A genomic profile of local immunity in the melanoma microenvironment following treatment with α particle-emitting ultrasmall silica nanoparticles Journal Article

   

Authors:	Urbanska, A. M.; Khanin, R.; Alidori, S.; Wong, S.; Mello, B. P.; Almeida, B. A.; Chen, F.; Ma, K.; Turker, M. Z.; Korontsvit, T.; Scheinberg, D. A.; Zanzonico, P. B.; Wiesner, U.; Bradbury, M. S.; Quinn, T. P.; McDevitt, M. R.
Article Title:	A genomic profile of local immunity in the melanoma microenvironment following treatment with α particle-emitting ultrasmall silica nanoparticles
Abstract:	An alpha particle-emitting nanodrug that is a potent and specific antitumor agent and also prompts significant remodeling of local immunity in the tumor microenvironment (TME) has been developed and may impact the treatment of melanoma. Biocompatible ultrasmall fluorescent core-shell silica nanoparticles (C ' dots, diameter similar to 6.0 nm) have been engineered to target the melanocortin-1 receptor expressed on melanoma through alpha melanocyte-stimulating hormone peptides attached to the C ' dot surface. Actinium-225 is also bound to the nanoparticle to deliver a densely ionizing dose of high-energy alpha particles to cancer. Nanodrug pharmacokinetic properties are optimal for targeted radionuclide therapy as they exhibit rapid blood clearance, tumor-specific accumulation, minimal off-target localization, and renal elimination. Potent and specific tumor control, arising from the alpha particles, was observed in a syngeneic animal model of melanoma. Surprisingly, the C ' dot component of this drug initiates a favorable pseudopathogenic response in the TME generating distinct changes in the fractions of naive and activated CD8 T cells, Th1 and regulatory T cells, immature dendritic cells, monocytes, M phi and M1 macrophages, and activated natural killer cells. Concomitant upregulation of the inflammatory cytokine genome and adaptive immune pathways each describes a macrophage-initiated pseudoresponse to a viral-shaped pathogen. This study suggests that therapeutic alpha-particle irradiation of melanoma using ultrasmall functionalized core-shell silica nanoparticles potently kills tumor cells, and at the same time initiates a distinct immune response in the TME.
Keywords:	ipilimumab; melanoma; radiotherapy; immunotherapy; peptides; natural killer cell; receptor; macrophage; therapy; checkpoints; expression; blockade; t cell; tumor microenvironment; actinium-225; nivolumab; cancer-targeted probes; alpha particle; ultrasmall silica nanoparticles; c ' dot; pseudopathogen
Journal Title:	Cancer Biotherapy and Radiopharmaceuticals
Volume:	35
Issue:	6
ISSN:	1084-9785
Publisher:	Mary Ann Liebert, Inc
Date Published:	2020-08-01
Start Page:	459
End Page:	473
Language:	English
ACCESSION:	WOS:000561884800008
DOI:	10.1089/cbr.2019.3150
PROVIDER:	wos
PMCID:	PMC7462037
PUBMED:	32013538
Notes:	Article -- Source: Wos

https://synapse.mskcc.org/synapse/works/has_related_data_chk/171444