E7766

Using STING deficient mice, and CRISPR/Cas9 gene editing, we demonstrated that STS clearance following STING therapy was dependent on host STING and not tumor-intrinsic STING pathway functionality. E7766 represents a promising candidate able to remodel the TME of murine STS tumors toward an inflamed phenotype independent of tumor-intrinsic STING functionality, and should be considered for potential translation in STS treatment.

In total, E7766 generated on-target pharmacodynamic effects in patients with solid tumors. Further exploration in a homogeneous patient population is necessary to assess efficacy.

P1, N=24, Terminated, Eisai Inc. | Completed --> Terminated; The study was terminated earlier due to a business decision; which was unrelated to safety. In addition, there was no clinical activity data that informed the decision.

We have shown that E7766 mediated STING activation is a promising immunotherapeutic strategy for UPS in our murine model. E7766 therapy can induce tumor clearance and adaptive immune protection against UPS re-challenge. Excitingly, E7766 STING therapy can also sensitize our model to anti-PD1 ICB therapy.

Herein, we demonstrate that eribulin is unique from paclitaxel in its ability to enhance expression of the immunogenic cytokine interferon beta (IFNβ) in combination with STING agonists in both immune cells and TNBC models, including profound synergism with ADU-S100 and E7766, which are currently undergoing clinical trials. We further interrogated the combination of eribulin with ADU-S100 in the MMTV-PyVT spontaneous murine mammary tumor model where we observed significant antitumor efficacy with combination treatment. Together, our findings demonstrate that microtubule targeted chemotherapeutics have distinct immunological effects and that eribulin's ability to enhance innate immune sensing pathways supports its use in combination with immunotherapies, such as STING agonists, for the more effective treatment of TNBC and other malignancies.

In this study, we characterized in vitro and in vivo antitumor effects of E7766, a macrocyle-bridged STING agonist, via intravesical instillation in two syngeneic orthotopic murine NMIBC tumor models resistant to therapeutic doses of BCG and anti-PD-1 agents...These results revealed a previously unrecognized role of schweinfurthins in trans-Golgi-network trafficking and linked mechanistically this cellular effect with mTOR/AKT signaling and with cancer cell survival and growth. Our findings suggest a new opportunity to modulate oncogenic signaling by interfering with TGN trafficking to treat mTOR/AKT-dependent human cancers.

These preclinical studies demonstrated a potent anti-tumor activity and induction of tumor-specific memory response by intravesically administered STING agonist E7766 in orthotopic murine models for BCG- and anti-PD1-insensitive NMIBC. A clinical study for intravesical E7766 in NMIBC patients has been initiated (NCT04109092) in North America.