a whole, ROR1 MAb-based immunotherapy, particularly using BiTEs, seems to not only target ROR1+ cells present in the bulk of the tumour but, crucially, it also eliminates ROR1+ CSC subsets in PaCa. This approach represents a relevant and much needed addition to the current options for cancer treatment. Further preclinical and clinical studies will ultimately reveal the true therapeutic potential of ROR1 BiTEs alone and in combination.

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