Localized Immunotherapy via Liposome-Anchored Anti-CD137+IL-2 Prevents Lethal Toxicity and Elicits Local and Systemic Antitumor Immunity
ABSTRACT Immunostimulatory agonists such as anti-CD137 and interleukin (IL)-2 have elicited potent antitumor immune responses in preclinical studies, but their clinical use is limited by inflammatory toxicities that result upon systemic administration. We hypothesized that by rigorously restricting the biodistribution of immunotherapeutic agents to a locally accessible lesion and draining lymph node(s), effective local and systemic antitumor immunity could be achieved in the absence of systemic toxicity. We anchored anti-CD137 and an engineered IL-2Fc fusion protein to the surfaces of PEGylated liposomes, whose physical size permitted dissemination in the tumor parenchyma and tumor-draining lymph nodes but blocked entry into the systemic circulation following intratumoral injection. In the B16F10 melanoma model, intratumoral liposome-coupled anti-CD137 + IL-2Fc therapy cured a majority of established primary tumors while avoiding the lethal inflammatory toxicities caused by equivalent intratumoral doses of soluble immunotherapy. Immunoliposome therapy induced protective antitumor memory and elicited systemic antitumor immunity that significantly inhibited the growth of simultaneously established distal tumors. Tumor inhibition was CD8 T-cell-dependent and was associated with increased CD8 T-cell infiltration in both treated and distal tumors, enhanced activation of tumor antigen-specific T cells in draining lymph nodes, and a reduction in regulatory T cells in treated tumors. These data suggest that local nanoparticle-anchored delivery of immuno-agonists represents a promising strategy to improve the therapeutic window and clinical applicability of highly potent but otherwise intolerable regimens of cancer immunotherapy. Cancer Res; 73(5); 1547-58. ©2012 AACR.
SourceAvailable from: Muhammad Asadullah Madni[Show abstract] [Hide abstract]
ABSTRACT: Liposomes are lipid based vesicular systems that offer novel platform for versatile drug delivery to target cell. Liposomes were first reported by Bangham and his co-workers in 1964 (1). Since then, liposomes have undergone extensive research with the prime aim to optimize encapsulation, stability, circulation time and target specific drug delivery. Manipulation of a liposome's lipid bilayer and surface decoration with selective ligands has transformed conventional liposomes into adaptable and multifunctional liposomes. Development of liposomes with target specificity provide the prospect of safe and effective therapy for challenging clinical applications. Bioresponsive liposomes offer the opportunity to release payload in response to tissue specific microenvironment. Incorporation of novel natural and synthetic materials has extended their application from stable formulations to controlled release targeted drug delivery systems. Integration and optimization of multiple features into one system revolutionized research in the field of cancer, gene therapy, immunotherapy and infectious diseases. After 50 years since the first publication, this review is aimed to highlight next generation of liposomes, their preparation methods and progress in clinical applications. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
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ABSTRACT: Proteins are a vital constituent of the body as they perform many of its major physiological and biological processes. Recently, proteins and peptides have attracted much attention as potential treatments for various dangerous and traditionally incurable diseases such as cancer, AIDS, dwarfism and autoimmune disorders. Furthermore, proteins could be used for diagnostics. At present, most therapeutic proteins are administered via parenteral routes that have many drawbacks, for example, they are painful, expensive and may cause toxicity. Finding more effective, easier and safer alternative routes for administering proteins and peptides is the key to therapeutic and commercial success. In this context, much research has been focused on non-invasive routes such as nasal, pulmonary, oral, ocular, and rectal for administering proteins and peptides. Unfortunately, the widespread use of proteins and peptides as drugs is still faced by many obstacles such as low bioavailability, short half-life in the blood stream, in vivo instability and numerous other problems. In order to overcome these hurdled and improve protein/peptide drug efficacy, various strategies have been developed such as permeability enhancement, enzyme inhibition, protein structure modification and protection by encapsulation. This review provides a detailed description of all the previous points in order to highlight the importance and potential of proteins and peptides as drugs. Copyright © 2014 Elsevier B.V. All rights reserved.International Journal of Pharmaceutics 10/2014; 477(1-2):578-589. DOI:10.1016/j.ijpharm.2014.10.059 · 3.79 Impact Factor
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ABSTRACT: The World Health Organization (WHO) recently reported that the total number of global cancer cases in 2013 reached 14 million, a 10% rise since 2008, while the total number of cancer deaths reached 8.2 million, a 5.2% increase since 2008. Metastasis is the major cause of death from cancer, accounting for 90% of all cancer related deaths. Tumor-draining lymph nodes (TDLN), the sentinel nodes, are the first organs of metastasis in several types of cancers. The extent of metastasis in the TDLN is often used in disease staging and prognosis evaluation in cancer patients. Here, we describe the microenvironment of the TDLN and review the recent literature on liposome-based therapies directed to immune cells within the TDLN with the intent to target cancer cells.International Journal of Molecular Sciences 11/2014; 15(11):20209-20239. DOI:10.3390/ijms151120209 · 2.34 Impact Factor