Combination delivery of TGF-β inhibitor and IL-2 by nanoscale liposomal polymeric gels enhances tumour immunotherapy

Abstract

The tumour microenvironment thwarts conventional immunotherapy through multiple immunologic mechanisms, such as the secretion of the transforming growth factor-β (TGF-β), which stunts local tumour immune responses. Therefore, high doses of interleukin-2 (IL-2), a conventional cytokine for metastatic melanoma, induces only limited responses. To overcome the immunoinhibitory nature of the tumour microenvironment, we developed nanoscale liposomal polymeric gels (nanolipogels; nLGs) of drug-complexed cyclodextrins and cytokine-encapsulating biodegradable polymers that can deliver small hydrophobic molecular inhibitors and water-soluble protein cytokines in a sustained fashion to the tumour microenvironment. nLGs releasing TGF-β inhibitor and IL-2 significantly delayed tumour growth, increased survival of tumour-bearing mice, and increased the activity of natural killer cells and of intratumoral-activated CD8+ T-cell infiltration. We demonstrate that the efficacy of nLGs in tumour immunotherapy results from a crucial mechanism involving activation of both innate and adaptive immune responses.

Targeting TGF-β Signaling for Therapeutic Gain

“…This attenuates the efficiency of delivery of some drugs to the tumor, because, under positive IFP, small molecule drugs do not efficiently penetrate tumor tissue (Heldin et al 2004). Conversely, the leaky nature of tumor vasculature presents an opportunity for drug delivery of novel nanoparticles to the tumor (Kano et al 2007;Park et al 2012), which is enhanced by TbRI blockade (Kano et al 2007). …”

Multifunctional nanoparticles for cancer immunotherapy

“…To achieve sustained release of the hydrophobic drug in conjunction with encapsulated proteins, b-cyclodextrins as solubilization agent was incorporated into the interior of the liposomes. 81 TGF-b inhibitor and IL-2 released from liposomal polymeric gels significantly delayed tumor growth, improved survival of tumorbearing mice, and increased CD8 C T-cell and NK cell expansion while blocking a key immunosuppressive pathway. In this study it was demonstrated that a new biodegradable nanoparticle (120 nm) could facilitate sustained co-delivery of hydrophilic and hydrophobic immunomodulators to enhance antitumor activity against subcutaneous and metastatic melanomas.…”

“…In one study, TGF-b receptor-I inhibitor in combination with IL-2 as an immunostimulant has been used to induce tumor immunity against immunosuppressive tumor microenvironment. 81 In this work Park et al designed a multifunctional core¡shell delivery system comprising nanoscale liposome encapsulated polymeric gels (nanolipogels) for co-delivery of TGF-b inhibitor (a hydrophobic small drug molecule) and IL-2 (a hydrophilic protein). To achieve sustained release of the hydrophobic drug in conjunction with encapsulated proteins, b-cyclodextrins as solubilization agent was incorporated into the interior of the liposomes.…”

“…In this study it was demonstrated that a new biodegradable nanoparticle (120 nm) could facilitate sustained co-delivery of hydrophilic and hydrophobic immunomodulators to enhance antitumor activity against subcutaneous and metastatic melanomas. 81 Intelligent multifunctional nanoparticle targeted to tumor-associated macrophages (TAMs)…”

Nanoparticle design to induce tumor immunity and challenge the suppressive tumor microenvironment

“…For instance, Park and coworkers developed nanoscale liposomal polymeric gels co-encapsulating a TGFβ inhibitor and IL-2 that were shown to be delivered to the tumor upon intravenous administration. This resulted in an increased NK cell infiltration and a higher CTL-to-T reg ratio, which in turn delayed tumor growth and prolonged overall survival in a mouse melanoma model [111]. Another strategy could be to even go one step further backwards by opposing two of the Recently developed NPs for tumor microenvironment modulation attempt to address specific subsets of tumor-infiltrating immune cells.…”