HDL in Endocrine Carcinomas: Biomarker, Drug Carrier, and Potential Therapeutic

High-density lipoprotein (HDL) have long been studied for their protective role against cardiovascular diseases, however recently relationship between HDL and cancer came into focus. Several epidemiological studies have shown an inverse correlation between HDL-cholesterol (HDL-C) and cancer risk, and some have even implied that HDL-C can be used as a predictive measure for survival prognosis in for specific sub-population of certain types of cancer. HDL itself is an endogenous nanoparticle capable of removing excess cholesterol from the periphery and returning it to the liver for excretion. One of the main receptors for HDL, scavenger receptor type B-I (SR-BI), is highly upregulated in endocrine cancers, notably due to the high demand for cholesterol by cancer cells. Thus, the potential to exploit administration of cholesterol-free reconstituted or synthetic HDL (sHDL) to deplete cholesterol in endocrine cancer cell and stunt their growth of use chemotherapeutic drug loaded sHDL to target payload delivery to cancer cell has become increasingly attractive. This review focuses on the role of HDL and HDL-C in cancer and application of sHDLs as endocrine cancer therapeutics

HDL in Endocrine Carcinomas: Biomarker, Drug Carrier, and Potential Therapeutic

High-density lipoprotein (HDL) have long been studied for their protective role against cardiovascular diseases, however recently relationship between HDL and cancer came into focus. Several epidemiological studies have shown an inverse correlation between HDL-cholesterol (HDL-C) and cancer risk, and some have even implied that HDL-C can be used as a predictive measure for survival prognosis in for specific sub-population of certain types of cancer. HDL itself is an endogenous nanoparticle capable of removing excess cholesterol from the periphery and returning it to the liver for excretion. One of the main receptors for HDL, scavenger receptor type B-I (SR-BI), is highly upregulated in endocrine cancers, notably due to the high demand for cholesterol by cancer cells. Thus, the potential to exploit administration of cholesterol-free reconstituted or synthetic HDL (sHDL) to deplete cholesterol in endocrine cancer cell and stunt their growth of use chemotherapeutic drug loaded sHDL to target payload delivery to cancer cell has become increasingly attractive. This review focuses on the role of HDL and HDL-C in cancer and application of sHDLs as endocrine cancer therapeutics

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Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155986/1/art41237.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155986/2/art41237_am.pd

High‐Density Lipoprotein in Lupus: Disease Biomarkers and Potential Therapeutic Strategy

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152788/1/art41059_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/152788/2/art41059.pd

Battle of GLP-1 delivery technologies

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) belong to an important therapeutic class for treatment of type 2 diabetes. Six GLP-1 RAs, each utilizing a unique drug delivery strategy, are now approved by the Food and Drug Administration (FDA) and additional, novel GLP-1 RAs are still under development, making for a crowded marketplace and fierce competition among the manufacturers of these products. As rapid elimination is a major challenge for clinical application of GLP-1 RAs, various half-life extension strategies have been successfully employed including sequential modification, attachment of fatty-acid to peptide, fusion with human serum albu- min, fusion with the fragment crystallizable (Fc) region of a monoclonal antibody, sustained drug delivery sys- tems, and PEGylation. In this review, we discuss the scientific rationale of the various half-life extension strategies used for GLP-1 RA development. By analyzing and comparing different approved GLP-1 RAs and those in development, we focus on assessing how half-life extending strategies impact the pharmacokinetics, pharmacodynamics, safety, patient usability and ultimately, the commercial success of GLP-1 RA products. We also anticipate future GLP-1 RA development trends. Since similar drug delivery strategies are also applied for de- veloping other therapeutic peptides, we expect this case study of GLP-1 RAs will provide generalizable concepts for the rational design of therapeutic peptides products with extended duration of action

A Multidimensional Analytical Comparison of Remicade and the Biosimilar Remsima

In April 2016, the Food and Drug Administration approved the first biosimilar monoclonal antibody (mAb) – Inflectra/Remsima (Celltrion) based off the original product Remicade (infliximab, Janssen). Biosimilars promise significant cost savings for patients, but the unavoidable differences between innovator and copycat biologics raise questions regarding product interchangeability. In this study, Remicade and Remsima were examined by native mass spectrometry, ion mobility and quantitative peptide mapping. The levels of oxidation, deamidation and mutation of individual amino acids were remarkably similar. We found different levels of C-terminal truncation, soluble protein aggregates and glycation that all likely have a limited clinical impact. Importantly, we identified over 25 glycoforms for each product and observed glycoform population differences, with afucosylated glycans accounting for 19.7% of Remicade and 13,2% of Remsima glycoforms, which translated into a 2-fold reduction in FcγRIIIa binding for Remsima. While this difference was acknowledged in Remsima regulatory filings, our glycoform analysis and receptor binding results appear to be somewhat different from the published values, likely due to methodological differences between laboratories and improved glycoform identification by our laboratory using a peptide map-based method. Our mass spectrometry based analysis provides rapid and robust analytical information vital for biosimilar development. We have demonstrated the utility of our multiple attribute monitoring workflow using the model mAbs Remicade and Remsima, and have provided a template for analysis of future mAb biosimilars

Robust Anti‐Tumor T Cell Response with Efficient Intratumoral Infiltration by Nanodisc Cancer Immunotherapy

Potent anti‐tumor T cell response and efficient intratumoral T cell infiltration are the major challenges for therapeutic cancer vaccines. To address these issues, a nanovaccine system is designed to promote anti‐tumor T cell responses, and intratumoral infiltration is examined in various murine tumor models. Subcutaneous vaccination with nanodiscs carrying human papillomavirus (HPV)‐16 E7 antigen elicits as high as ∼32% E7‐specific CD8α+ T cell responses in circulation, representing a 29‐fold improvement over the soluble peptide vaccination. Importantly, nanodisc vaccination also promotes robust intratumoral T cell infiltration and eliminates HPV16 E6/E7‐expressing TC‐1 tumors at mucosal sites, including lungs, inner lip, and intravaginal tissues. In a benchmark study with a live Listeria vaccine combined with anti‐PD‐1 IgG, nanodiscs plus anti‐PD‐1 immune checkpoint blockade elicits comparable levels of T cell responses with anti‐tumor efficacy. Furthermore, compared with Complete Freund’s Adjuvant combined with tetanus toxoid, nanodisc vaccination in HLA‐A02 mice generates >200‐fold stronger IFN‐γ+ T cell responses against a neoantigen from an HLA‐A02 melanoma patient. Overall, these results show that the nanodisc system is a promising cancer vaccine platform for inducing anti‐tumor T cell responses.Efficient infiltration of T cells in solid cancer is a major challenge for cancer immunotherapy. A nanoparticle vaccine system is developed to promote T cell infiltration into peripheral mucosal tissues and eliminate disseminated tumors. Nanodiscs are broadly applicable with a wide range of tumor antigens, thus providing a versatile and potent vaccine platform for eliciting T cell immunity.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156420/3/adtp202000094.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156420/2/adtp202000094-sup-0001-SuppMat.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156420/1/adtp202000094_am.pd

Immunotherapy for gliomas: shedding light on progress in preclinical and clinical development

Gliomas are infiltrating brain tumors associated with high morbidity and mortality. Current standard of care includes radiation, chemotherapy and surgical resection. Today, survival rates for malignant glioma patients remain dismal and unchanged for decades. The glioma microenvironment is highly immunosuppressive and consequently this has motivated the development of immunotherapies for counteracting this condition, enabling the immune cells within the tumor microenvironment to react against this tumor.Areas covered: The authors discuss immunotherapeutic strategies for glioma in phase-I/II clinical trials and illuminate their mechanisms of action, limitations and key challenges. They also examine promising approaches under preclinical development.Expert opinion: In the last decade there has been an expansion in immune-mediated anti-cancer therapies. In the glioma field, sophisticated strategies have been successfully implemented in preclinical models. Unfortunately, clinical trials have not yet yielded consistent results for glioma patients. This could be attributed to our limited understanding of the complex immune cell infiltration and its interaction with the tumor cells, the selected time for treatment, the combination with other therapies and the route of administration of the agent. Applying these modalities to treat malignant glioma is challenging, but many new alternatives are emerging to by-pass these hurdles.Fil: Garcia Fabiani, Maria Belen. University of Michigan; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ventosa, Maria. University of Michigan; Estados UnidosFil: Comba, Andrea. University of Michigan; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Candolfi, Marianela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; ArgentinaFil: Nicola Candia, Alejandro Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; ArgentinaFil: Alghamri, Mahmoud S.. University of Michigan; Estados UnidosFil: Kadiyala, Padma. University of Michigan; Estados UnidosFil: Carney, Stephen. University of Michigan; Estados UnidosFil: Faisal, Syed M.. University of Michigan; Estados UnidosFil: Schwendeman, Anna. University of Michigan; Estados UnidosFil: Moon, James J.. University of Michigan; Estados UnidosFil: Scheetz, Lindsay. University of Michigan; Estados UnidosFil: Lahann, Joerg. University of Michigan; Estados UnidosFil: Mauser, Ava. University of Michigan; Estados UnidosFil: Lowenstein, Pedro R.. University of Michigan; Estados UnidosFil: Castro, Maria Gabriela. University of Michigan; Estados Unido

Genetic Alterations in Gliomas Remodel the Tumor Immune Microenvironment and Impact Immune-Mediated Therapies

High grade gliomas are malignant brain tumors that arise in the central nervous system, in patients of all ages. Currently, the standard of care, entailing surgery and chemo radiation, exhibits a survival rate of 14-17 months. Thus, there is an urgent need to develop new therapeutic strategies for these malignant brain tumors. Currently, immunotherapies represent an appealing approach to treat malignant gliomas, as the pre-clinical data has been encouraging. However, the translation of the discoveries from the bench to the bedside has not been as successful as with other types of cancer, and no long-lasting clinical benefits have been observed for glioma patients treated with immune-mediated therapies so far. This review aims to discuss our current knowledge about gliomas, their molecular particularities and the impact on the tumor immune microenvironment. Also, we discuss several murine models used to study these therapies pre-clinically and how the model selection can impact the outcomes of the approaches to be tested. Finally, we present different immunotherapy strategies being employed in clinical trials for glioma and the newest developments intended to harness the immune system against these incurable brain tumors.Fil: Garcia Fabiani, Maria Belen. University of Michigan; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Haase, Santiago. University of Michigan; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Comba, Andrea. University of Michigan; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Carney, Stephen. University of Michigan; Estados UnidosFil: McClellan, Brandon. University of Michigan; Estados UnidosFil: Banerjee, Kaushik. University of Michigan; Estados UnidosFil: Alghamri, Mahmoud S.. University of Michigan; Estados UnidosFil: Syed, Faisal. University of Michigan; Estados UnidosFil: Kadiyala, Padma. University of Michigan; Estados UnidosFil: Nuñez, Felipe. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Candolfi, Marianela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; ArgentinaFil: Asad, Antonela Sofía. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; ArgentinaFil: González, Nazareno. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; ArgentinaFil: Aikins, Marisa E.. University of Michigan; Estados UnidosFil: Schwendeman, Anna. University of Michigan; Estados UnidosFil: Moon, James J.. University of Michigan; Estados UnidosFil: Lowenstein, Pedro R.. University of Michigan; Estados UnidosFil: Castro, Maria G.. University of Michigan; Estados Unido