1069 OX40/CD137 dual agonism potentiates anti-tumour immunity by driving functional reprogramming and instability of regulatory T (T_reg) cells

Background

Immunomodulatory therapies targeting the effector T (T_eff) cell inhibitory signalling pathways PD-1/PD-L1 and CTLA-4 induce striking objective clinical responses in patients with certain cancer types, but are ineffective at inducing durable responses in a majority of patients.¹ CD4⁺ regulatory T (T_reg) cells, dependent on the transcription factor Foxp3, powerfully suppress T_eff cells and prevent immune-mediated rejection of tumours.^2,3 Low T_reg to T_eff cell ratios in humans are associated with favourable survival in multiple cancer types and murine models show that ablation of T_reg cells results in activation of CD4⁺ or CD8⁺ T_eff cells and rejection of tumours. T_reg cells therefore represent an attractive target for immunostimulatory therapy. FS120 is a novel tetravalent bispecific antibody targeting OX40 and CD137 (4-1BB), both tumour necrosis factor (TNF) receptor superfamily members which are expressed on activated and memory T-cell subsets, T_reg and NK cells. Preclinically, an FS120 mouse surrogate antibody has demonstrated significant anti-tumour immunity in syngeneic tumour models.⁴ FS120 is currently being evaluated in a Phase 1 trial (NCT04648202) which aims to identify a well-tolerated and pharmacologically active dose of FS120 for exploration as monotherapy, and in combination with anti-PD-1.⁵

Methods

We elucidate mechanisms of action of OX40/CD137 dual agonist therapy with a mouse-specific FS120 surrogate molecule, using syngeneic tumour models, in conjunction with genetic T_reg lineage tracing, high-dimensional flow cytometry, transcriptome analyses and functional studies.

Results

FS120 treatment invokes profound anti-tumour immune responses resulting in substantially reduced growth of syngeneic MC38 colorectal adenocarcinoma tumours. FS120 treatment induces two distinct phenomena within tumours: 1) T_reg lineage instability, marked by accumulation of ‘ex-T_reg’ cells from T_reg progenitors, which gain the ability to express IFN-γ and TNF-a, and 2) T_reg functional reprogramming, where Foxp3+ T_reg cells are induced to produce effector cytokines IFN-γ and TNF-a. The ability of FS120 surrogate to drive T_reg instability and functional reprogramming are not shared by anti-PD-1 therapy, suggesting a mode of therapeutic efficacy distinct from anti-PD-1. Accordingly, FS120 treatment synergises with PD-1 checkpoint blockade therapy to induce profound anti-tumour responses.

Conclusions

Treatment with FS120 surrogate causes lineage instability and functional reprogramming of T_reg cells, resulting in their ability to produce effector cytokines and drive tumour regression. This mode of action is distinct from anti-PD-1 therapy. These findings support a combination therapy approach exploiting the distinct anti-tumour immune activities of FS120 and anti-PD-1 in cancer patients.

References

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