1073P - Overcoming resistance to immunotherapy with FGFR inhibition in GU cancer models

Background

Despite the encouraging success of checkpoint inhibitors, approximately 70% of tumors can eventually become resistant over time. The tumor microenvironment, in particular cancer-associated fibroblasts (CAFs), is one of the important mechanisms of resistance. OM-RCA-01, a anti-FGFR1 humanized antibody, and alofanib, a FGFR2 allosteric inhibitor showed promising results in previous studies.

Methods

Renal cancer cells (Renca; 5×10⁵) were implanted by subcutaneous (sc) injection into C57BL/6 mice. Additional Renca cells and human kidney CAFs (1.5×10⁶) were premixed in Matrigel and implanted sc in second cohort of C57BL/6 mice. Treatment with ipilimumab (ipi, 200 mcl on days 7, 10, and 13) was initiated in both cohorts when tumor volumes reached 70 mm³. Treatment with OM-RCA-01 (30 mg/kg every 3 days) or IgG2a isotype control was initiated after ipi when tumor volumes reached 1,500 mm³. Prostate cancer cells (DU-145; 4×10⁶) were implanted sc in female BALB/c mice. Treatment with human anti-LAG3 antibody (1 mg/kg, biweekly) or control was initiated when tumor volumes reached 150 mm³. Treatment with alofanib (116 mg/kg, iv daily) or control was initiated when tumor volumes reached 1,900 mm³. Tumor growth was monitored by caliper measurement every 3 days. The primary endpoint was tumor growth delay (TGD) from the initiation of immunotherapy.

Results

Treatment with OM-RCA-01 resulted in higher levels of IFNγ release by 43% and increased IL-2 secretion by 65% over control. IHC showed a significantly lower number of α-SMA/FSP/vimentin-positive CAFs in the OM-RCA-01 cohort. The table summarizes the results of in vivo studies.

Table: 1073P

Conclusions

Inhibition of FGFR1 and FGFR2 following immunotherapy resulted in a twofold suppression of tumor growth, especially in the CAFs+ cohort.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Bureau for Cancer Research (BUCARE).

Disclosure

All authors have declared no conflicts of interest.