Abstract 1695P
Background
Several studies showed the role of FGFR inhibition on remodeling the immune microenvironment, which in turn acts in concert with anti-PD-1 to promote antitumor immunity. We explored the combination potential of OM-RCA-01, an anti-FGFR1 humanized antibody (Kd of 1.59 nM), with PD-1 blockade.
Methods
In vitro assays using human T cells were performed to evaluate lymphocyte responses to stimulation with nivolumab alone (1-100 nmol/l) or with OM-RCA-01 (1-10 nmol/l). These assays include an allogeneic mixed lymphocyte reaction (MLR) and stimulation of human PBMC by the superantigen Staphylococcal enterotoxin B (SEB) (Wang, Cancer Immunol Res 2014). IFNγ and IL-2 levels were measured by ELISA (BD Biosciences) in MLR and SEB assays, respectively. To evaluate the efficacy of FGFR1 and PD-1 co-inhibition in vivo, patient explants were obtained from surgical PD-L1-positive lung adenocarcinoma specimens, and PDX models were generated by implantation of PDX into humanized NSG mice (Jackson Lab; FASEB 2018). Treatment with OM-RCA-01 (30 mg/kg) and pembrolizumab (10 mg/kg) or pembrolizumab alone or saline (vehicle) every 3 days was started when the tumors reached 70 mm3. Measurements of tumor volume (mm3) were performed by digital calipers every 3 days during 31 days.
Results
In an allogeneic MLR, PD-1 blockade systematically resulted in an enhancement of IFNγ release and combination of nivolumab and OM-RCA-01 resulted in higher levels of IFNγ release by 31%. In some donor T-cell/dendritic cell pairs, enhanced T-cell proliferation was also observed. An increase in the concentration of antibodies led to an increase in the release of IFNγ, especially in the combination group. Nivolumab and OM-RCA-01 also enhanced IL-2 secretion over nivolumab alone in response to SEB by a mean of 29% to 74% over nivolumab. In the PDX study, the differences between groups were statistically significant (all P<0.001). Median tumor volume was 97.1 mm3 in the combination group (N=7), 417.1 mm3 in the pembrolizumab only group (N=7), and 863.5 mm3 in the vehicle group (N=7). No group mean body weight losses or clinical manifestations of toxicity were observed.
Conclusions
Co-inhibition of FGFR1 and PD-1 drives activation of T-cell clones to support enhanced antitumor activity.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.