The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform

Louis M Weiner - One of the best experts on this subject based on the ideXlab platform.

  • a mechanism of resistance to Antibody targeted immune attack
    Cancer immunology research, 2019
    Co-Authors: Dalal Aldeghaither, David J Zahavi, Joseph C Murray, Elana J Fertig, Garrett T Graham, Yongwei Zhang, Allison Oconnell, Sandra A Jablonski, Louis M Weiner
    Abstract:

    Targeted Monoclonal Antibody Therapy is a promising therapeutic strategy for cancer, and Antibody-dependent cell-mediated cytotoxicity (ADCC) represents a crucial mechanism underlying these approaches. The majority of patients have limited responses to Monoclonal Antibody Therapy due to the development of resistance. Models of ADCC provide a system for uncovering immune-resistance mechanisms. We continuously exposed epidermal growth factor receptor (EGFR+) A431 cells to KIR-deficient NK92-CD16V effector cells and the anti-EGFR cetuximab. Persistent ADCC exposure yielded ADCC-resistant cells (ADCCR1) that, compared with control ADCC-sensitive cells (ADCCS1), exhibited reduced EGFR expression, overexpression of histone- and interferon-related genes, and a failure to activate NK cells, without evidence of epithelial-to-mesenchymal transition. These properties gradually reversed following withdrawal of ADCC selection pressure. The development of resistance was associated with lower expression of multiple cell-surface molecules that contribute to cell–cell interactions and immune synapse formation. Classic immune checkpoints did not modulate ADCC in this unique model system of immune resistance. We showed that the induction of ADCC resistance involves genetic and epigenetic changes that lead to a general loss of target cell adhesion properties that are required for the establishment of an immune synapse, killer cell activation, and target cell cytotoxicity.

  • Monoclonal Antibody Therapy of cancer
    Nature Biotechnology, 2005
    Co-Authors: Gregory P Adams, Louis M Weiner
    Abstract:

    Treatment of cancer has dramatically changed in recent years. Some of this change is because of the introduction of Monoclonal antibodies into clinical practice. The exact mechanism of action of the clinically relevant antibodies remains unknown. This chapter provides an overview of the science and techniques used in the construction of these antibodies in addition to a brief review of some of the available clinical data.

  • Monoclonal Antibody Therapy for cancer
    Annual Review of Medicine, 2003
    Co-Authors: Margaret Von Mehren, Gregory P Adams, Louis M Weiner
    Abstract:

    Monoclonal Antibody Therapy has emerged as an important therapeutic modality for cancer. Unconjugated antibodies show significant efficacy in the treatment of breast cancer, non-Hodgkin's lymphoma, and chronic lymphocytic leukemia. Promising new targets for unconjugated Antibody Therapy include cellular growth factor receptors, receptors or mediators of tumor-driven angiogenesis, and B cell surface antigens other than CD20. Immunoconjugates composed of antibodies conjugated to radionuclides or toxins show efficacy in non-Hodgkin's lymphoma. One immunoconjugate containing an Antibody and a chemoTherapy agent exhibits clinically meaningful antitumor activity in acute myeloid leukemia. Numerous efforts to exploit the ability of antibodies to focus the activities of toxic payloads at tumor sites are under way and show early promise. The ability to create essentially human Antibody structures has reduced the likelihood of host-protective immune responses that otherwise limit the duration of Therapy. Antibody structures now can be readily manipulated to facilitate selective interaction with host immune effectors. Other structural manipulations that improve the selective targeting properties and rapid systemic clearance of immunoconjugates should lead to the design of effective new treatments, particularly for solid tumors.

David M Goldenberg - One of the best experts on this subject based on the ideXlab platform.

  • abstract a07 phase i evaluation of anti human leukocyte antigen dr Monoclonal Antibody Therapy in spontaneous canine lymphoma
    Molecular Cancer Research, 2014
    Co-Authors: B J Biller, Rodney L Page, Robert M Sharkey, David M Goldenberg
    Abstract:

    IMMU-114 (also known as hL243) is a humanized anti-HLA-DR Monoclonal Antibody (mAb) with potent anti-tumor activity against a broad range of human hematopoietic malignancies. As MHC Class II antigens are also expressed on canine lymphocytes, IMMU-114 has previously been found to recognize and kill malignant lymphocytes collected from dogs with spontaneous B cell lymphoma. Canine lymphoma is a highly relevant animal model of B-cell non-Hodgkin9s lymphoma (NHL) in humans with many advantages over rodent models. In addition, clinical trials in pet dogs can be designed to address therapeutic endpoints relevant to phase II/III studies in both dogs and humans. This study is being undertaken to determine the safety, pharmacodynamic and pharmacokinetic profiles of IMMU-114 in dogs with heavily pre-treated B cell lymphoma (NHL). Our hypothesis is that the mAb can safely be administered to tumor-bearing dogs and that it will be preferentially cytotoxic to B lymphocytes. Our overall objectives are to characterize the toxicity and biologic profile of IMMU-114 to advance the Therapy of canine lymphoma and to better inform human clinical trials using anti-HLA-DR mAbs. Thirteen pet dogs with B cell lymphoma demonstrating binding to IMMU-114 have been enrolled in an on-going phase I clinical trial at the Flint Animal Cancer Center at Colorado State University. Enrollment follows a standard 3 x 3 dose escalation to identify the maximally tolerated dose (MTD) of the mAb, starting at a dose of 3 mg/kg, and escalating thus far to 6, 12, and 24 mg/kg. Data collection includes pre and post-infusion peripheral blood mononuclear cells (PBMCs), serum, serial lymph node measurements, complete blood counts and serum chemistry profiles. Preliminary pharmacodynamic evaluation shows a significant and transient dose-dependent decrease in the percentage and absolute number of B lymphocytes in the blood of treated dogs 24 hours post infusion. This corresponds to a transient increase in the relative percentage of T lymphocytes. Neutropenia and other bone marrow toxicities have not been observed. Infusion related side effects appear common but have been mild to moderate in nature with 10/13 patients experiencing grade 1 or grade 2 allergic reactions (fever, urticaria, and hypersalivation) and 2/13 with grade 1 nausea. No dose limiting toxicities have been observed; therefore the MTD has not yet been reached. Thus far 2/13 dogs (15%) have had prolonged disease stabilization and received multiple weekly infusions of 12 mg/kg while 11/13 dogs have had progressive disease (lymph node enlargement) within one week post Therapy. Pharmacokinetic data obtained at the end of infusion, 2, 24 hours and 1 and 2 weeks post infusion showed minimally detectable levels at doses of 3 and 6 mg/kg. At 12 mg/kg, 2 animals had evidence of persistent Antibody levels in serum for 24 hours, followed by return to pre-treatment levels within 6 days. Two dogs currently treated at 24 mg/kg maintained hL243 levels in their blood over 1 day, with residual Antibody still found in the blood 6 days later Four of the 13 dogs developed anti-hL243 responses 2 to 4 weeks after treatment initiation. These findings provide a rationale for larger clinical studies to investigate the efficacy of anti-HLA-DR mAbs for both veterinary and human applications. Citation Format: Barbara J. Biller, Rodney Page, Robert Sharkey, David M. Goldenberg. Phase I evaluation of anti-human leukocyte antigen-DR Monoclonal Antibody Therapy in spontaneous canine lymphoma. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr A07.

  • evaluation of anti human leukocyte antigen dr Monoclonal Antibody Therapy in spontaneous canine lymphoma
    Leukemia & Lymphoma, 2011
    Co-Authors: Rhona Stein, Rodney L Page, Cheryl E Balkman, Susan Chen, K M Rassnick, Margaret C Mcentee, David M Goldenberg
    Abstract:

    A pilot study of anti-human leukocyte antigen (HLA)-DR Monoclonal Antibody (mAb) in dogs with lymphoma was undertaken to verify the suitability of a canine model to address therapeutically relevant endpoints prior to a full trial in dogs, and ultimately human investigation. In vitro studies demonstrated that L243, a murine IgG1 anti-HLA-DR, binds to normal and malignant canine lymphocytes and induces apoptosis in canine lymphoma cells. Moreover, L243 was administered safely to normal dogs and dogs with lymphoma, and bound to malignant cells in nodal tissue. Preliminary evidence of transient disease stabilization was observed in a subset of dogs with advanced-stage lymphoma following L243 immunoTherapy. hL243γ4P (IMMU-114), a humanized IgG4 anti-HLA-DR, currently under evaluation preclinically for human trials, was also shown to bind malignant canine lymphocytes, and safety and pharmacokinetic data from the administration of IMMU-114 to normal dogs indicate similar behavior to L243 in these assessments. Th...

Patricia T Greipp - One of the best experts on this subject based on the ideXlab platform.

  • anti cd20 Monoclonal Antibody Therapy in multiple myeloma
    British Journal of Haematology, 2008
    Co-Authors: Prashant Kapoor, Patricia T Greipp, William G Morice, Vincent S Rajkumar, Thomas E Witzig
    Abstract:

    CD20 is a particularly appealing target that is expressed on the surface of almost all B cells, with no significant shedding, secretion or internalization. In contrast to the demonstrated efficacy of anti-CD20 strategies in various B-cell lymphoproliferative disorders, the role of such Therapy in multiple myeloma is undetermined and controversial. The expression of CD20 by myeloma cells is heterogeneous, and can be detected only in 13-22% of patients. However, there is increasing interest in testing anti-CD20 Therapy in myeloma because of recent studies suggesting the existence of clonogenic CD20-positive precursor B cells in the disease. This article reviews the rationale, preclinical and clinical activity of anti-CD20 Therapy in myeloma. Clinical trials show that anti-CD20 Therapy with rituximab elicits a partial response in approximately 10% of CD20+ patients with multiple myeloma. In addition, there is preliminary evidence of disease stabilization in 50-57% of CD20+ patients for a period of 10-27 months. Further large-scale clinical trials are therefore needed to establish the role of this promising strategy in the treatment of myeloma.

Jayanth Panyam - One of the best experts on this subject based on the ideXlab platform.

  • novel tlr 7 8 agonists for improving nk cell mediated Antibody dependent cellular cytotoxicity adcc
    Scientific Reports, 2021
    Co-Authors: Vidhi Khanna, Hyunjoon Kim, Wenqiu Zhang, Peter Larson, Manan Shah, Thomas S Griffith, David M Ferguson, Jayanth Panyam
    Abstract:

    There is a significant interest in designing therapeutic agents that can enhance ADCC and thereby improve clinical responses with approved antibodies. We recently reported the combination of an imidazoquinoline-based TLR7/8 agonist (522) with a Monoclonal Antibody improved ADCC in vitro and in vivo. In the present study, we tested several new small molecule TLR7/8 agonists that induce significantly higher cytokines compared to both the FDA-approved TLR7 agonist, imiquimod, and 522. We evaluated these agonists in combination with Monoclonal Antibody Therapy, with the main goal of enhancing ADCC. Our studies show these TLR7/8 agonists induce robust pro-inflammatory cytokine secretion and activate NK cells. Specifically, we found the agonists 574 and 558 significantly enhanced NK cell-mediated ADCC in vitro as well as enhanced the anti-cancer efficacy of Monoclonal antibodies in two different in vivo mouse models. Additionally, we found the agonists were able to stimulate CD8 T cells, likely indicative of an early adaptive immune response.

John E Levine - One of the best experts on this subject based on the ideXlab platform.

  • nci first international workshop on the biology prevention and treatment of relapse after allogeneic hematopoietic stem cell transplantation report from the committee on treatment of relapse after allogeneic hematopoietic stem cell transplantation
    Biology of Blood and Marrow Transplantation, 2010
    Co-Authors: David L Porter, Edwin P Alyea, Joseph H Antin, Marcos Delima, E Estey, J Frederik H Falkenburg, Nancy M Hardy, Nicolaus Kroeger, Jose F Leis, John E Levine
    Abstract:

    Relapse is a major cause of treatment failure after allogeneic hematopoietic stem cell transplantation (alloHSCT). Treatment options for relapse have been inadequate, and the majority of patients ultimately die of their disease. There is no standard approach to treating relapse after alloHSCT. Withdrawal of immune suppression and donor lymphocyte infusions are commonly used for all diseases; although these interventions are remarkably effective for relapsed chronic myelogenous leukemia, they have limited efficacy in other hematologic malignancies. Conventional and novel chemoTherapy, Monoclonal Antibody Therapy, targeted therapies, and second transplants have been utilized in a variety of relapsed diseases, but reports on these therapies are generally anecdotal and retrospective. As such, there is an immediate need for well-designed, disease-specific trials for treatment of relapse after alloHSCT. This report summarizes current treatment options under investigation for relapse after alloHSCT in a disease-specific manner. In addition, recommendations are provided for specific areas of research necessary in the treatment of relapse after alloHSCT.