Journal Article

Biomimetic nanoparticles deliver mRNAs encoding costimulatory receptors and enhance T cell mediated cancer immunotherapy

Zeng, Chunxi, Zhang, Xinfu, Du, Shi, Li, Wenqing, Zhang, Chengxiang, Yan, Jingyue, Hou, Xucheng, Zhang, Yuebao, Zhao, Weiyu, Dong, Yizhou, Deng, Binbin, Kang, Diana D., Carson, William E., Li, Junan, McComb, David W.

2021

Overview

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. Antibodies targeting OX40 or CD137, two T cell costimulatory receptors, have been shown to improve antitumor immunity. Here the authors design a phospholipid-derived nanoparticle to deliver OX40 or CD137 mRNA to T cells in vivo, improving efficacy of anti-OX40 and anti-CD137 antibody therapy in preclinical tumor models.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/31 / 14/5 / 38 / 42/62 / 59/5 / 631/154/152 / 631/250/251/1567 / 64/60 / 692/4028/67/580 / 82/80 / Animals / Antibodies / Anticancer properties / Antitumor activity / Biomimetic Materials - administration & dosage / Biomimetic Materials - chemistry / Biomimetics / Cancer / Cancer immunotherapy / CD137 antigen / Cell activation / CTLA-4 protein / Drug Delivery Systems / Glycolipids - administration & dosage / Glycolipids - chemistry / Humanities and Social Sciences / Immune response / Immune system / Immunity / Immunotherapy / Immunotherapy - methods / Lymphocytes / Lymphocytes T / Lymphocytes, Tumor-Infiltrating - immunology / Lymphocytes, Tumor-Infiltrating - metabolism / Mice / mRNA / multidisciplinary / Nanoparticles / Nanoparticles - administration & dosage / Nanoparticles - chemistry / Neoplasms, Experimental - immunology / Neoplasms, Experimental - therapy / PD-1 protein / Phospholipids / Phospholipids - administration & dosage / Phospholipids - chemistry / Receptors / Receptors, OX40 - antagonists & inhibitors / Receptors, OX40 - genetics / Receptors, OX40 - immunology / Receptors, OX40 - metabolism / RNA, Messenger - administration & dosage / RNA, Messenger - chemistry / Science / Science (multidisciplinary) / T-Lymphocytes - immunology / T-Lymphocytes - metabolism / Tumor cells / Tumor necrosis factor / Tumor Necrosis Factor Receptor Superfamily, Member 9 - antagonists & inhibitors / Tumor Necrosis Factor Receptor Superfamily, Member 9 - genetics / Tumor Necrosis Factor Receptor Superfamily, Member 9 - immunology / Tumor Necrosis Factor Receptor Superfamily, Member 9 - metabolism / Tumor-infiltrating lymphocytes / Tumors