Abstract
Antibodies targeting costimulatory receptors of T cells have been developed for the activation of T cell immunity in cancer immunotherapy. However, costimulatory molecule expression is often lacking in tumor-infiltrating immune cells, which can impede antibody-mediated immunotherapy. Here, we hypothesize that delivery of costimulatory receptor mRNA to tumor-infiltrating T cells will enhance the antitumor effects of antibodies. We first design a library of biomimetic nanoparticles and find that phospholipid nanoparticles (PL1) effectively deliver costimulatory receptor mRNA (CD137 or OX40) to T cells. Then, we demonstrate that the combination of PL1-OX40 mRNA and anti-OX40 antibody exhibits significantly improved antitumor activity compared to anti-OX40 antibody alone in multiple tumor models. This treatment regimen results in a 60% complete response rate in the A20 tumor model, with these mice being resistant to rechallenge by A20 tumor cells. Additionally, the combination of PL1-OX40 mRNA and anti-OX40 antibody significantly boosts the antitumor immune response to anti-PD-1 + anti-CTLA-4 antibodies in the B16F10 tumor model. This study supports the concept of delivering mRNA encoding costimulatory receptors in combination with the corresponding agonistic antibody as a strategy to enhance cancer immunotherapy.
Highlights
Antibodies targeting costimulatory receptors of T cells have been developed for the activation of T cell immunity in cancer immunotherapy
PL1 nanoparticles delivered the costimulatory receptor mRNA to a T-cell line in vitro, but were able to deliver costimulatory receptor mRNA to T cells within the tumor in vivo, which provided a useful delivery material for the modulation of T-cell function
Previous studies reported that low expression of OX40 hampered the anti-OX40 antibody immunotherapy effects in many tumor models (e.g., B16F10)[54]
Summary
Antibodies targeting costimulatory receptors of T cells have been developed for the activation of T cell immunity in cancer immunotherapy. The use of immune checkpoint inhibitors has led to improved overall survival for many cancer patients by targeting the T-cell co-inhibitory pathways such as PD-1 and CTLA-425 These antibodies are used routinely in the clinic, the percentage of patients that experience a meaningful tumor response is only about 25%26. We hypothesized that delivering costimulatory receptor mRNAs increases their expression on tumor-infiltrating T cells, and when coupled with the use of corresponding agonistic antibodies, this treatment regimen directly activates T cells and improve cancer immunotherapy (Fig. 1a). The combination of PL1-OX40 mRNA and antiOX40 antibody exhibits significantly improved antitumor activity compared to anti-OX40 antibody alone in multiple tumor models This treatment approach significantly improves the immunotherapeutic effect of anti-PD-1 + anti-CTLA-4 antibodies. This study provides a platform to deliver costimulatory receptor mRNA to immune cells in order to boost antitumor immunity
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