Stephan MT, Moon JJ, Um SH et al.Therapeutic cell engineering with surface-conjugated synthetic nanoparticles. Nat Med 16:1035-1041

Department of Material Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Nature medicine (Impact Factor: 27.36). 09/2010; 16(9):1035-41. DOI: 10.1038/nm.2198
Source: PubMed


A major limitation of cell therapies is the rapid decline in viability and function of the transplanted cells. Here we describe a strategy to enhance cell therapy via the conjugation of adjuvant drug-loaded nanoparticles to the surfaces of therapeutic cells. With this method of providing sustained pseudoautocrine stimulation to donor cells, we elicited marked enhancements in tumor elimination in a model of adoptive T cell therapy for cancer. We also increased the in vivo repopulation rate of hematopoietic stem cell grafts with very low doses of adjuvant drugs that were ineffective when given systemically. This approach is a simple and generalizable strategy to augment cytoreagents while minimizing the systemic side effects of adjuvant drugs. In addition, these results suggest therapeutic cells are promising vectors for actively targeted drug delivery.

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Available from: Darrell J Irvine
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    • "They will be recognized by overexpressed molecular patterns at the tissues/cells intended to target, facilitating NP recognition and subsequent receptor-mediated endocytosis (Figure 6) (Cheng et al., 2007; Kumar et al., 2009; Danhier et al., 2010; Aslan et al., 2013; Nicolas et al., 2013; Wang et al., 2013a; Gao et al., 2014). Surface modifications represent an outstanding tool for cell targeting allowing a specific contact of nanoparticulate systems with critical immune cells, as evidenced in Stephan et al. (2010). For example, the ligand DEC-205 is highly expressed by CD8+DCs, cells particularly efficient at " cross-presenting " exogenous antigens on MHCI, constituting a highly relevant pathway for the development of a cytolytic immune response. "
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    ABSTRACT: Cancer is one of the most common diseases afflicting people globally. New therapeutic approaches are needed due to the complexity of cancer as a disease. Many current treatments are very toxic and have modest efficacy at best. Increased understanding of tumor biology and immunology has allowed the development of specific immunotherapies with minimal toxicity. It is important to highlight the performance of monoclonal antibodies, immune adjuvants, vaccines and cell-based treatments. Although these approaches have shown varying degrees of clinical efficacy, they illustrate the potential to develop new strategies. Targeted immunotherapy is being explored to overcome the heterogeneity of malignant cells and the immune suppression induced by both the tumor and its microenvironment. Nanodelivery strategies seek to minimize systemic exposure to target therapy to malignant tissue and cells. Intracellular penetration has been examined through the use of functionalized particulates. These nano-particulate associated medicines are being developed for use in imaging, diagnostics and cancer targeting. Although nano-particulates are inherently complex medicines, the ability to confer, at least in principle, different types of functionality allows for the plausible consideration these nanodelivery strategies can be exploited for use as combination medicines. The development of targeted nanodelivery systems in which therapeutic and imaging agents are merged into a single platform is an attractive strategy. Currently, several nanoplatform-based formulations, such as polymeric nanoparticles, micelles, liposomes and dendrimers are in preclinical and clinical stages of development. Herein, nanodelivery strategies presently investigated for cancer immunotherapy, cancer targeting mechanisms and nanocarrier functionalization methods will be described. We also intend to discuss the emerging nano-based approaches suitable to be used as imaging techniques and as cancer treatment options.
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    • "T-cell-bound particles provided pseudo-autocrine drug delivery to the transferred cells that greatly increased the effective potency of adjuvant drugs while simultaneously minimizing systemic exposure to these potent supporting signals. This approach allowed autocrine delivery of interleukin cytokines that dramatically enhanced the efficacy of ACT T-cells in a metastatic melanoma model [15] and the delivery of immunosuppression-blocking drugs that enhanced expansion of T-cells within large established tumors in a prostate cancer model [16]. A limitation of the pharmacyte approach is the one-time nature of the intervention: ACT T-cells can only be loaded once with a cargo of adjuvant drug prior to transfer, and the duration of stimulation is inherently limited by expansion of the cell population in vivo, since cell-bound particles are diluted with each cell division. "
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    ABSTRACT: In adoptive cell therapy (ACT), autologous tumor-specific T-cells isolated from cancer patients are activated and expanded ex vivo, then infused back into the individual to eliminate metastatic tumors. A major limitation of this promising approach is the rapid loss of ACT T-cell effector function in vivo due to the highly immunosuppressive environment in tumors. Protection of T-cells from immunosuppressive signals can be achieved by systemic administration of supporting adjuvant drugs such as interleukins, chemotherapy, and other immunomodulators, but these adjuvant treatments are often accompanied by serious toxicities and may still fail to optimally stimulate lymphocytes in all tumor and lymphoid compartments. Here we propose a novel strategy to repeatedly stimulate or track ACT T-cells, using cytokines or ACT-cell-specific antibodies as ligands to target PEGylated liposomes to transferred T-cells in vivo. Using F(ab')2 fragments against a unique cell surface antigen on ACT cells (Thy1.1) or an engineered interleukin-2 (IL-2) molecule on an Fc framework as targeting ligands, we demonstrate that >95% of ACT cells can be conjugated with liposomes following a single injection in vivo. Further, we show that IL-2-conjugated liposomes both target ACT cells and are capable of inducing repeated waves of ACT T-cell proliferation in tumor-bearing mice. These results demonstrate the feasibility of repeated functional targeting of T-cells in vivo, which will enable delivery of imaging contrast agents, immunomodulators, or chemotherapy agents in adoptive cell therapy regimens.
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    • "Especially in the area of signaling, significant progress has been made over the past few years. Biomaterials that slowly deliver proteins,[25] drugs,[26] plasmids,[27] viruses,[27] and microRNAs[28] to surrounding tissue are currently available. "
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    ABSTRACT: Cardiovascular disease is a major cause of morbidity and mortality throughout the world. Most cardiovascular diseases, such as ischemic heart disease and cardiomyopathy, are associated with loss of functional cardiomyocytes. Unfortunately, the heart has a limited regenerative capacity and is not able to replace these cardiomyocytes once lost. In recent years, stem cells have been put forward as a potential source for cardiac regeneration. Pre-clinical studies that use stem cell-derived cardiac cells show promising results. The mechanisms, though, are not well understood, results have been variable, sometimes transient in the long term, and often without a mechanistic explanation. There are still several major hurdles to be taken. Stem cell-derived cardiac cells should resemble original cardiac cell types and be able to integrate in the damaged heart. Integration requires administration of stem cell-derived cardiac cells at the right time using the right mode of delivery. Once delivered, transplanted cells need vascularization, electrophysiological coupling with the injured heart, and prevention of immunological rejection. Finally, stem cell therapy needs to be safe, reproducible, and affordable. In this review, we will give an introduction to the principles of stem cell based cardiac repair.
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