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Pandolfi F.,Institute of Internal Medicine | Frosali S.,Institute of Internal Medicine | Petruzziello L.,Catholic University of Rome | Newton E.E.,Cytocure, Llc | Costamagna G.,Catholic University of Rome
Mini-Reviews in Medicinal Chemistry | Year: 2016

We review our experience on Rifaximin in uncomplicated diverticular disease. Our data show that a 2 week treatment induces modifications in the immune system: local mucosal lymphocytes with TLR-4 were increased. In the peripheral blood CD103 cells, which increased before treatment, returned to normal values after Rifaximin. © 2016 Bentham Science Publishers.


The Direct RNA Template (DRT) hypothesis proposes that an early stage of genetic code evolution involved RNA molecules acting as stereochemical recognition templates for assembly of specific amino acids in sequence-ordered arrays, providing a framework for directed covalent peptide bond formation. It is hypothesized here that modern biological precedents may exist for RNA-based structural templating with functional analogies to hypothetical DRT systems. Beyond covalent molecular assembly, an extension of the DRT concept can include RNA molecules acting as dynamic structural template guides for the specific non-covalent assembly of multi-subunit complexes, equivalent to structural assembly chaperones. However, despite numerous precedents for RNA molecules acting as scaffolds for protein complexes, true RNA-mediated assembly chaperoning appears to be absent in modern biosystems. Another level of function with parallels to a DRT system is possible if RNA structural motifs dynamically guided specific patterns of catalytic modifications within multiple target sites in a pre-formed polymer or macromolecular complex. It is suggested that this type of structural RNA templating could logically play a functional role in certain areas of biology, one of which is the glycome of complex organisms. If any such RNA templating processes are shown to exist, they would share no necessary evolutionary relationships with events during early molecular evolution, but may promote understanding of the practical limits of biological RNA functions now and in the ancient RNA World. Awareness of these formal possibilities may also assist in the current search for functions of extensive non-coding RNAs in complex organisms, or for efforts towards artificial rendering of DRT systems. © 2011 Elsevier Ltd.


Haggerty T.J.,Cytocure, Llc | Haggerty T.J.,Harvard University | Dunn I.S.,Cytocure, Llc | Rose L.B.,Cytocure, Llc | And 3 more authors.
Assay and Drug Development Technologies | Year: 2012

Although a series of melanoma differentiation antigens for immunotherapeutic targeting has been described, heterogeneous expression of antigens such as Melan-A/MART-1 and gp100 results from a loss of antigenic expression in many late stage tumors. Antigen loss can represent a means for tumor escape from immune recognition, and a barrier to immunotherapy. However, since antigen-negative tumor phenotypes frequently result from reversible gene regulatory events, antigen enhancement represents a potential therapeutic opportunity. Accordingly, we have developed a cell-based assay to screen for compounds with the ability to enhance T-cell recognition of melanoma cells. This assay is dependent on augmentation of MelanA/MART-1 antigen presentation by a melanoma cell line (MU89). T-cell recognition is detected as interleukin-2 production by a Jurkat T cell transduced to express a T-cell receptor specific for an HLA-A2 restricted epitope of the Melan-A/MART-1 protein. This cellular assay was used to perform a pilot screen by using 480 compounds of known biological activity. From the initial proof-of-principle primary screen, eight compounds were identified as positive hits. A panel of secondary screens, including orthogonal assays, was used to validate the primary hits and eliminate false positives, and also to measure the comparative efficacy of the identified compounds. This cell-based assay, thus, yields consistent results applicable to the screening of larger libraries of compounds that can potentially reveal novel molecules which allow better recognition of treated tumors by T cells. © Copyright 2012, Mary Ann Liebert, Inc.


Haggerty T.J.,Cytocure, Llc | Haggerty T.J.,Harvard University | Dunn I.S.,Cytocure, Llc | Rose L.B.,Cytocure, Llc | And 4 more authors.
Cancer Immunology, Immunotherapy | Year: 2011

While there are many obstacles to immune destruction of autologous tumors, there is mounting evidence that tumor antigen recognition does occur. Unfortunately, immune recognition rarely controls clinically significant tumors. Even the most effective immune response will fail if tumors fail to express target antigens. Importantly, reduced tumor antigen expression often results from changes in gene regulation rather than irrevocable loss of genetic information. Such perturbations are often reversible by specific compounds or biological mediators, prompting a search for agents with improved antigen-enhancing properties. Some recent findings have suggested that certain conventional chemotherapeutic agents may have beneficial properties for cancer treatment beyond their direct cytotoxicities against tumor cells. Accordingly, we screened an important subset of these agents, topoisomerase inhibitors, for their effects on antigen levels in tumor cells. Our analyses demonstrate upregulation of antigen expression in a variety of melanoma cell lines and gliomas in response to nanomolar levels of certain specific topoisomerase inhibitors. To demonstrate the ability of CD8+ T cells to recognize tumors, we assayed cytokine secretion in T cells transfected with T cell receptors directed against Melan-A/MART-1 antigen. Three days of daunorubicin treatment resulted in enhanced antigen expression by tumor cells, in turn inducing co-cultured antigen-specific T cells to secrete Interleukin-2 and Interferon-γ. These results demonstrate that specific topoisomerase inhibitors can augment melanoma antigen production, suggesting that a combination of chemotherapy and immunotherapy may be of potential value in the treatment of otherwise insensitive cancers. © Springer-Verlag 2010.


Dunn I.S.,Cytocure, Llc
Origins of Life and Evolution of Biospheres | Year: 2013

Terrestrial biosystems depend on macromolecules, and this feature is often considered as a likely universal aspect of life. While opinions differ regarding the importance of small-molecule systems in abiogenesis, escalating biological functional demands are linked with increasing complexity in key molecules participating in biosystem operations, and many such requirements cannot be efficiently mediated by relatively small compounds. It has long been recognized that known life is associated with the evolution of two distinct molecular alphabets (nucleic acid and protein), specific sequence combinations of which serve as informational and functional polymers. In contrast, much less detailed focus has been directed towards the potential universal need for molecular alphabets in constituting complex chemically-based life, and the implications of such a requirement. To analyze this, emphasis here is placed on the generalizable replicative and functional characteristics of molecular alphabets and their concatenates. A primary replicative alphabet based on the simplest possible molecular complementarity can potentially enable evolutionary processes to occur, including the encoding of secondarily functional alphabets. Very large uniquely specified ('non-alphabetic') molecules cannot feasibly underlie systems capable of the replicative and evolutionary properties which characterize complex biosystems. Transitions in the molecular evolution of alphabets can be related to progressive bridging of barriers which enable higher levels of biosystem organization. It is thus highly probable that molecular alphabets are an obligatory requirement for complex chemically-based life anywhere in the universe. In turn, reference to molecular alphabets should be usefully applied in current definitions of life. © 2014 Springer Science+Business Media Dordrecht.


Pagliari D.,Catholic University of the Sacred Heart | Cianci R.,Catholic University of the Sacred Heart | Frosali S.,Catholic University of the Sacred Heart | Landolfi R.,Catholic University of the Sacred Heart | And 3 more authors.
Cytokine and Growth Factor Reviews | Year: 2013

IL-15 is a member of the IL-2 family of cytokines whose signaling pathways are a bridge between innate and adaptive immune response. IL-15 is part of the intestinal mucosal barrier, and functions to modulate gut homeostasis. IL-15 has pivotal roles in the control of development, proliferation and survival of both innate and adaptive immune cells. IL-15 becomes up-regulated in the inflamed tissue of intestinal inflammatory disease, such as IBD, Celiac Disease and related complications. Indeed, several studies have reported that IL-15 may participate to the pathogenesis of these diseases. Furthermore, although IL-15 seems to be responsible for inflammation and autoimmunity, it also may increase the immune response against cancer. For these reasons, we decided to study the intestinal mucosa as an 'immunological niche', in which immune response, inflammation and local homeostasis are modulated. Understanding the role of the IL-15/IL-15R system will provide a scientific basis for the development of new approaches that use IL-15 for immunotherapy of autoimmune diseases and malignancies. Indeed, a better understanding of the complexity of the mucosal immune system will contribute to the general understanding of immuno-pathology, which could lead to new therapeutical tools for widespread immuno-mediated diseases. © 2013 Elsevier Ltd.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 300.00K | Year: 2012

DESCRIPTION (provided by applicant): The ultimate goal of this proposal is to develop agents to increase the efficacy of immunotherapy of malignant melanoma. The studies in this proposal involve a proof-of-principle combination immunotherapy protocol in amouse model, using drugs to increase antigen expression and tumor targeting by adoptively transferred T cells specific for tumor antigens. As a product of a screening assay to identify compounds that enhance tumor antigen expression while allowing T cellfunction, we identified an enzyme inhibitory drug that increased melanoma antigen and MHC Class I expression in a panel of melanoma and glioma cell lines. As a follow-up to in vitro assays showing better T cell recognition of human tumors that were treatedwith the compound, we propose to exploit a mouse model melanoma for evaluation of combination in vivo therapy by adding the antigen-enhancing drug to adoptively transferred antigen-specific (TRP2 antigen presented on H2-Kb) T cells. The addition of the antigen enhancer to the treatment protocol will allow us to determine if we can first achieve enhanced antigen expression in an animal. We have confirmed in vitro that the mouse melanoma does respond to drug treatment with increased TRP2 and H2- Kb antigenexpression. We will extend these in vitro studies with in vivo determinations of the doses needed for in vivo enhancement of antigen expression. From an analysis of a panel of related drugs, we will select a single best candidate for use in the combinationtherapy model to test whether pre-treatment with the antigen enhancer will make tumors more susceptible to immune cell targeting and destruction. The identification of a new drug that enhances immune-recognition is of great potential benefit for cancer therapy. If we are successful at demonstrating that the compounds are stimulatory to tumor antigen recognition in vivo, these murine studies will be invaluable in the design and implementation of human clinical trials using combination of antigen-enhancingdrug and immunotherapy. The large number of related compounds that have proved safe for human in the treatment of a variety of diseases suggests that the class of antigen enhancing drugs we will evaluate could be highly beneficial in synergy with effectiveanti-tumor immunity. PUBLIC HEALTH RELEVANCE: We propose to use a mouse model to perform a combination cancer therapy that involves the use of drugs that we have found to increase targeting of tumor cells, together with immunotherapy that we hope to show will allow better tumor killing. The cancer we will treat is melanoma, a highly malignant cancer of pigmented cells that is highly resistant to conventional cancer therapies (irradiation and chemotherapy). We have already shown that tumors in cell culture can be recognized better after they are treated with the antigen enhancing drugs we propose to test in a mouse model that will provide proof-of-principle for eventual human therapy of melanoma. Melanoma has increased dramatically in the past 50 years, particularly as northern European peoples have migrated to more tropical locations, leading to epidemic increases in sun-damage related skin cancers, with striking increases in the highly lethal melanomas. There is increasing evidence that targetingmelanoma cells with immune therapies can be beneficial in a small percentage of the treated patients, and that strategies to improve tumor targeting could provide a breakthrough in resistant tumors.


Patent
Cytocure, Llc | Date: 2011-10-19

The invention provides methods of modulating tumor antigen associated (TAA) expression, and methods of modulating TAA expression in order to treat a tumor. More particularly, the invention provides methods of increasing an immune response against a tumor cell. Methods include administering to a subject with a tumor an amount of IFN- receptor agonist and tumor associated antigen (TAA) sufficient to increase an immune response against the tumor cell.


PubMed | Catholic University of the Sacred Heart and Cytocure, Llc
Type: | Journal: Analytical cellular pathology (Amsterdam) | Year: 2015

Osteoporosis is characterized by low bone mass and microarchitectural deterioration of bone tissue. The etiology and pathogenetic mechanisms of osteoporosis have not been clearly elucidated. Osteoporosis is linked to bone resorption by the activation of the osteoclastogenic process. The breakdown of homeostasis among pro- and antiosteoclastogenic cells causes unbalanced bone remodeling. The complex interactions among these cells in the bone microenvironment involve several mediators and proinflammatory pathways. Thus, we may consider the bone microenvironment as a complex system in which local and systemic immunity are regulated and we propose to consider it as an immunological niche. The study of the bone immunological niche will permit a better understanding of the complex cell trafficking which regulates bone resorption and disease. The goal of a perfect therapy for osteoporosis would be to potentiate good cells and block the bad ones. In this scenario, additional factors may take part in helping or hindering the proosteoblastogenic factors. Several proosteoblastogenic and antiosteoclastogenic agents have already been identified and some have been developed and commercialized as biological therapies for osteoporosis. Targeting the cellular network of the bone immunological niche may represent a successful strategy to better understand and treat osteoporosis and its complications.


Patent
The General Hospital Corporation and Cytocure, Llc | Date: 2012-05-25

The invention features methods, compositions, and kits for the administration of an HSP90 inhibitor, OBAA, flunarizine, aphidicolin, damnacanthal, dantrolene, or an analog thereof, alone, or in combination with, e.g., a TAA, an antigen-binding scaffold (e.g., an antibody, a soluble T cell receptor, or a chimeric receptor) specific for a TAA, a cell (e.g., a white blood cell that targets a cancer cell), and/or an IFN- receptor agonist or an IFN- receptor agonist, for the treatment of cancer.

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