Ullah, Suriyea Yasmin; (2025) Combining ROR1 T-cell engagers with PD-1/PD-L1 blockade to enhance anti-tumour activity towards ROR1 positive solid tumours. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

T-cell engagers (TCEs) direct CD3+ T lymphocytes towards targeted tumour-associated antigens (TAA) to induce T-cell mediated cytotoxicity of tumour cells. There are 12 TCEs approved or in late-stage review by the FDA and/or EMA; however, multiple barriers remain in effectively treating solid tumours, including immunosuppression mediated by inhibitory checkpoint pathways. This challenge can be mitigated with checkpoint blockade therapy. ROR1 is a TAA and a ROR1 bispecific TCE (ROR1 BiTE) demonstrated efficacy in various solid malignancies. It was hypothesised that combining ROR1 TCEs with checkpoint blockade (e.g., PD-1 blockade, pembrolizumab) would improve tumour killing via a synergistic effect. The hypothesis was tested using two approaches: 1) a combination of the ROR1 BiTE with an intact pembrolizumab monoclonal antibody; and 2) an in-cis approach where an anti-ROR1, an anti-CD3, and a pembrolizumab Fab moiety were combined into one tri-specific molecule, named a PD-1 tribody (TBD). Notably, TBDs possess a higher molecular weight compared to BiTEs (~100 kDa vs. ~55 kDa, respectively). The tumour-killing capacity and mechanism-of-action were assessed via in vitro co-cultures with solid tumour cell lines and T-cells. Pilot in vivo mice experiments were undertaken to assess half-life and tumour regression. Results showed that a low T-cell to tumour cell ratio, combined with an extended incubation period, closely recapitulated the immunosuppressive tumour microenvironment. Under these conditions, the ROR1 TCEs + PD-1 blockade significantly improved tumour killing compared to their respective PD-1 negative controls and pembrolizumab-only conditions, indicating a synergistic effect. Improved tumour killing was due to the significant increase of long-term anti-tumour memory T-cells, and increased levels of IL-2, IFN-γ and granzyme B. In vivo mouse studies showed that the TBD had a higher half-life than the ROR1 BiTE. Lastly, ROR1 BiTE, ROR1 BiTE + pembrolizumab and PD-1 TBD impeded tumour growth in a breast cancer tumour mouse model. Collectively, these results are consistent with the hypothesis and the TBD represents a promising and alternative approach to combination treatment. Further in vivo studies are required to prove the pharmacokinetic and safety advantages of the PD-1 TBD.

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