Tumor-targeted delivery of sunitinib base enhances vaccine therapy for advanced melanoma by remodeling the tumor microenvironment

Abstract

Development of an effective treatment against advanced tumors remains a major challenge for cancer immunotherapy. We have previously developed a potent mannose-modified lipid calcium phosphate (LCP) nanoparticle (NP)-based Trp2 vaccine for melanoma therapy, but because this vaccine can induce a potent anti-tumor immune response only during the early stages of melanoma, poor tumor growth inhibition has been observed in more advanced melanoma models, likely due to the development of an immune-suppressive tumor microenvironment (TME). To effectively treat this aggressive tumor, a multi-target receptor tyrosine kinase inhibitor, sunitinib base, was efficiently encapsulated into a targeted polymeric micelle nano-delivery system (SUNb-PM), working in a synergistic manner with vaccine therapy in an advanced mouse melanoma model. SUNb-PM not only increased cytotoxic T-cell infiltration and decreased the number and percentage of MDSCs and Tregs in the TME, but also induced a shift in cytokine expression from Th2 to Th1 type while remodeling the tumor-associated fibroblasts, collagen, and blood vessels in the tumor. Additionally, inhibition of the Stat3 and AKT signaling pathways by SUNb-PM may induce tumor cell apoptosis or decrease tumor immune evasion. Our findings indicated that targeted delivery of a tyrosine kinase inhibitor to tumors can be used in a novel synergistic way to enhance the therapeutic efficacy of existing immune-based therapies for advanced melanoma.

Delivering safer immunotherapies for cancer

“…PLGA-PEG block copolymer nanoparticles ~80 nm in diameter were used to promote accumulation of the kinase inhibitor sunitinib in tumors, which among other activities inhibits the key immunosuppressive transcription factor STAT3 [232]. Nanoparticle delivery of the inhibitor led to a pro-immune remodeling of the tumor microenvironment that synergized with therapeutic vaccination in a murine melanoma model [233]. With similar goals in mind, it has also been shown that delivery of siRNA targeting the immunosuppressive cytokine TGF-β to tumors using lipid/protamine/hyaluronic acid nanoparticles led to knockdown of TGF-β in tumors but not lymph nodes, and reversed accumulation of Tregs and MDSCs in tumors following therapeutic vaccination [234].…”

Nanoformulations for combination or cascade anticancer therapy

“…For instance, the use of immunomodulatory antibodies, or checkpoint blockade antibodies such as Programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), would block negative regulatory receptors on T cells, allowing stronger endogenous immune response against tumors brought up by therapeutic vaccines [222]. In achievement of synergistic therapy with Trp2 peptide vaccine, we have successfully co-delivered: a) multi-target receptor tyrosine kinase inhibitor sunitinib base into polymeric micelles (SUN b-PM ), [223] b) Anti-inflammatory triterpenoid methyl-2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate (CDDO-Me) into PLGA NPs, [224] c) siRNA silencing immune-suppressive cytokines TGF-β into liposome-protamine-hyaluronic acid (LPH) NPs, [29] and d) Curcumin–polyethylene glycol conjugate into an amphiphilic micelle [225]. The targeted delivery of these TME modulating agents to tumors would enhance the therapeutic efficacy of the existing vaccine, leading to increased T cell activation and proliferation, decreased MDSCs and Tregs in the TME and shifted cytokine expression from the Th2 to Th1 type, thus achieving a more profound inhibitory effect on tumor growth and metastasis, improving overall survival.…”

Organic Nanocarriers for Delivery and Targeting of Therapeutic Agents for Cancer Treatment

“…They demonstrated that Combo NPs treated tumors became 2.75‐fold more permeable by first targeting CAFs and were more effective for tumor growth inhibition than free drug combination, GMP NP, or Cisplatin NP alone . In the following study, they used a targeted polymeric micelle system to deliver sunitinib base, which is a multi‐target receptor tyrosine kinase inhibitor to potentiate the therapeutic effect of a previously developed mannose‐modified lipid calcium phosphate (LCP) nanoparticle (NP)‐based Trp2 vaccine for treating advanced melanoma . This vaccine had been demonstrated to exert strong inhibitory effect at the early stages of melanoma, but not at a later stage where the immunosuppressive tumor microenvironment had developed.…”

“…This vaccine had been demonstrated to exert strong inhibitory effect at the early stages of melanoma, but not at a later stage where the immunosuppressive tumor microenvironment had developed. They had showed that the combination therapy could remodel the CAFs and it significantly inhibited advanced melanoma . Researchers have demonstrated that CAFs had upregulated expression of sigma receptor and contributed to the binding site barrier (BSB) which compromised the accumulation and internalization of NPs into tumor cells, resulting in NPs non‐specific uptake by stroma cells and adverse off‐target effects.…”