High-capacity poly(2-oxazoline) formulation of TLR 7/8 agonist extends survival in a chemo-insensitive, metastatic model of lung adenocarcinoma

Abstract

About 40% of patients with non–small cell lung cancer (NSCLC) have stage IV cancer at the time of diagnosis. The only viable treatment options for metastatic disease are systemic chemotherapy and immunotherapy. Nonetheless, chemoresistance remains a major cause of chemotherapy failure. New immunotherapeutic modalities such as anti–PD-1 immune checkpoint blockade have shown promise; however, response to such strategies is highly variable across patients. Here, we show that our unique poly(2-oxazoline)–based nanomicellar formulation (PM) of Resiquimod, an imidazoquinoline Toll-like receptor (TLR) 7/8 agonist, had a superior tumor inhibitory effect in a metastatic model of lung adenocarcinoma, relative to anti–PD-1 therapy or platinum-based chemotherapy. Investigation of the in vivo immune status following Resiquimod PM treatment showed that Resiquimod-based stimulation of antigen-presenting cells in the tumor microenvironment resulted in the mobilization of an antitumor CD8+ immune response. Our study demonstrates the promise of poly(2-oxazoline)-formulated Resiquimod for treating metastatic NSCLC.

Toll-Like Receptor 7 Mediates Inflammation Resolution and Inhibition of Angiogenesis in Non-Small Cell Lung Cancer

“…A very recent study highlights the strong antitumor activity of resiquimod (TLR7 agonist, analogue to imiquimod) in NSCLC due to its effects of immuno-modulation of the tumor microenvironment. In particular, the authors demonstrate that the TLR7 agonist had a superior tumor inhibitory effect in a metastatic model of lung adenocarcinoma, relative to anti-PD1 therapy or platinum-based chemotherapy [ 59 ]. Our data identifying TLR7 as a modulator of the angiogenic response of NSCLC could enrich and complete the scenario of the effects of TLR7 agonists in NSCLC cancer.…”

Poly(2‐oxazoline)‐ and Poly(2‐oxazine)‐Based Self‐Assemblies, Polyplexes, and Drug Nanoformulations—An Update

“…Reproduced with permission. [ 185 ] Copyright 2020, American Association for the Advancement of Science (AAAS).…”

“…[ 184 ] An encapsulation of Resiquimod, an immune response modifier, into pMeOx‐ b ‐pBuOx‐ b ‐pMeOx micelles has been investigated for immunotherapy of non‐small cell lung cancer. [ 185 ] As a comparison, conventional anticancer drugs, such as cisplatin and PTX, were also formulated with POx. Interestingly, the micellar formulations of the conventional drugs exhibited in most cases lower cytotoxicity in vitro in comparison to free drugs, and in this case, they did not lead to improved survival in vivo, in comparison to control group treated with saline.…”

Polymeric Micelles in Cancer Immunotherapy

“…They have shown that this POx-R848 formulation demonstrated a superior tumor-inhibiting effect in a metastatic model of NSCLC, relative to anti–PD-1 therapy or platinum-based chemotherapy. Investigation of the in vivo immune status showed that the R848-based stimulation of antigen-presenting cells in the tumor microenvironment resulted in the mobilization of an antitumor CD8 + immune response [ 147 ].…”