Background Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have shown therapeutic efficacy in clinical studies. However, a big proportion of patients shows drug insensitivity or develops drug resistance during treatment. One of the approaches to improve the clinical outcome is to combine PD-1/PD-L1 inhibitors with other therapeutic regiments, e.g., immune modulating drugs targeting a different pathway. In the current study, we explored a combination treatment with our novel micelle-based formulation of the TLR7 agonist MBS8(1V270) and anti-PD1 or anti-PD-L1 antibodies in immunocompetent mice bearing syngeneic tumors. Previously, we have shown that MBS8(1V270) monotherapy led to complete eradication of established tumors in several syngeneic mouse models and to establishment of an immune memory response. Here, we have tested whether in models with sub-optimal response to MBS8(1V270) and low/no response to anti-PD-1 combination of the drugs can provide therapeutic benefit.
Methods Anti-PD-1 (clone RMP1–14) or anti-PD-L1 (clone 10F.9G2) antibodies were tested either as monotherapy or in combination with MBS8(1V270) in mice bearing established tumors. MBS8(1V270) was administered intravenously on five occasions given every fourth day. Antibodies were administered intraperitoneally on six occasions given every fourth day. Tumor volume was measured every other day, and the percentage of tumor growth inhibition was calculated on the day when all mice in the control (vehicle-treated) group were all alive. Body weight change was monitored throughout the treatment period as a surrogate read-out for toxicity.
Results Six tumor models which in our previous study showed sub-optimal response to MBS8(1V270) monotherapy (tumor growth inhibition 30–60%) were used in the current study on the combination treatment with anti-PD-1.
Two types of responses were observed:
In Hepa1–6 (hepatoma) and M38 (colon cancer) models, both anti-PD-1 and MBS8(1V270) showed therapeutic activity in monotherapy. Combo therapy showed an additive benefit.
In models which were not responsive to anti-PD-1, including RM-1 (prostate cancer), LL/2 (Lewis lung cancer), Pan02 (pancreatic cancer) and Renca (kidney cancer), combination treatment with MBS8(1V270) resulted in synergistic activity by turning anti-PD-1 non-responsive tumor models into responsive ones.
Efficacy of the combination treatment with MBS8(1V270) and anti-PD-L1 was assessed in CT26 (colon cancer) at sub-optimal dose of MBS8(1V270). In this model, an additive effect was observed.
Conclusions Combination of anti-PD-1/anti-PD-L1 with MBS8(1V270) resulted in significant therapeutic benefit in syngeneic mouse tumor models. MBS8(1V270) was able to restore sensitivity to immune checkpoint inhibitors in otherwise non-responsive models and show a significant synergistic effect in models with low response to anti-PD-1.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.