Abstract 748P
Background
The immune cells within the tumor microenvironment (TME) play important roles in tumorigenesis. The immune evasion capability, as a new hallmark of cancer, provides opportunities for new strategies of cancer therapy, namely harnessing the immune cells to battle the cancer cells. Within the TME, regulatory T cells (Tregs) are one attractive cell type for targeting as they play a critical role in immunosuppression in TME. Therapeutic strategies that specifically inhibit tumor-infiltrating Tregs while sparing peripheral and normal tissue Tregs are highly desirable.
Methods
The tumor-associated Tregs express the chemokine receptor CCR8, which plays a role in the induction, expansion, chemotactic migration, and immunosuppression of tumor-associated Tregs. Thus, targeted inhibition of CCR8 is a potential therapeutic strategy against cancer.
Results
We have developed a monoclonal antibody antagonist of CCR8, IPG0521, which potently inhibited the receptor-mediated signaling and chemotaxis in Treg cells with single digital nanomolar IC50. IPG0521 potently inhibited the growth of multiple tumor types in both syngeinic and immune-humanized mouse models, including lung cancer, liver cancer, breast cancer, etc. More important, IPG0521 effectively suppressed anti-PD-1 resistant cancer and showed synergy with anti-PD-1. Mechanistically, IPG0521 significantly reduced Treg cells and enhanced CD8+ T cells in the tumor microenvironment. Other immunosuppressive cells in the TME, e.g., tumor-associated macrophages, were also down-regulated in response to IPG051 treatment.
Conclusions
Based on these pre-clinical data IPG0521, a highly selective CCR8 antagonist, is being developed for the selective inhibition of tumor-infiltrating Tregs. IPG0521 may be useful in PD-1 resistant settings and may restore the activity of PD-1 inhibitors in the setting of primary or acquired resistance to immune checkpoint blockers.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Nanjing Immunophage Biotech Co., Ltd.
Funding
Has not received any funding.
Disclosure
The authors has declared no conflicts of interest.