Abstract 1023P
Background
Despite the clinical success of immune checkpoint inhibitors (ICI) in many cancers, a large unmet need exists, as many patients respond inadequately. Fecal microbiome transplant from anti-PD-1 responders into non-responders improves response to ICI, providing a strong rationale that gut microbiome influences response to ICI. Using Second Genome's proprietary algorithms, we derived an ICI responder-specific microbial signature. Here, we report the antitumor activity and immunomodulatory functions of a novel, microbiome-secreted peptide SG-3-00802.
Methods
SG-3-00802 showed robust CXCL10 induction in vitro and markedly increased CXCL10 and CD8 levels in tumors, without affecting IFNγ and IL-12. SG-3-00802 showed improved antitumor responses in combination with anti-PD-1 in the anti-PD-1-insensitive RENCA mouse model vs control peptide or anti-PD-1 antibody alone. Treatment with SG-3-00802 ± anti-PD-1, significantly improved overall survival with many mice showing complete tumor regression. Surviving mice with fully regressed tumors (83%) rejected newly implanted tumors when rechallenged with RENCA cells, showing that the SG-3-00802 + anti-PD-1 combination yields long-lasting anti-tumor memory responses.
Results
Using an LC MS/MS-based platform, we identified CXCR3, CXCR4, and CCR7 as putative binding partners of SG-3-00802. G-protein-coupled receptor activation assays in reporter cells revealed that addition of SG-3-00802 enhanced the activity of CXCR3 in the presence of its innate ligand CXCL11, validating CXCR3 as the functional target of SG-3-00802. This observation was confirmed in vivo, as CXCR3 inhibition decreased the activity of SG-3-00802 alone and in combination with anti-PD-1, supporting our hypothesis that in vivo activity of SG-3-00802 is CXCR3 dependent.
Conclusions
In summary, we showed that the microbiome directly interacts with the human immune system to impact antitumor immunity. SG-3-00802 shows great potential to improve responses in ICI-resistant patients and potentially acts as a CXCR3 receptor sensitizer by increasing CXCR3 activation in response to its ligands CXCL9/10/11, leading to recruitment of effector cells to mount a robust immune response.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Second Genome.
Funding
Second Genome.
Disclosure
H. Kiefel: Financial Interests, Personal, Full or part-time Employment: Second Genome. D. Haria: Financial Interests, Personal, Full or part-time Employment: Second Genome. J.D. Ravichandar: Financial Interests, Personal, Full or part-time Employment: Second Genome. J. Desnoyer: Financial Interests, Personal, Full or part-time Employment: Second Genome. J. Guagua: Financial Interests, Personal, Full or part-time Employment: Second Genome. S. Lau: Financial Interests, Personal, Full or part-time Employment: Second Genome. J. Lee: Financial Interests, Personal, Full or part-time Employment: Second Genome. E. Rutherford: Financial Interests, Personal, Full or part-time Employment: Second Genome. K. Dabbagh: Financial Interests, Personal, Full or part-time Employment: Second Genome. P. Lal: Financial Interests, Personal, Full or part-time Employment: Second Genome.