Principal Investigator: Thomas Kupper, MD (BWH)
Co-Investigator: Wayne Marasco, MD, PhD (DFCI)

Description
Cutaneous T cell lymphomas (CTCLs) are a heterogeneous group of lymphoproliferative disorders caused by clonally derived, skin-invasive T cells. Current therapies for patients with advanced disease are palliative and durable long-term remissions are rare.  The poor 5-year survival of these patients using existing therapies clearly emphasizes the importance of developing new targeted therapies to treat this fatal disease.  Over the past decade, monoclonal antibody (Mab) based immunotherapies have become standard of care in a growing number of human cancers. The long-term goal of this proposal is to produce a therapeutic human Mab capable of immunodepleting malignant CTCL cells while minimizing collateral damage to an already compromised immune system. Based upon work that we have performed and published in the first funding period, our choice of target is the chemokine receptor CCR4 which is uniformly expressed at high levels on CD4+/CLA+ CTCL cells at all stages of disease.  CCR4 has been demonstrated to have a critical role in the migration of memory T cells to the skin, first through interactions with its ligand CCL17 on endothelial cells that mediate T cell extravasation and then with CCL22 that is expressed in the local skin microenvironment.  In this five proposal, we provide data that our lead chimeric anti-CCR4 Mab1567 induces potent ADCC activity, inhibits the growth of CCR4+ human tumors in vivo, blocks CCL22 mediated chemotaxis, abrogates human Treg suppressor activity and cross-reacts with rhesus macaque CCR4.  In addition, our preliminary studies on humanization of Mab1567 have been successful and should yield a humanized antibody in short order.  In this revised application, we will focus our efforts on completing humanization of Mab1567 with a target binding affinity for CCR4 of £1 nM.  Additional studies will examine the ability of Mab1567 to immunodeplete primary blood cell populations expressing CCR4 from health donors and CTCL patients.  We will also evaluate the ability of Mab1567 to modulate CTCL viability and function in vitro and to delineate its mechanism(s) of action.  In vivo studies in SCID mouse models of CTCL and in non-human primates will provide validation of this MAb’s ability to cause immunodepletion of CD4+CCR4+ cells.  As part of this proposal, we will present our timetable and plans that will result in a separate IND filing to conduct a phase I/II clinical trial to evaluate anti-CCR4 Mab immunotherapy for the treatment of advanced CTCL.

 

 

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