752 CCR8-targeted Treg depletion and PD-1 blockade combine to divert CD8+ T cells from exhaustion associated transcriptional trajectories within the tumor microenvironment

Background Within tumors, regulatory T cells (Tregs) are a key suppressive population known to prevent anti-tumor immune responses, and an increased presence of intratumoral Tregs has been associated with poorer patient outcomes in several cancers. CCR8 is enriched on intratumoral Tregs in many human cancers and is an attractive immuno-oncology target to mediate selective antibody-driven intratumoral Treg depletion via antibody-dependent cellular cytotoxicity (ADCC). Methods We have explored the anti-tumor immune response mediated by anti-CCR8/anti-PD-1 combination therapy through scRNAseq and TCRseq studies performed in the Pan02 mouse syngeneic tumor model. Anti-CTLA-4 was also compared to anti-CCR8 treatment in these studies, given that anti-CTLA-4 has both Treg-depleting and checkpoint blocking functions in mouse models, while the effects of anti-CCR8 are restricted to Treg depletion. Results The immune response, and particularly the intratumoral CD8+ T cell response, is dramatically modulated upon anti-CCR8 monotherapy and anti-CCR8/anti-PD-1 combination therapy. Anti-PD-1 treatment increases an intratumoral CD8+ T effector cell subset bearing high expression of exhaustion associated markers. In contrast, Treg depletion leads to enrichment of a phenotypically distinct effector/memory-like CD8+ T cell population, which is further augmented with anti-CCR8/anti-PD-1 combination therapy. Greater enrichment of this CD8+ T cell subset correlates with better tumor growth inhibition. Follow-up studies are underway to determine whether combination with other mechanistically rational immuno-oncology therapies may further enhance anti-CCR8 mediated tumor growth inhibition in this model. Conclusions In comparison to what is observed with anti-PD-1 treatment, the transcriptional and phenotypic profiles of intratumoral CD8+ T cells are greatly altered upon anti-CCR8 mediated tumor Treg depletion, and these effects are associated with increased tumor control. A human CCR8 specific afucosylated IgG1 antibody (ABBV-514) is currently being evaluated in a Phase I clinical trial both as monotherapy and in combination with budigalimab, a PD-1-blocking antibody (NCT05005403). Ethics Approval AbbVie is committed to ensuring the humane care and use of laboratory animals in the company’s research and development programs. Our programs aim to exceed regulatory agency standards, and we are committed to the internationally accepted principles of the 3Rs (refinement, reduction, replacement). All animal studies were reviewed and approved by AbbVie’s Institutional Animal Care and Use Committee or Oversight Body (in accordance with national regulations). Animal studies were conducted under an AAALAC accredited program, where veterinary care and oversight was provided to ensure optimal animal care.