Abstract 1073P
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
Comparison between groups | TGD, % (P-value) |
Ipilimumab, CAFs- vs. CAFs+ cohorts | 44.0 (0.027) |
Renal cancer, CAFs+, OM-RCA-01 vs. IgG2a | 96.1 (<0.001) |
Renal cancer, CAFs-, OM-RCA-01 vs. IgG2a | 74.5 (<0.001) |
Prostate cancer, anti-LAG3 vs. control | 19.4 (0.035) |
Prostate cancer, alofanib iv vs. control | 69.4 (0.012) |
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.
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