ATLANTA, GA - Scientists from the Translational Lymphoma Research Laboratory of Myron S. Czuczman, MD, Departments of  Medicine and Immunology at Roswell Park Cancer Institute (RPCI), will present preliminary laboratory and pre-clinical findings for the treatment of Non-Hodgkins Lymphoma (NHL) at the 47^th Annual Meeting of the American Society of Hematology, December 10-13, Atlanta, GA.

The number of cases of non-hodgkins lymphoma, a cancer of the lymphatic system, has nearly doubled since the 1970s, making its rate of increase the third highest of all cancers, just behind that of lung cancer in women and skin cancer in both sexes. An estimated 56,390 cases will be diagnosed and 19,200 deaths will occur in 2005.

“Targeting CD20 and CD22 with Rituximab in Combination with CMC-544 Results in Improved Antitumor Activity Against Non-Hodgkins Lymphoma (NHL)

(Abstract # 1473)

Embargoed until Saturday, December 10 - 9:15 am

Hall B4 Georgia World Congress Center

F.J. Hernandez-Ilizaliturri, MD, and his colleagues at RPCI investigated whether the antitumor activity of rituximab could be enhanced by the addition of CMC-544. Laboratory models treated with the combination of CMC-544 and rituximab had the longest median survival, compared with either monoclonal antibody alone when administered as monotherapy. The researchers note that clinical trials with this combination in the planning stages and are needed to determine whether these results will be validated in future studies. 

Rituximab and CMC-544 are monoclonal antibodies that target tumor-associated antigens, CD20 and CD22, respectively. When CMC-544 binds to CD22, it internalizes and brings a drug called calicheamicin into the cell that induces cell death. Alternatively rituximab, once bound to CD20, works on activating a patient’s immune system and kills cells via antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity.  

 “Structural Changes in the Internal Domain of CD20 Antigen Associated with the Emergence of Rituximab Resistance: Effects of Proteasome Inhibition in CD20 Structure and Rituximab Antitumor Activity in Rituximab-Resistant Cell Lines (RRCL)” (Abstract # 1474)

Embargoed until Saturday, December 10 - 9:15 am

Hall B4 – Georgia World Congress Center

            F.J. Hernandez-Ilizaliturri, MD, and his colleagues are defining the molecular basis for rituximab resistance including changes in CD20 structure, membrane reorganization and signaling events following therapy. Researchers evaluated the effects of proteasome inhibition in the structure of CD20 antigen and rituximab-resistant cell lines (RRCL). While no significant changes were observed in the external domain of the CD antigen, significant changes in the internal domain were observed in RRCL. In vitro exposure

to PS341, a proteasome inhibitor, partially improves rituximab responsiveness and may be a target to moderate rituximab-resistance.

Rituximab locks on to a protein called CD20 which is found on the surface of one of the main types of normal blood cells (B-cell lymphocytes). It also is present on the surface of most abnormal b-cell lymphocytes associated with non-Hodgkins lymphoma. Rituximab (a monoclonal antibody), alone or combined with chemotherapy, has significantly improved survival rates for patients with non-Hodgkins lymphoma. Still, many patients subsequently relapse with varying degrees of resistance to drugs and/or rituximab.

“In vitro Synergistic Antitumor Activity by Targeting Trail L-R1 and CD20 Antigen by Combining HGS-ETR1 (Agonistic Human Monoclonal Antibody to TRAIL Receptor 1) and Rituximab Monoclonal Antibody Against Non-Hodgkins Lymphoma (NHL) Cells (Abstract # 1475)

Embargoed until Saturday, December 10 - 9:15 am

Hall B4 - Georgia World Congress Center

Myron Czuczman, MD, and his colleagues investigated whether combining TRAIL-1 receptor against monoclonal antibodies with the biological agent, rituximab, may result in synergistic effects against NHL. Targeting TRAIL-R1, a death receptor expressed in a number of cancers including lymphoma, with HGS-ETR1, a monoclonal antibody, induced cancer cell death (apoptosis), arrested cell growth and, in some cell lines tested, both antibody-dependent cellular cytotoxicity and complement mediated cytotoxicity. Further, the combination of HGS-ETR1 and rituximab resulted in significant synergistic activity (i.e., antiproliferation). The researchers conclude that the combination warrants further preclinical and clinical evaluation in B-cell lymphomas.

Dr. Czuczman also is the senior author on the first clinical trial of an antibody directed against a surface “death” receptor in lymphoma.

“Results for a Phase II Trial of HGS-ETR1 (Agonistic Human Monoclonal Antibody to Trail Receptor 1) in Subjects with Relapsed/Refractory Non-Hodgkin’s Lymphoma (NHL) (Abstract # 489)

Embargoed until Monday, December 12 - 2 pm

Hall B4 - Georgia World Congress Center

            Myron Czuczman, MD, is the principal investigator of this multi-center phase II clinical trial where 40 patients with relapsed or refractory NHL were given a first-of-its-class monoclonal antibody, HGS-ETR1. The monoclonal antibody targets a cell surface “death” receptor called TRAIL-R1 at two dose levels for up to six cycles. Three patients (8%) had clinical responses; 12 patients (40%) had stable disease and the remainder had progressive disease at the time of first evaluation. Two cell death receptors, TRAIL-R1 and TRAIL-R2 are expressed in a number of cancer cell types including lymphoma. HGS-ETR1 is a monclonal antibody that has demonstrated preclinical evidence of antitumor activity in vitro and in vivo.

Data shows that treatment with HGS-ETR1 is well tolerated with minimal toxicity. While it is important to note that these results are preliminary and involve a relatively small number of patients, they provide adequate evidence of potential therapeutic benefits of HGS-ETR1, and serve as the basis for continued evaluation in patients.

The American Society of Hematology’s (ASH) annual meeting provides a forum for nearly 20,000 clinicians, scientists and others from around the world to discuss the latest developments in scientific research in hematology. ASH strives to further the understanding, diagnosis, treatment, and prevention of disorders affecting the blood, bone marrow, and the immunologic, hemostatic and vascular systems, by promoting research, clinical care, education, training, and advocacy in hematology.

Roswell Park Cancer Institute, founded in 1898, is the nation’s first cancer research, treatment, and education center and is the only National Cancer Institute-designated comprehensive cancer center in Upstate New York. RPCI is a member of the prestigious National Comprehensive Cancer Network, an alliance of the nation’s leading cancer centers. For more information, visit RPCI’s website at www.roswellpark.org, call 1-877-ASK-RPCI (1-877-275-7724) or email askrpci@roswellpark.org

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