We thank the reviewer for this question. Indeed, the sorafenib dose used in this study proved to be slightly more efficacious than TTFields in controlling tumor fold increase. Nevertheless, these differences between the monotherapies, did not reach statistical significance. In accordance, there was no statistical difference between the monotherapies in the expression levels of the LC3 marker and the levels of cleaved PARP. In order to better understand the mechanism of action, we have added experiments to better characterize the autophagy-apoptosis interplay for treatment with concomitant TTFields and sorafenib, which are described in response 3. Of note, the clinical development of TTFields does not aim to replace sorafenib with TTFields, but rather to add TTFields on top of sorafenib and therefore this work focused mainly on the potential added value in combining these 2 modalities.
1) The authors demonstrate the efficacy of TTFields in vivo even when used as monotherapy. As shown in the Figure 4 C and D, TTFields were found less effective in terms of reducing the tumors volume and weight when compared with sorafenib. However, no differences in expression of LC3 marker were observed between these groups (treated with TTFields or with sorafenib)(as shown in Figure 4D). Similarly, low evidence of apoptosis (expression of cleaved PARP) was found in these groups, as shown in Figure 4F. What is the mechanism illustrating higher efficiency of sorafenib against HCC?