METTL3 IO abstract for SITC

STC-15, an oral small molecule inhibitor of the RNA methyltransferase METTL3, inhibits tumour growth through activation of anti-cancer immune responses and synergises with immune checkpoint blockade

Authors: Yaara Ofir-Rosenfeld1, Lina VasiliauskaitÄ—1, Claire Saunders1*, Alexandra Sapetschnig1, Georgia Tsagkogeorga1,2, Mark Albertella1+, Marie Carkill3, Jezrom Self-Fordham3, Josefin-Beate Holz1, Oliver Rausch1 and Jerry McMahon1

1Storm Therapeutics Ltd, Cambridge, UK

2Milner Therapeutics Institute, University of Cambridge, Cambridge, UK

3Charles River, Portishead, UK

*Current address: UCL Cancer Institute, London, UK

+Current address: Oncology R&D, AstraZeneca, Cambridge UK

Background

METTL3 is an RNA methyltransferase responsible for the deposition of N-6-methyladenosine (m6A) modification on mRNA and long non-coding RNA (lncRNA) transcripts, to regulate their stability, splicing, transport and translation. Small molecule inhibitors of METTL3 catalytic activity have previously demonstrated direct anti-tumour efficacy in models of acute myeloid leukemia (AML). Here we present pre-clinical data showing that STC-15, an orally bioavailable small molecule inhibitor of METTL3, restrains cancer growth and induces anti-cancer immunity.

Materials & Methods

To characterise transcriptomic changes following METTL3 inhibition, RNA sequencing studies were performed on several cancer cell lines treated with STC-15. Induction of specific genes was validated by qPCR and Western Blots. The functional consequence of the upregulation of innate immune pathways was investigated in vitro using a co-culture system of SKOV3 ovarian cancer cells and human peripheral blood mononuclear cells (PBMC) or purified primary CD8+ T-cells, and animal studies using subcutaneous A20 and MC38 mouse syngeneic tumour models.

Results

Inhibition of METTL3 by STC-15 in cancer cell lines leads to prominent upregulation of genes associated with innate immunity, including type-I and type-III IFNs, as well as many interferon stimulated genes. Cells treated with STC-15 accumulated double-stranded RNA suggesting that activation of IFN signalling is triggered by innate pattern recognition sensors.

In an in vitro co-culture system, STC-15 demonstrated strong and dose-dependent enhancement of PBMC-mediated killing of cancer cells. Similar results were obtained when replacing PBMC with purified CD8+ T-cells.

In MC38 colorectal and A20 lymphoma syngeneic models, oral treatment of immune-competent tumour bearing mice with STC-15 significantly inhibited tumour growth. In vivo depletion of CD8+ T-cells abrogated the response to STC-15.

Combination of STC-15 with anti-PD1 antibody resulted in tumour regression in both models, with mice remaining tumour-free long after treatment ceased. When regressed mice from the A20 model were re-challenged with a new batch of A20 cells, no new tumour growth was observed, further demonstrating the induction of durable anti-tumour immunity.

Conclusions

In pre-clinical cancer models, STC-15 treatment results in activation of innate immune pathways, inhibits tumour growth via activation of CD8+ T-cell mediated tumour cell killing, and enhances the anti-tumour properties of anti-PD1 therapy to generate a durable anti-tumour immune response. These data provide the rationale for the development of STC-15 both as monotherapy and in combination with checkpoint inhibition for the treatment of solid tumour malignancies. A Phase I, First-in-Human clinical trial is planned to begin in 2022.

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