Abstract 751P
Background
The CXCR3 chemokine system plays a critical role in generating productive anti-tumor immune response at multiple steps. CXCR3 upregulation serves as an important driver for the recruitment of anti-tumorigenic effector cells including CD8+ T cells, NK cells, cDC1s, and Th1 cells from the blood into the tumor microenvironment (TME). Within tumor proximal lymph nodes, efficient CXCR3 signaling contributes to proper CD4 and CD8 T cell positioning to promote the differentiation and expansion of tumor antigen specific T cells. Maintenance and promotion of CXCR3-dependent mechanisms have the potential to be a new emerging immunotherapy strategy that goes beyond checkpoint blockade, by facilitating the ability of effector cells to efficiently access the TME and better carry out their anti-tumor function.
Methods
We report preclinical in vitro data on positive allosteric modulation of CXCR and in vivo pharmacodynamic and efficacy data in tumor models for our optimized lead candidate SG-3-06686.
Results
SG-3-06686 is a positive allosteric modulator of CXCR3-dependent signaling and chemotaxis. Mechanistically, SG-3-06686 enhances responsiveness of activated human primary T cells to all three CXCR3 ligands (ie. CXCL9, 10, and 11). A single IV dose of SG-3-06686 in naïve mice amplifies CXCR3-dependent ex vivo T cell migration up to 24h after administration. We have further shown that SG-3-06686 improves anti-tumor activity in multiple syngeneic tumor models alone and in combination with different cancer therapies via promotion of effector cell mobilization in lymphoid tissues and TME. Based on in vitro safety pharmacology and health monitoring in mouse tumor models, we anticipate SG-3-06686 to be well tolerated.
Conclusions
CXCR3 pathway modulation is a well validated and exciting immunotherapy approach to potentially enhance effector cell recruitment and amplify anti-tumor activity. Additionally, CXCR3 ligands CXCL9 and CXL10 are upregulated in response to certain established cancer treatments such as radiotherapy and chemotherapy and contribute to their efficacy, providing a strong rationale for combination strategy with SG-3-06686.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Second Genome Inc.
Funding
Second Genome Inc.
Disclosure
All authors have declared no conflicts of interest.