John P Leonard   Associate Dean of Clinical Research

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Novel immunotherapies and other translational strategies for lymphoma and other malignancies

Over several years, chemotherapy and radiation therapy have been the main treatments for patients with lymphoma and other hematologic malignancies. While some patients with certain disorders may be cured, others could benefit from improvements in available treatments either by improving efficacy against the tumor and/or reducing toxicity. More recently, a new category of treatment called immunotherapy has demonstrated effectiveness against many of these diseases. Within this class, monoclonal antibodies are the furthest along in development. Rituximab, a monoclonal antibody directed against the CD20 molecule commonly present on the surface of lymphoma cells, was the first antibody approved for the treatment of cancer. When administered to patients, these molecules can specifically target tumor cells, while relatively sparing normal cells, and can kill them via both direct and indirect mechanisms, including activation of the immune system. In the past few years, this type of treatment has made a major impact in the lives of patients with lymphoma, causing tumor shrinkage and improvement in symptoms, and potentially improving survival.

Our efforts are focused on defining the optimal roles for new therapies in the armamentarium of treatments for lymphoma. We have established one of the leading centers in the world for monoclonal antibody based therapies of lymphoma. Some ongoing and recent activities include clinical trials exploring:

1) Optimization of currently available monoclonal antibodies, such as rituximab, through the addition of cytokines and other immune system "boosters" such as interleukin 2 (IL2) and CPG oligonucleotides

2) Development of new monoclonal antibodies which are directed against other targets on lymphoma cells. We have conducted the first major clinical trial of epratuzumab, a monoclonal antibody against the CD22 molecule on lymphoma cells, and have led other trials exploring its role as lymphoma therapy, including the first trial of combination antibody therapy (epratuzumab and rituximab) which could allow patients to delay or avoid chemotherapy. Other antibodies which we are studying include Hu1D10 and anti-CD80.

3) Evaluation of radiolabeled monoclonal antibodies, including Bexxar (Iodine 131 tositumomab) and Zevalin (Yttrium 90 ibritumomab tiuxetan), which in addition to their immune-based activity also allow for the delivery of targeted radiation. We have one of the largest experiences in the world with this type of treatment (radioimmunotherapy), and have used this modality both as a single agent and in sequential combination with chemotherapy.

4) Use of "patient specific immunotherapy" using a customized vaccine developed from each individual patient's own lymphoma. After chemotherapy, patients have been treated with vaccination in order to try to delay or prevent tumor recurrence. Studies at our center have included patients with both indolent and aggressive lymphomas

5) Study of new anti-lymphoma agents, including novel chemotherapeutic compounds and combination regimens, as well as new biologics such as bcl-2 antisense therapy.

6) Evaluation (in collaboration with colleagues in nuclear medicine) of new imaging technologies, such as positron emission tomography (PET) scanning, in order to define their utility for lymphoma patients in evaluating extent of disease and response to therapy.

7) Other translational research activities, with collaborations with laboratory based scientists and pathologists, to explore new potential therapeutic targets and to optimize the use of those treatments currently available in the clinic

The quality of our research program has been recognized by its peer-reviewed grant support through the National institutes of Health, and several of our trials are conducted through the Cancer and Leukemia Group B (CALGB) of the National Cancer Institute. Additionally our work has been presented in numerous national and international meetings, including those of the American Society of Hematology and the American Society of Clinical Oncology, and has been published in journals including Blood, Cancer, Cancer Investigation, Journal of Clinical Oncology, Journal of Nuclear Medicine, Leukemia and Lymphoma, among others.

The ultimate goal of these efforts, in addition to providing the best possible care to our patients and access to promising new treatments, is to improve the chance of cure for patients with lymphoma, while potentially minimizing treatment-related toxicity to improve quality of life.


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