1015P - The efficacy and mechanism of pan-FGFR inhibitor (AZD4547) combined with immunoagonists or immunosuppressants in FGFR-positive tumors

Background

Four Fibroblast growth factor receptor (FGFR) inhibitors have been approved for market, which are promising and potential anti-tumor drugs. However, its drug resistance is inevitable, and how to overcome its clinical drug resistance is an urgent problem to be solved. The combination of FGFR inhibitors with immunotherapy can modify the tumor microenvironment (TME) to achieve the purpose of enhancing the anti-tumor effect, which may become a new strategy to address its drug resistance. The purpose of this study was to explore the combination of FGFR inhibitor and immunosuppressant or immunoagonist has the best effect in FGFR-positive solid tumors preliminatively. The effects on the TME were analyzed to provide a preclinical basis for the clinical FGFR inhibitor combination therapy model.

Methods

4T1 breast cancer and CT26 colon cancer tumor model were constructed respectively, and different drug administration schemes were used for intervention, and the tumor size and survival of each group of mice were compared. At the same time, the proportion of T cells, NK cells, DC cells, macrophages and MDSCs and the expression of effector molecules in peripheral blood, spleen, bone marrow and tumor of mice were detected by FCM, IHC and Western Blot, so as to observe the influence of different interventions on TME.

Results

1. AZD4547 combined with 4-1BB agonist significantly inhibited tumor growth and prolonged the survival time of tumor-bearing mice; Surprisingly, the addition of PD-1 inhibitors did not increase the therapeutic effect of AZD4547 in the 4T1 and CT26 models. 2. 4-1BB agonist combined with AZD4547 improved TME and immune status in mice: The proportion of CD8+ 4-1BB+, CD8+ IFN-γ+ T cells, DC (CD11b+ CD11c+) cells and NK cells in peripheral blood, spleen and tumor was significantly increased, and the local infiltration of MDSC in spleen and tumor was effectively inhibited, and the inhibitory effect of MDSC against tumor immunity was weakened.

Conclusions

Pan-FGFR inhibitor (AZD4547) combined with 4-1BB antibody have synergistic anti-tumor effects, which not only directly inhibit tumor cell proliferation, but also enhance anti-tumor immunity, further inhibit tumor growth, and significantly prolong survival.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Q. Ma.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.