We aimed to investigate the role of anti-bevacizumab antibodies, regulatory T, CD4+ and CD8+ cells on the efficacy of bevacizumab plus chemotherapy combination in patients with mCRC.
Thirty consecutive patients treated with bevacizumab plus either irinotecan or oxaliplatin based chemotherapy regimens were included. The levels of Tregs (CD4 + CD25(hi)FoxP3+), CD4+ and CD8+ cells from peripheral blood were assayed by flow cytometry before the onset and after 4 cycles of bevacizumab. The anti-bevacizumab antibody levels were assayed by ELISA 3 months after the onset of bevacizumab.
The median age was 59 years. The majority of the patients had metastatic disease at the time of diagnosis. The chemotherapy backbone was FOLFIRI in 75% of the patients. The median number of treatment cycles was 7. The objective response (OR) and disease stabilization rates were 30% and 73.3%, respectively. The median progression-free survival (PFS) and overall survival times were 8.0 and 16.0 months. Four patients had measurable anti-bevacizumab levels. There was no OR in patients with measurable anti-bevacizumab antibody levels. The levels of Treg cells were between 0.15 and 4.82% (median 0.40%) and the ratio of CD4 + /CD8+ cells between 0.91 and 4.30 (median 1,9) on peripheral blood before the treatment. There were no significant changes in the levels of Tregs and the ratio of CD4 + cell/CD8+ cells on bevacizumab treatment. The patients with higher CD4 + /CD8+ cells before the bevacizumab had favorable PFS times (14 vs 6 mos, P = 0.065). The patients having low Treg levels after 4 cycles of bevacizumab had favorable PFS time (14 vs 7 mos, p = 0.061). The chemotherapy backbone had no significant effect on trial parameters.
The Tregs and the ratio of CD4+ /CD8 + cells could be predictors of PFS for bevacizumab treatment in patients with mCRC. The pre-treatment ratio of CD4+ /CD8+ cells, the levels of Tregs and anti-bevacizumab antibodies might influence the efficacy of long term use of bevacizumab in patients with mCRC. The improved PFS in patients having lower Tregs after bevacizumab treatment may provide a rationale for the combination of bevacizumab and immune checkpoint inhibitors.
Clinical trial identification
Legal entity responsible for the study
TUBITAK (The Scientific and Technological Research Council of Turkey) (Grant# 114S496)
All authors have declared no conflicts of interest.