Abstract 477P
Background
Activation of the cGAS-cGAMP-STING pathway is essential for sensing foreign DNA from pathogens or self-DNA from dying cancer cells. This pathway is critical for the innate immune response and directs the full efficacy of cancer therapeutics, including checkpoint and PARP inhibitors, radiotherapy, and CAR T-cells. Intense efforts have focused on triggering this pathway with cGAMP analogs, which are small-molecule activators of STING. However, recent reports show that STING is downregulated by promoter methylation in various cancers. Furthermore, T-cells activated by cGAMP undergo apoptosis, which limits the efficacy of T-cells based tumor eradication. Indeed, emerging studies suggest that STING activation in myeloid cells is most critical for maximal anti-cancer efficacy of therapeutics.
Methods
Oncogenic silencing of STING expression is generally considered as “undruggable”. At MiNA Therapeutics, we utilized our proprietary platform of RNA activation (RNAa) to design small activating RNA (saRNA) oligos that restore the transcription of the STING gene to levels that are necessary for eliciting anti-tumor effect either alone or in combination with other drugs, including cGAMP analogs.
Results
The clinical lead, saSTING increases in vitro STING expression in the range of 4 to 11-fold in multiple cell lines, and the upregulation is sustained for at least a week. The increase in STING expression is also confirmed at the protein level and an RNAseq experiment validated the functional increase of genes downstream of the STING pathway. The clinical development candidate, MTL-STING, encapsulates saSTING in NOV340 liposomes for intratumoral administration. NOV340 liposomes have previously been clinically validated to efficiently deliver saRNA to myeloid cells, which is the critical cellular subset to benefit from STING activation from an anti-tumor perspective. In the first preclinical proof of concept study, the murine surrogate of MTL-STING combined with PD-1 antibody resulted in early inhibition of tumor growth and was the only group to regress tumor below pre-treatment sizes.
Conclusions
MTL-STING is expected to enter phase I in 2023.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
MiNA Therapeutics.
Funding
MiNA Therapeutics.
Disclosure
C.P. Tan, B.M. Ryan, V. Gomez, R. Hodgson, L. Sinigaglia, G. Pizza, K.S. Stathaki, S. Hegre: Financial Interests, Institutional, Full or part-time Employment: MiNA Therapeutics. R. Habib, N. Habib: Financial Interests, Institutional, Leadership Role: MiNA Therapeutics. J. Rossi: Financial Interests, Institutional, Advisory Role: MiNA Therapeutics.