Biomedicines

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Open AccessFeature PaperReview

by Jasper J. P. Van Beek, Anne W. J. Martens, Ghaith Bakdash and I. Jolanda M. De Vries

Biomedicines 2016, 4(1), 7; https://doi.org/10.3390/biomedicines4010007 - 25 Feb 2016

Cited by 25 | Viewed by 7541

Innate lymphoid cells (ILCs) are a group of immune cells of the lymphoid lineage that do not possess antigen specificity. The group includes natural killer (NK) cells, lymphoid tissue inducer (LTi) cells and the recently identified ILC1s, ILC2s and ILC3s. Although the role [...] Read more.

Innate lymphoid cells (ILCs) are a group of immune cells of the lymphoid lineage that do not possess antigen specificity. The group includes natural killer (NK) cells, lymphoid tissue inducer (LTi) cells and the recently identified ILC1s, ILC2s and ILC3s. Although the role of NK cells in the context of cancer has been well established, the involvement of other ILC subsets in cancer progression and resistance is just emerging. Here, we review the literature on the role of the different ILC subsets in tumor immunity and discuss its implications for cancer treatment and monitoring. Full article

(This article belongs to the Special Issue Dendritic Cells and Cancer Immunotherapy)

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Open AccessArticle

Direct Lymph Node Vaccination of Lentivector/Prostate-Specific Antigen is Safe and Generates Tissue-Specific Responses in Rhesus Macaques

by Bryan C. Au, Chyan-Jang Lee, Orlay Lopez-Perez, Warren Foltz, Tania C. Felizardo, James C.M. Wang, Ju Huang, Xin Fan, Melissa Madden, Alyssa Goldstein, David A. Jaffray, Badru Moloo, J. Andrea McCart and Jeffrey A. Medin

Biomedicines 2016, 4(1), 6; https://doi.org/10.3390/biomedicines4010006 - 19 Feb 2016

Cited by 2 | Viewed by 5414

Abstract

Anti-cancer immunotherapy is emerging from a nadir and demonstrating tangible benefits to patients. A variety of approaches are now employed. We are invoking antigen (Ag)-specific responses through direct injections of recombinant lentivectors (LVs) that encode sequences for tumor-associated antigens into multiple lymph nodes [...] Read more.

Anti-cancer immunotherapy is emerging from a nadir and demonstrating tangible benefits to patients. A variety of approaches are now employed. We are invoking antigen (Ag)-specific responses through direct injections of recombinant lentivectors (LVs) that encode sequences for tumor-associated antigens into multiple lymph nodes to optimize immune presentation/stimulation. Here we first demonstrate the effectiveness and antigen-specificity of this approach in mice challenged with prostate-specific antigen (PSA)-expressing tumor cells. Next we tested the safety and efficacy of this approach in two cohorts of rhesus macaques as a prelude to a clinical trial application. Our vector encodes the cDNA for rhesus macaque PSA and a rhesus macaque cell surface marker to facilitate vector titering and tracking. We utilized two independent injection schemas demarcated by the timing of LV administration. In both cohorts we observed marked tissue-specific responses as measured by clinical evaluations and magnetic resonance imaging of the prostate gland. Tissue-specific responses were sustained for up to six months—the end-point of the study. Control animals immunized against an irrelevant Ag were unaffected. We did not observe vector spread in test or control animals or perturbations of systemic immune parameters. This approach thus offers an “off-the-shelf” anti-cancer vaccine that could be made at large scale and injected into patients—even on an out-patient basis. Full article

(This article belongs to the Special Issue Dendritic Cells and Cancer Immunotherapy)

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Open AccessArticle

In Vivo Efficacy of Artesunate/Sulphadoxine-Pyrimethamine versus Artesunate/Amodiaquine in the Treatment of Uncomplicated P. falciparium Malaria in Children around the Slope of Mount Cameroon: A Randomized Controlled Trial

by Tobias O. Apinjoh, Judith K. Anchang-Kimbi, Marcelus U. Ajonina, Esther T. Njonguo, Clarisse Njua-Yafi, Andre N. Ngwai, Regina N. Mugri and Eric A. Achidi

Biomedicines 2016, 4(1), 5; https://doi.org/10.3390/biomedicines4010005 - 15 Feb 2016

Cited by 5 | Viewed by 5517

Abstract

Background: The development and spread of antimalarial drug resistant parasites contributes to the global impact of the disease. In vivo efficacy assessments of treatments for Plasmodium falciparum malaria are essential for ensuring effective case management. Artemisinin-based combinations have been adopted as the first-line [...] Read more.

Background: The development and spread of antimalarial drug resistant parasites contributes to the global impact of the disease. In vivo efficacy assessments of treatments for Plasmodium falciparum malaria are essential for ensuring effective case management. Artemisinin-based combinations have been adopted as the first-line treatment for uncomplicated P. falciparum malaria in Cameroon since 2004. Methods: A total of 177 children aged six-months to 10 years with uncomplicated mono-infected falciparum malaria were randomized (1:1) to receive artesunate/sulphadoxine-pyrimethamine (AS/SP) or artesunate/amodiaquine (AS/AQ) pediatric tablets and followed up for 28 days according to the standard World Health Organization in vivo drug efficacy monitoring protocol. The primary and secondary endpoints were PCR uncorrected and corrected cure rates, as measured by adequate clinical and parasitological response (ACPR) on day 28. Results: The PCR corrected cure rate was high, overall (88.1%, 95% CI 83.1–93.1), 85.9% (95% CI 78.2–93.6), and 90.2% (95% CI 83.8–96.6) for AS/SP and AS/AQ, respectively. Twenty-one treatment failures were observed during follow-up, constituting one (4.6%), 14 (8.2%), and six (3.5%) early treatment failure (ETF), late clinical failure (LCF), and late parasitological failure (LPF), respectively. The drugs were well tolerated with no serious adverse events. Conclusions: Both AS/SP and AS/AQ are highly effective and well-tolerated treatments for uncomplicated P. falciparum malaria around the slope of Mount Cameroon. Full article

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Open AccessReview

Insulators to Improve the Safety of Retroviral Vectors for HIV Gene Therapy

by Diana L. Browning and Grant D. Trobridge

Biomedicines 2016, 4(1), 4; https://doi.org/10.3390/biomedicines4010004 - 02 Feb 2016

Cited by 8 | Viewed by 5911

Abstract

Retroviral vector gene therapy is a promising approach to treating HIV-1. However, integrated vectors are mutagens with the potential to dysregulate nearby genes and cause severe adverse side effects. Leukemia has already been a documented severe adverse event in gene therapy clinical trials [...] Read more.

Retroviral vector gene therapy is a promising approach to treating HIV-1. However, integrated vectors are mutagens with the potential to dysregulate nearby genes and cause severe adverse side effects. Leukemia has already been a documented severe adverse event in gene therapy clinical trials for the treatment of primary immunodeficiencies. These side effects will need to be reduced or avoided if retroviral vectors are to be used clinically for HIV-1 treatment. The addition of chromatin insulators to retroviral vectors is a potential strategy for reducing adverse side effects. Insulators have already been effectively used in retroviral vectors to reduce genotoxicity in pre-clinical studies. Here, we will review how insulators function, genotoxicity in gene therapy clinical trials, the design of insulated retroviral vectors, promising results from insulated retroviral vector studies, and considerations for the development of insulated retroviral treatment vectors for HIV-1 gene therapy. Full article

(This article belongs to the Special Issue Gene Therapy Strategies for HIV/AIDS)

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Open AccessArticle

In Vitro Synergistic Enhancement of Newcastle Disease Virus to 5-Fluorouracil Cytotoxicity against Tumor Cells

by Ahmed M. Al-Shammari, Marwa I. Salman, Yahya D. Saihood, Nahi Y. Yaseen, Khansaa Raed, Hiba Kareem Shaker, Aesar Ahmed, Aseel Khalid and Ahlam Duiach

Biomedicines 2016, 4(1), 3; https://doi.org/10.3390/biomedicines4010003 - 29 Jan 2016

Cited by 72 | Viewed by 6346

Abstract

Background: Chemotherapy is one of the antitumor therapies used worldwide in spite of its serious side effects and unsatisfactory results. Many attempts have been made to increase its activity and reduce its toxicity. 5-Fluorouracil (5-FU) is still a widely-used chemotherapeutic agent, especially in [...] Read more.

Background: Chemotherapy is one of the antitumor therapies used worldwide in spite of its serious side effects and unsatisfactory results. Many attempts have been made to increase its activity and reduce its toxicity. 5-Fluorouracil (5-FU) is still a widely-used chemotherapeutic agent, especially in combination with other chemotherapies. Combination therapy seems to be the best option for targeting tumor cells by different mechanisms. Virotherapy is a promising agent for fighting cancer because of its safety and selectivity. Newcastle disease virus is safe, and it selectively targets tumor cells. We previously demonstrated that Newcastle disease virus (NDV) could be used to augment other chemotherapeutic agents and reduce their toxicity by halving the administered dose and replacing the eliminated chemotherapeutic agents with the Newcastle disease virus; the same antitumor activity was maintained. Methods: In the current work, we tested this hypothesis on different tumor cell lines. We used the non-virulent LaSota strain of NDV in combination with 5-FU, and we measured the cytotoxicity effect. We evaluated this combination using Chou–Talalay analysis. Results: NDV was synergistic with 5-FU at low doses when used as a combination therapy on different cancer cells, and there were very mild effects on non-cancer cells. Conclusion: The combination of a virulent, non-pathogenic NDV–LaSota strain with a standard chemotherapeutic agent, 5-FU, has a synergistic effect on different tumor cells in vitro, suggesting this combination could be an important new adjuvant therapy for treating cancer. Full article

(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer)

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Open AccessFeature PaperReview

Stem Cell Therapies for Treatment of Liver Disease

by Clara Nicolas, Yujia Wang, Jennifer Luebke-Wheeler and Scott L. Nyberg

Biomedicines 2016, 4(1), 2; https://doi.org/10.3390/biomedicines4010002 - 06 Jan 2016

Cited by 35 | Viewed by 14021

Abstract

Cell therapy is an emerging form of treatment for several liver diseases, but is limited by the availability of donor livers. Stem cells hold promise as an alternative to the use of primary hepatocytes. We performed an exhaustive review of the literature, with [...] Read more.

Cell therapy is an emerging form of treatment for several liver diseases, but is limited by the availability of donor livers. Stem cells hold promise as an alternative to the use of primary hepatocytes. We performed an exhaustive review of the literature, with a focus on the latest studies involving the use of stem cells for the treatment of liver disease. Stem cells can be harvested from a number of sources, or can be generated from somatic cells to create induced pluripotent stem cells (iPSCs). Different cell lines have been used experimentally to support liver function and treat inherited metabolic disorders, acute liver failure, cirrhosis, liver cancer, and small-for-size liver transplantations. Cell-based therapeutics may involve gene therapy, cell transplantation, bioartificial liver devices, or bioengineered organs. Research in this field is still very active. Stem cell therapy may, in the future, be used as a bridge to either liver transplantation or endogenous liver regeneration, but efficient differentiation and production protocols must be developed and safety must be demonstrated before it can be applied to clinical practice. Full article

(This article belongs to the Special Issue Stem Cell Engineering: From Reprogramming Technologies to Translational Biomedicines)

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Open AccessArticle

Synthesis and Preliminary Biological Evaluations of Fluorescent or ¹⁴⁹Promethium Labeled Trastuzumab-Polyethylenimine

by Jonathan Fitzsimmons, Tapan Nayak, Cathy Cutler and Robert Atcher

Biomedicines 2016, 4(1), 1; https://doi.org/10.3390/biomedicines4010001 - 30 Dec 2015

Cited by 1 | Viewed by 6381

Abstract

Background: Radioimmunotherapy utilize a targeting antibody coupled to a therapeutic isotope to target and treat a tumor or disease. In this study we examine the synthesis and cell binding of a polymer scaffold containing a radiotherapeutic isotope and a targeting antibody. Methods: The [...] Read more.

Background: Radioimmunotherapy utilize a targeting antibody coupled to a therapeutic isotope to target and treat a tumor or disease. In this study we examine the synthesis and cell binding of a polymer scaffold containing a radiotherapeutic isotope and a targeting antibody. Methods: The multistep synthesis of a fluorescent or ¹⁴⁹Promethium-labeled Trastuzumab-polyethyleneimine (PEI), Trastuzumab, or PEI is described. In vitro uptake, internalization and/or the binding affinity to the Her2/neu expressing human breast adenocarcinoma SKBr3 cells was investigated with the labeled compounds. Results: Fluorescent-labeled Trastuzumab-PEI was internalized more into cells at 2 and 18 h than fluorescent-labeled Trastuzumab or PEI. The fluorescent-labeled Trastuzumab was concentrated on the cell surface at 2 and 18 h and the labeled PEI had minimal uptake. DOTA-PEI was prepared and contained an average of 16 chelates per PEI; the compound was radio-labeled with ¹⁴⁹Promethium and conjugated to Trastuzumab. The purified ¹⁴⁹Pm-DOTA-PEI-Trastuzumab had a radiochemical purity of 96.7% and a specific activity of 0.118 TBq/g. The compound demonstrated a dissociation constant for the Her2/neu receptor of 20.30 ± 6.91 nM. Conclusion: The results indicate the DOTA-PEI-Trastuzumab compound has potential as a targeted therapeutic carrier, and future in vivo studies should be performed. Full article

(This article belongs to the Special Issue Development, Manufacture and Clinical Application of Drug Conjugates in Cancer Therapy)

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Biomedicines, Volume 4, Issue 1 (March 2016) – 7 articles

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