Page: 3-80 (78)
Author: Gabriella Marfe, Giovanna Mirone, Arvind Shukla and Carla Di Stefano
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Chronic myeloid leukemia (CML) originates from pluripotent hematopoietic stem cells that acquire translocation between the BCR gene on chromosome 22 and the ABL proto-oncogene on chromosome 9. Such rearrangement leads to the the Philadelphia (Ph) chromosome and the oncogenic fusion protein formation. This oncoprotein induces cell proliferation, causes abnormal migration, and reduces apoptosis. The suppression of BCR-ABL protein with imatinib and other specific tyrosine kinase inhibitors (TKIs) has revolutionized CML treatment and is currently regarded as the gold standard of targeted cancer therapy. However, drug resistance to anti-cancer chemotherapy is a significant barrier to the treatment of leukemia patients. Many times, resistance results from molecular adaptation to drug exposure, such as genetic mutation of key enzymes, upregulation of pro-survival compensatory signaling pathways, and altered drug transport. In this chapter, we reviewed the literature on the CML molecular biology, molecular targeted agents and their mechanisms of resistance.
Page: 81-131 (51)
Author: Michael Stanglmaier and Juergen Hess
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With about 40 approved monoclonal antibodies these biologicals are of high significance especially for cancer treatment. Nevertheless, since anti-tumor responses to antibody therapies are often limited and a lot of patients finally relapse, much effort is spent to increase the therapeutic efficacy, e.g., by optimizing the Fc-part of antibodies, thereby developing second generation antibodies. Albeit, monoclonal antibodies, even second generation formats are limited inasmuch as immune effector cells could only be unspecifically redirected via Fc-receptor binding and even more important, T cells as the most potent immune effector cells cannot be addressed at all. Thus, the idea arose to create antibodies with two different specificities. This enables specifically redirecting selected immune effector cells to target cells like tumor cells. A lot of different bispecific and multispecific antibody formats and platforms were designed to circumvent these constraints, like diabodies, single chain diabodies, chemically crosslinked F(ab)s fragments, tandem single chain Fv fragments, bispecific T cell engagers (BiTEs), triplebodies or knob in a hole as well as the dock and lock platforms. Despite major efforts in producing and testing new bsAb formats, the first approved bispecific antibody was the quadroma produced trifunctional antibody catumaxomab (anti-EpCAM x anti-CD3), demonstrating the eminent therapeutic potency of this full length antibody format. The recent approval of the anti-CD3 x anti-CD19 BiTE blinatumomab by the FDA furthermore emphasized the eminent role of bispecific antibodies. In this chapter an overview of the current development of bi- and multispecific antibodies for treatment of B-cell malignancies will be presented.
Natural Killer Cells as an Immune Cell Therapy Option for Bone Marrow Transplantation in Hematological Malignancies: Implications for New Therapies Based on Lipid Transfer and Cell-to- Cell Communication
Page: 132-175 (44)
Author: Beatriz Martín-Antonio, Nuria Martínez-Cibrian, Alvaro Urbano- Ispizua and Ciril Rozman
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Natural killer (NK) cells belong to the innate immune system. In recent years it has been suggested that their use could improve the outcome of stem cell transplantation for hematological malignancies, mainly due to the high anti-tumor effect they mediate and because they are not associated with an increase of the graft versus host disease, a complication which decreases the survival of patients submitted to this procedure. Once activated by several mechanisms, NK cells deliver cytolytic molecules triggering different cell death pathways, which can be caspase-3 dependent or caspase-3 independent, such as endoplasmic reticulum stress or lysosomal cell death. Apparently, NK cells take advantage of the particular features of different tumor cells to attack them in a more efficient way. Understanding the factors that contribute to cancer cell death is therefore critical for the development of novel therapies and to circumvent chemo-resistance.
Lipids are emerging as new targets for anti-inflammatory and cancer therapies as they interact extensively with organelles, are involved in immune responses, and can lead to initiation of different types of cell death. Interactions between lipids with membranes are crucial for the effects they mediate in cell-to-cell communication. Our group demonstrated that cord blood derived NK cells (CB-NK) can be efficiently expanded in vitro and exert anti-tumor activity both in vitro and in vivo in a multiple myeloma (MM) model thus, providing a clinically applicable strategy for the generation of highly functional NK cells which can be used to eradicate this and potentially other hematological malignancies. Our group also showed that CB-NK mediate a specific tumor cell death against MM which is transmissible between cells, and where lipidprotein vesicle trafficking play a relevant role. These findings provide the rationale for the development of CB-NK based therapeutic strategies in the treatment of hematological malignancies.
In this paper, the strengths and the weaknesses of clinical trials using NK cells are discussed. In addition, some guidelines for the development of future trials are suggested.
Nanoparticles in Health and Disease: An Overview of Nanomaterial Hazard, Benefit and Impact on Public Health Policy - Current State and Outlook
Page: 176-255 (80)
Author: Stanislav Janousek, Dagmar Jirova, Kristina Kejlova and Marketa Dvorakova
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Nanotechnology is a new interdisciplinary platform for medical research offering a novel experience in the disease treatment at the nanoscale level where most of the biological molecules functionate. In this chapter we address the application of nanomaterials in human life and medical practice which may anticipate a great impact on public and individual health. Nanoparticles and nanotherapeutics have recently been regulated by a conventional regulatory framework. The European Commission has worked out an Action Plan for Europe “Nanoscience and Nanotechnologies” and has called on the Member States for its implementation. Namely, the regulatory agency for responsibility, supervision, protection and promotion of human (animal) health in the European Union (EMA) provides regulatory guidance and authorization for the safety of nanomedicines. Interdisciplinary approaches are recommended for the application of scientific results in practice with simultaneous strict adherence to the Community legislative requirements on nanoproduct safety. The Report recommends additional specialized expertise, together with adaptation of existing methodologies and development of new methods for the evaluation of nanoproduct quality, safety, efficacy and risk management. In this chapter we will focus on liposome-, nanocrystal, virosome-, polymer therapeutic-, nanoemulsion-, and nanoparticle-based approaches to nanotherapeutics, which represent the most successful and commercialized categories within the field of nanomedicine. In addition, we will inform about generic nanotherapeutics and pitfalls of similar colloidal-based nanoformulations. We will pay attention to topics such as nanoparticles and nanomaterials in hematological and malignant disorders. Finally, we will discuss consumer nanoproduct safety (or risks) as well as future directions in nanomaterial commercialization, i.e. what are the forthcoming human (animal) health safety concerns and how relevant is the potential negative impact on the environment, life cycle and living systems when nanoproducts (and their use) are expected to be extended.
Page: 256-299 (44)
Author: Esmeralda Chi-yuan Teo and Colin Phipps
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Monoclonal antibodies (moAbs) have changed the landscape of lymphoma therapy. The chimeric anti-CD20 antibody, rituximab was the first to show significant activity in B-cell lymphomas. Since its FDA approval in 1997, rituximab has become a standard of care whether in combination with chemotherapy, or as a single-agent in induction and maintenance regimens in B-cell lymphoma. The success with rituximab paved the way for a steady stream of anti-lymphoma moAb therapies. Ofatumumab and obinutuzumab are next generation anti-CD20 antibodies designed to improve the cytotoxic effect of rituximab and enhance tumor cell killing. The breath of receptors amenable to Moab targeting extends far beyond CD20 and this chapter will review the most clinically impactful moAbs that have emerged over the past decade.
Frontiers in Clinical Drug Research &ndash; Hematology is an eBook series that brings updated reviews to readers interested in learning about advances in the development of pharmaceutical agents for the treatment of hematological disorders. The scope of the eBook series covers a range of topics including medicinal chemistry, pharmacology, molecular biology and biochemistry of natural and synthetic drugs employed in the treatment of anemias, coagulopathies, vascular diseases and hematological malignancies. Reviews in this series also include research on specific antibody targets, therapeutic methods, genetic hemoglobinopathies and pre-clinical / clinical findings on novel pharmaceutical agents. Frontiers in Clinical Drug Research &ndash; Hematology is a valuable resource for pharmaceutical scientists and postgraduate students seeking updated and critically important information for developing clinical trials and devising research plans in the field of hematology, oncology and vascular pharmacology. The second volume of this series features 5 chapters that cover a variety of topics including: -Chronic myeloid leukemia -Bispecific and multivalent antibodies -Natural Killer cells therapy for bone marrow transplantation -Nanoparticles in health and disease -Monoclonal antibody therapy for lymphoma