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Jul 16, 2012

New Hope for Metastatic Melanoma

  • A nanolipogel-based immunotherapy that simultaneously delivers both a soluble cytokine and hydrophobic small molecule growth factor inhibitor directly to tumors led to markedly reduced cancer growth in mice and increased survival, scientists report. A team at Yale University School of Medicine, and School of Engineering and Applied Sciences, has developed a biodegradable liposomal polymeric nanocarrier that combines features of both liposomal and solid polymer systems and incorporates the pharmacokinetic properties of PEGylated liposomes.

    In a paper published in Nature Materials, Tarek M. Fahmy, Ph.D., Jason Park, Ph.D., and colleagues report on experiments in which the nanolipogels (nLGs) were used to deliver both a commercially available TGF-β receptor-I inhibitor SB505124 (SB) and high doses of IL-2 to mice carrying metastatic melanoma tumors. The treatment blocked the immunosuppressive effects mediated by tumor-secreted TGF-β, and enhanced the ability of IL-2 to induce activation of melanoma-specific T cell responses against the cancer. The authors claim the technology could provide the foundation for a tumor immunotherapy platform that can activate both innate and adaptive immune responses. Their published paper is titled “Combination delivery of TGF-β inhibitor and IL-2 by nanoscale liposomal polymeric gels enhances tumour immunotherapy.”

    Tumors secrete immunosuppressive factors that are widely believed to play a key role in dampening the immune system’s ability to recognize the tumor as non-self and mount an immunological attack. In particular, signaling by tumor-secreted TGF-β has been implicated in preventing high dose IL-2 therapy from stimulating an immunological offense when used to treat cancers such as metastatic melanoma. Indeed high levels of TGF-β have been found in a large number of different tumors, including melanomas.

    The Yale team’s work to evaluate combining a TGF-β inhibitor with IL-2 therapy hinged on the ability to deliver both molecules simultaneously and in a sustained manner to the tumor bed. They thus needed to develop a carrier that was capable of delivering both the soluble protein cytokine and a hydrophobic small-molecule TGF-β inhibitor.

    Their hybrid liposomal-polymer core-shell platform comprised a lipid bilayer surrounding a hydrogel core fabricated from a degradable polymer. The design incorporated methacrylate-conjugated cyclodextrins (CDs) into the interior of the liposomes, to allow the co-encapsulation of a protein as well as the small hydrophobic drug within the interior of the lipid bilayer.

    In vivo tests showed that treating mice bearing B16 melanoma-derived tumors using intratumoral injections of the SB/IL-2-carrying nLGs resulted in a significant reduction in tumor growth rate and increased survival, when compared with treatment using either soluble SB, or SB combined with IL-2. Forty percent of the nLG-treated cohort demonstrated complete tumor regression and survived for the whole of the 60-day trial duration. Encouragingly, significant survival benefits were also evident when the dual agent-carrying nLGs were administered systemically to treat mice bearing melanoma-derived lung metastases. These treated animals also demonstrated a much lower burden of lung metastases than those given soluble SB with or without IL-2 cotherapy.

    Biodistribution and localization studies using fluorescent marker-carrying nLGs demonstrated that when administered intravenously the nanoparticles traveled to sites of both distant subcutaneous tumors and metastatic lung tumors, and trafficked within the tumor vasculature, squeezing out of the leaky tumor blood vessels to reach the tumors themselves. The fact that tumor vasculature is defective and allows the nanoparticles to permeate is a major advantage, the researchers suggest. “Passive targeting can therefore result in several-fold increases in particulate concentrations in solid tumors compared to free administration of antibodies or other drugs, and may explain the increased survival and effective treatment of metastasis observed after intravenous injection.”

    Further studies evaluating the numbers of and types of tumor-infiltrating lymphocytes (TILs) that were recruited to tumors after different therapeutic regimens threw up interesting results. Mice treated using a combination of SB-carrying nLGs and separately administered IL-2 demonstrated increased numbers of activated CD8+ T cells in tumors, with minimal impact on overall CD4/CD8 ratios and regulatory T cells (Tregs). In contrast, treatment using nLGs that carried both SB and IL-2 resulted in substantially increased numbers of NK cells in the tumor beds, when compared with treatment using either "empty" nLGs or with particles that carried and released either IL-2 or SB alone. The key role of NK cells to the antitumor response was confirmed by the finding that in NK-depleted mice (achieved using NK antibodies), therapy using nLGs that released by SB and IL-2 didn’t have a major impact on tumor mass.

    “Thus, the maximum therapeutic benefit observed in mice treated with particles simultaneously delivering SB and IL-2 therapies was probably related to enhanced numbers of NK cells at the tumor site, resulting in increased effector cell populations in the tumor,” the team writes. “Absence of therapeutic efficacy following NK depletion demonstrated that stimulation of the innate arm by nanoparticles releasing both agents was crucial for achieving an improvement in survival.”

    The Yale-based team says their results indicate that core-shell nanoparticle systems capable of simultaneously delivering two different types of immunotherapy molecule represent an attractive prospect for anticancer therapy. “This work provides an essential proof-of-concept demonstration of a biodegradable nanoparticle technology that facilitates sustained delivery of hydrophilic and hydrophobic immunomodulators to enhance anti-tumor activity against subcutaneous and metastatic melanomas,” they conclude. “This therapeutic approach warrants further preclinical evaluation, as sustained delivery of immunotherapeutics such as IL-2 and SB by hybrid, core-shell, nanoparticle technology could ultimately provide a novel, clinically relevant approach to treat metastatic melanoma patients.”


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