Expression of mutant STING enables immune activation by DMXAA in STING-silenced cancer cells
A promising approach for cancer immunotherapy involves activation of stimulator of interferon genes (STING), a cytosolic sensor that can detect damaged DNA present in cancer cells. STING activation induces cytokine production, intratumoral CD8+ T cell infiltration, and antitumor T cell responses. While this approach represents a promising immunotherapeutic strategy, numerous cancer types, including Merkel cell carcinoma (MCC), are not candidates due to STING silencing.
To enable immunotherapy for STING-silenced cancers, scientists at the University of Pennsylvania developed a method to express a mutant human STING variant within the tumor, and subsequent activation using the well-characterized mouse STING agonist, DMXAA.
Activation of mutant STING in cultured MCC cells using DMXAA enhances antitumor cytokine production, co-cultured T-cell activation, and MCC cell death. In vivo, mutant STING can be delivered directly to the tumor by adeno-associated virus (AAV) vectors or other gene delivery modalities. DMXAA does not stimulate normal human STING, and therefore, limits activation to the mutant-expressing tumor, preventing pathology associated with STING activation in healthy cells.
Tumor-specific STING activation also causes rapid and robust induction of cell death in MCCs as well as several other STING-silenced cancers. The tumor antigens and DNA released by dying cancer cells have the potential to amplify innate immune response and activate antitumor adaptive immune responses. Therefore, targeted activation of STING in tumor cells holds great therapeutic promise for the treatment of MCC and many other STING-silenced cancers.
Figure: DMXAA stimulation of a human MCC cell line (MKL-1) stably expressing mutant STING leads to robust induction of interferon and proinflammatory chemokine and cytokine expression. No response to DMXAA was observed in a control line stably expressing RFP or in either line in response to DMSO. DAPI represents cell nuclei.
Treatment of STING-silenced cancers, including Merkel cell carcinoma, colorectal carcinoma, and pancreatic cancer
- DMXAA is inactive against human STING, avoiding inflammation associated with overstimulation of STING in healthy human cells
- Strategy may be combined with other immune-checkpoint therapies
- Mutant STING can be delivered by adeno-associated virus (AAV) or other gene delivery modalities
Stage of Development:
- Validated method in vitro using AAV vectors to deliver mutant STING
- Demonstrated targeting of human cells expressing mutant STING by DMXAA in vivo
Provisional patent application filed
Docket # 19-8751