Regulatory T Cells

In cancer, the secretion of certain chemokines from tumor cells and tumor-resident immune cells recruits immunosuppressive T cells called Treg to tumor sites. Treg represent a dominant pathway for downregulating the immune response.

Blocking the migration of Treg has been shown to have both the potential to unleash naturally-occurring anti-tumor immunity and to synergize with a variety of both conventional and immune-based therapies, such as radiation, chemotherapy, checkpoint inhibitors, and adoptive T cell therapy.

Treg recruitment into tumors is dependent on CCR4, whose ligands are produced by tumor cells themselves or by tumor-associated macrophages. CCR4 is highly expressed on Treg and not highly expressed or used by effector or cytotoxic T cells, suggesting that targeting CCR4 may selectively block Treg migration into tumors.

Our proprietary drug discovery and development engine has identified certain tumors where we believe FLX475 has the greatest probability of demonstrating clinical benefit.. We refer to these tumors as “charged” as defined by (i) their expression of high levels of CCR4 ligands, (ii) their enrichment for Treg cells and (iii) their enrichment for CD8+ effector cells. Tumors with high levels of these three parameters imply they have the necessary components to generate a potent immune response; however, the presence of Treg dampens this response. We have identified numerous tumors as being charged, including non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), head and neck squamous cell carcinoma (HNSCC), nasopharyngeal carcinoma (NPC), gastric cancer, certain Hodgkin and non-Hodgkin lymphomas (HL and NHL), and cervical cancer.

In addition, we have discovered that the presence of oncogenic viruses, such as EBV and HPV, is associated with tumors that are highly “charged” and can be prospectively selected. In preclinical studies, we have demonstrated the association between EBV and CCR4 ligand expression, which is believed to be causal to Treg migration. These studies are further validated by scientific publications linking EBV to Treg tumor infiltration in HL, gastric cancer and NPC.

We have completed a Phase 1 dose escalation trial of FLX475 in healthy volunteers demonstrating dose-dependent inhibition of CCR4 with no observed immune related adverse events or significant clinical adverse events. We are currently conducting a Phase 1/2 clinical trial investigating FLX475 as a single agent and in combination with pembrolizumab in patients with tumors that are likely to be “charged” where we believe FLX475 has the greatest probability of clinical benefit. We anticipate announcing proof-of-concept data from this study in the first half of 2020.