Ibrutinib-disabled immunosuppressive microenvironment sensitizes melanoma to PD-1/OX40 immune checkpoint modulators following immunization with dendritic cell-targeted nano-vaccines

Introduction

Low response rate, acquired resistance, and severe side effects have limited the clinical outcomes of immune checkpoint therapy. We hypothesized that the combination of cancer nano-vaccines with anti-PD-1 for immunosuppression blockade, and the agonist antibody anti-OX40 for effector T cell stimulation, expansion, and survival, could potentiate the efficacy of melanoma therapy.

Materials and Methods

We developed dendritic cell-targeted mannose-grafted poly(lactic-co-glycolic acid) nano-vaccines containing melan-A/MART-1 peptides and immune potentiators.

Results and Discussion

Both prophylactic and therapeutic combination regimens of mannosylated nano-vaccines with anti-PD-1/anti-OX40 (αPD-1/αOX40) demonstrated synergism, stimulating T cell infiltration into tumors at early stages of the treatment. The prophylactic regimen inhibited tumor growth to a greater extent compared to the αPD-1/αOX40 alone, however, treatment at the therapeutic regimen did not result in enhanced inhibition of tumor growth compared to the αPD-1/αOX40 alone. An increased infiltration of myeloid-derived suppressor cells (MDSC) was observed in tumors of animals treated at the therapeutic regimen with the combination of mannosylated nano-vaccines with αPD-1/αOX40. In fact, when combining ibrutinib, an MDSC-inhibitor, with the double therapy mannosylated nano-vaccines and αPD-1/αOX40, a remarkable tumor remission and prolonged survival was achieved in treated melanoma-bearing mice.

Conclusions

The synergy between the mannosylated nano-vaccines, ibrutinib and αPD-1/αOX40 provides essential insights to devise alternative regimens and combination therapies to improve the efficacy of immune checkpoint modulators in solid tumors, by regulating the endogenous immune response.