Research ArticleIMMUNOTHERAPY

Engineering nanoparticles to locally activate T cells in the tumor microenvironment

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Science Immunology  12 Jul 2019:
Vol. 4, Issue 37, eaau6584
DOI: 10.1126/sciimmunol.aau6584

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Targeted tumor immunotherapy

Although immunotherapy has transformed the cancer therapeutics landscape, a number of problems remain to be solved, from improving efficacy to limiting side effects. Here, Wang et al. have attempted to do this by engineering nanoparticles that can be specifically activated within tumors by conjugating antibodies against programmed death ligand 1 (PDL1) with matrix metalloproteinase protein 2 (MMP-2)–sensitive nanoparticles that carry a photosensitizer. MMP-2 is highly expressed in tumors, and delivery of the nanoparticle to tumors elicits release of the antibody from the nanoparticle. When used in conjunction with localized near-infrared radiation that activates the photosensitizer to produce reactive oxygen species, Wang et al. show that these nanoparticles outperform systemic anti-PDL1 in limiting growth and metastasis of murine tumors.

Abstract

Immunological tolerance of tumors is characterized by insufficient infiltration of cytotoxic T lymphocytes (CTLs) and immunosuppressive microenvironment of tumor. Tumor resistance to immune checkpoint inhibitors due to immunological tolerance is an ongoing challenge for current immune checkpoint blockade (ICB) therapy. Here, we report the development of tumor microenvironment–activatable anti-PDL1 antibody (αPDL1) nanoparticles for combination immunotherapy designed to overcome immunological tolerance of tumors. Combination of αPDL1 nanoparticle treatment with near-infrared (NIR) laser irradiation–triggered activation of photosensitizer indocyanine green induces the generation of reactive oxygen species, which promotes the intratumoral infiltration of CTLs and sensitizes the tumors to PDL1 blockade therapy. We showed that the combination of antibody nanoparticles and NIR laser irradiation effectively suppressed tumor growth and metastasis to the lung and lymph nodes in mouse models. The nanoplatform that uses the antibody nanoparticle alone both for immune stimulation and PDL1 inhibition could be readily adapted to other immune checkpoint inhibitors for improved ICB therapy.

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