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Lymphoma Research at the UC Davis Cancer Center

Dedicated to Improving Treatments for Lymphoma

Rare illness is a complex enigma

Cause and cure of disease that struck lawmaker are elusive.
By Dorsey Griffith -- Bee Medical Writer

The disease that led to the death Saturday of Rep. Robert Matsui is a rare and complex illness, which in many cases has no known cause and no sure cure.
Matsui had been diagnosed a few months ago with a form of a blood disorder called myelodysplastic syndrome, or MDS.

He was admitted to a Washington, D.C.-area hospital on Christmas Eve with pneumonia and died eight days later from the infection.

Matsui's office has not released additional details about his illness or any treatment he had received, so experts are reluctant to speculate about the lawmaker's particular struggle with the disease.

"Anybody who comes into the hospital with pneumonia can die of pneumonia, especially when they are over age 60," said Dr. Joseph Tuscano, an oncologist and associate professor of medicine at UC Davis.

"The fact that he already had a suppressed immune system really puts him at elevated risk of dying."

What is known is that MDS is really a constellation of disorders, some of which can progress to acute myeloid leukemia, a blood disease in the cancer family.

In MDS, a person's bone marrow does not produce enough blood cells.

Working normally, the bone marrow makes three major types of blood cells: red blood cells transport oxygen from the lungs to cells throughout the body; white blood cells help the body fight infections; and platelets help clot the blood and prevent bleeding.

Symptoms of the disease include a change in the blood count, anemia, weakness, fatigue, frequent infections, easy bruising, bleeding, fever and weight loss.

An estimated 7,000 to 12,000 new cases of the disease are diagnosed every year in the United States, typically in people over age 60, according to the Myelodysplastic Syndromes Foundation.

In rare cases, MDS can be caused by exposure to certain chemicals, including chemotherapy drugs. Patients being treated for Hodgkin's lymphoma, for example, are at risk for MDS.

Exposure to radiation, either for treatment of a disease or from radioactive weapons, also has been associated with MDS, as has exposure to high concentrations of benzene from tobacco smoke and gasoline.

Most MDS patients, however, have no known risk factors, said Dr. John Bennett, a leading authority on MDS at the University of Rochester in New York.

"Ninety-plus percent of patients have no history whatsoever that would suggest a risk factor, no significant smoking or occupational exposure or a history of another malignancy such as Hodgkin's lymphoma," he said.

Tuscano of UC Davis said early-stage MDS patients can live with their disease for many years, treated with blood transfusions, blood products and chemotherapy.

"With relatively close monitoring, the majority of patients really do well," Tuscano said.

The higher risk patients, however, are those close to developing leukemia and typically survive no more than two years after being diagnosed, he said.

Only one drug has been approved specifically to treat patients with advanced MDS. Vidaza, approved by the Food and Drug Administration in May 2004, is considered a novel approach because it activates genes that allow normal cell growth.

One risk of Vidaza, said Tuscano, is that it causes blood counts to drop even lower initially, further increasing the risk of infection or bleeding.

The only possible cure for MDS is a bone marrow transplant, but the procedure is usually reserved for patients under age 60, experts said. Matsui was 63.

Sacramento BEE - Published Tuesday, January 4, 2005

RAPID ACCESS: PROMISING LYMPHOMA THERAPY WINS FAST-TRACK TREATMENT
The National Cancer Institute puts its resources behind an investigational lymphoma treatment under development at UC Davis

Working as a research fellow in molecular immunology at the National Cancer Institute in Bethesda, Md., in the mid 1990s, Joseph Tuscano stumbled on a promising protein. The protein was an antibody, one of the thousands of protective substances the body manufactures to fight infection. Advance scouts in a stunningly sophisticated self-defense system, antibodies are programmed by the immune system to seek out specific invaders and flag them for destruction.
Antibodies also can be programmed in the lab to seek out and lock onto a particular target. Single-minded and precise, they make powerful research tools. During his years in Bethesda, Tuscano engineered 30 novel antibodies. Each was programmed to find and bind to the same immune system protein, human B cell protein #CD22, found on the surface of the human B lymphocyte. The new antibodies were extremely useful for researchers like Tuscano, who investigate how cells communicate. Unlike most other antibodies, which communicate only with other extra-cellular molecules, these antibodies helped transmit signals from the cell's surface to its interior.
"We wanted to know what those signals were saying," Tuscano says. "Today we understand a lot of what they're saying. And they're saying die."
Last year, the National Cancer Institute deemed one of Tuscano's antibodies, HB22.7, worthy of a RAID grant. The RAID program, for Rapid Access to Intervention Development, was launched in 2000 to ensure the most promising new molecular agents developed at academic medical centers make it to the testing stage. HB22.7 was one of just 12 projects nationwide approved for RAID funding in 2002. That funding, amounting to more than $1 million so far, will allow Tuscano to develop the antibody therapy to the point that it can be tested in lymphoma patients.
HB22.7, the seventh of the 30 antibodies Tuscano originally developed at the National Cancer Institute, sent an especially strong "die" signal. On its orders, not only did cancerous B lymphocytes die, but healthy B cells were left unharmed. No other antibody for lymphoma treatment, currently available or in development, has demonstrated such specificity.
Lymphocytes are a type of white blood cell; their job is to churn out antibodies to fight infection. Lymphoma, a cancer that will affect 61,000 people in the United States this year, arises in these white blood cells. Untreated, the cancer spreads from lymph node to lymph node throughout the body, killing some 24,000 Americans every year. For a cancer that targets the immune system's antibody factories, an antibody is a particularly fitting therapy.
By 1997, when Tuscano joined the UC Davis faculty as an assistant professor of hematology/oncology, he was ready to begin testing the antibody in mice. The first tests were done in collaboration with Gerald and Sally DeNardo, co-directors of the Radiodiagnosis and Therapy Program at UC Davis. A husband-wife team, the DeNardos were early pioneers of nuclear medicine. At the time, they were studying an investigational therapy they had developed, Lym-1 yttrium90. The agent delivered the radioactive element yttrium directly to lymphoma tumors, killing the malignant cells but causing minimal damage to healthy tissues nearby.
Tuscano and the DeNardos designed experiments to test whether HB22.7 might enhance the effectiveness of Lym-1 Y90. They tested the two therapies together and each therapy separately. The studies demonstrated that HB22.7 did enhance Lym-1 Y90. Compared with mice that received the yttrium treatment alone, the animals treated with both therapies lived longer.
But the mice treated with HB22.7 alone did best of all.
"It was the biggest surprise," Tuscano says, still shaking his head at the memory. "We repeated the experiments five or six times. The results were always the same. HB22.7 alone worked best, and it was magnitudes better than the antibody plus Lym-1Y90 or Lym-1Y90 alone."
Tuscano believed he was on to something. But advancing an investigational drug from the animal testing stage to the human testing stage is a difficult and expensive enterprise. Few academic institutions have the capacity to move a promising molecule from lab to clinic.
Enter RAID. Through the RAID program, the National Cancer Institute itself serves as a drug company, putting its vast laboratories and resources at the disposal of scientists like Tuscano. The program was created expressly to foster development of the next generation of cancer drugs — so-called molecular therapies.
New-generation therapy
Current chemotherapy drugs kill cancer cells and healthy cells alike. Molecular therapies, the product of biomolecular knowledge gained only over the past two decades, instead home in on molecular processes specific to a particular cancer. Cleverly targeted, the new agents have the potential to kill cancer cells with precision while causing little or no damage to normal cells.
Rituxan, Gleevac, Herceptin and Iressa were the first molecular agents on the market. The drugs have few side effects, and are stunningly successful at treating select cancers. Tuscano hopes HB22.7 will be among the next crop of molecular drugs to reach patients.
HB22.7 takes advantage of a normal cell process known as apoptosis, or programmed cell death: When a cell is damaged beyond repair or reaches the end of its programmed lifespan, it is supposed to self-destruct.
Cancer cells lose this mechanism, but in HB22.7 Tuscano has engineered an antibody that orders malignant lymphoma cells to do the right thing — die. Because the antibody targets only B lymphocytes, other immune system cells remain healthy. Tuscano anticipates the agent will be easily tolerated, without the side effects commonly associated with current chemotherapy drugs.
In addition to lymphoma, HB22.7 also may help patients with autoimmune diseases like rheumatoid arthritis. In these illnesses, the immune system malfunctions and produces antibodies that attack the body's own tissues. By instructing B lymphocytes to die, HB22.7 should reduce the load of these self-destructive antibodies, and reduce damage to body tissues.
In his office on the second floor of Research III, a 50,000-square-foot brick tower devoted to cancer research, Tuscano is ready to launch a RAID against lymphoma. "I'm very hopeful," he says. "And a lot of other people are, too."

© 2003 UC Regents. All rights reserved.

The Leukemia & Lymphoma Society Awards Grants to Researchers on the Forefront of New Cancer Treatments

September 8, 2003 (Press Releases) -
Contact: Jon Garbo, Director, Public Relations, The Leukemia & Lymphoma Society, (914) 821-8969

Translational Research Program Poised to Break $100 Million in Funding

WHITE PLAINS, NY - The Leukemia & Lymphoma Society today announced 32 Translational Research Program grants, totaling $11.3 million to researchers on the forefront of developing new treatments for leukemia, lymphoma and myeloma. The awards bring the program's total funding to more than $99 million since its inception in 1995.

The Society established the Translational Research Program to encourage and support research that shows strong promise for translating basic biomedical knowledge to new treatments that will ultimately prolong and enhance patients' lives. The program's goal is to accelerate the transfer of findings from the laboratory to clinical application. Significantly, six of the 32 recipients are renewal grants, which means their research has moved from the lab to an approved clinical trial.

"Every five minutes, someone in the U.S. is diagnosed with leukemia, lymphoma or myeloma, and every nine minutes, someone dies from these cancers," said Dwayne Howell, the Society's President and CEO. "We are thrilled to fund these outstanding scientists, who are working toward developing more effective treatments for the 670,000 Americans battling these cancers."

Among its accomplishments, the Translational Research Program has funded medical breakthroughs such as:

Funding the discovery that a compound called STI571 killed chronic myelogenous leukemia cells in the lab; this compound became the breakthrough treatment Gleevec®
Funding many of the research efforts surrounding the original trials examining molecularly-targeted cancer therapies of FLT-3 inhibitors for the treatment of acute myelogenous leukemia
Funding the discovery that the drug Velcade"! is a useful therapeutic agent in the treatment of mantle cell lymphoma
The Society funds two other major research programs. The Career Development Program provides stipends to investigators in early stages of their careers, allowing them to devote their time to leukemia, lymphoma and myeloma research. The Specialized Center of Research (SCOR) program encourages multidisciplinary research through the collaboration of leading-edge researchers from at least three research programs. The concept behind the program is that leukemia, lymphoma and myeloma treatments and cures will be discovered most quickly in an environment of collaboration and teamwork.

About The Leukemia & Lymphoma Society
The Society, headquartered in White Plains, NY, is the world's largest voluntary health organization dedicated to funding blood cancer research and providing education and patient services. The Society's mission is to cure leukemia, lymphoma, Hodgkin's disease and myeloma, and to improve the quality of life of patients and their families. Since its founding in 1949, the Society has provided more than $358 million for research specifically targeting blood cancers.

For more information, visit www.lls.org or call the Society's Information Resource Center (IRC), a call center staffed by master's level social workers, nurses and health educators who provide information, support and resources to patients and their families and caregivers. IRC specialists are available at (800) 955-4572, Monday through Friday, 9 a.m. to 6 p.m. Eastern time.

Translational Research Program Recipients
This fall's recipients include the following researchers:

Stephen Ansell, M.D., Ph.D., Mayo Clinic and Foundation, Division of Hematology, Rochester, MN. Research: "B-Lymphocyte Stimulator (BLyS) in Aggressive Non-Hodgkin Lymphoma"

Scott Armstrong, M.D., Ph.D., Dana-Farber Cancer Institute, Department of Cancer Immunology and AIDS, Boston, MA. Research: "New Therapeutic Targets in Leukemia"

Steven Bernstein, M.D., University of Rochester School of Medicine, James P. Wilmont Cancer Center, Departments of Medicine, Hematology and Oncology, Rochester, NY. Research: "VH Framework Region Multi-Epitope Vaccination for B-Cell Non-Hodgkin's Lymphoma"

Martin Carroll, M.D., University of Pennsylvania School of Medicine, Department of Medicine, Philadelphia, PA. Research: "Clinical Targeting of Signal Transduction Pathways in AML"

Bayard Clarkson, M.D., Sloan-Kettering Institute for Cancer Research, Department of Molecular Pharmacology and Chemistry, New York, NY. Research: "Selective Therapies and Curative Strategies for CML"

Robert Collins, M.D., University of Texas, Southwestern Medical Center at Dallas, Dallas, TX. Research: "The Use of Allodepleted T Cell Transplants in Patients with Leukemia"

Steven Collins, M.D., Fred Hutchinson Cancer Research Center, Seattle, WA. Research: "Calmodulin-Dependent Protein Kinase Inhibitors As Therapeutic Agents in Myeloid Leukemia"

Kenneth Cooke, M.D., University of Michigan Comprehensive Cancer Center, Department of Hematology and Oncology, Ann Arbor, MI. Research: "Etanercept for Non-Infectious Lung Injury Following Allogeneic BMT" (renewal grant)

Richard D'Andrea, Ph.D., Child Health Research Institute, Women's and Children's Hospital, North Adelaide, Australia. Research: "Identification of Growth Factor Receptor Mutations in Polycythemia Vera"

Albert Deisseroth, M.D., Ph.D., Sidney Kimmel Cancer Center, San Diego, CA. Research: "Development of New Tyrosine Kinase Inhibitors for CML"

Dean Felsher, M.D., Ph.D., Stanford University School of Medicine, Department of Pathology, Stanford, CA. Research: "Inactivating MYC for the Treatment of Lymphoma"

Robert Fenton, M.D., Ph.D., University of Maryland, Greenebaum Cancer Center, Baltimore, MD. Research: "Therapeutic Targeting of Mcl-1 in Multiple Myeloma" (renewal grant)

Wayne Godfrey, M.D., University of Minnesota Cancer Center, Minneapolis, MN. Research: "Human CD4+CD25+ Suppressor Cell Immunobiology"

Jianlin Gong, M.D., Boston University School of Medicine, Department of Medicine, Boston, MA. Research: "Dendritic/Leukemic Fusion Cell Vaccine Therapy for AML Patients in First Remission: A Phase I Clinical Trial" (renewal grant)

Stephen Gottschalk, M.D., Baylor College of Medicine, Department of Pediatrics-Hematology and Oncology, Houston, TX. Research: "Immunotherapy of EBV Positive Hodgkin's Disease with Cytotoxic T Cells Against the Subdominant LMP Antigens"

Thomas Kipps, M.D., Ph.D., University of California at San Diego, Department of Medicine, La Jolla, CA. Research: "Evaluation of Leukemia-Stroma Interactions That Promote Leukemia Cell Survival"

Jill Lacy, M.D, Yale University School of Medicine, Section of Medical Oncology, New Haven, CT. Research: "Development of Targeted Therapies for EBV-Associated Lymphoproliferative Diseases"

Uma Lakshmipathy, Ph.D., University of Minnnesota Stem Cell Institute, Department of Medicine, Minneapolis, MN. Research: "Correction of FANCC Gene via Homologous Recombination in Multipotent Adult Progenitor Cells"

Jane Liesveld, M.D., University of Rochester Medical Center, Department of Hematology and Oncology, Rochester, NY. Research: "Effect of Farnesyltransferase Inhibition in AML and MDS" (renewal grant)

Shakeel Modak, M.D., M.R.C.P., Memorial Sloan-Kettering Cancer Center, Department of Pediatrics, New York, NY. Research: "Beta Glucans Enhance Rituximab Therapy of Lymphoma"

Benjamin Neel, M.D., Ph.D., Beth Israel Deaconess Medical Center, Harvard Medical School, Department of Medicine, Boston, MA. Research: "Role of Shp2 Mutations in Leukemia"

Susan Nilsson, Ph.D., Peter MacCallum Cancer Institute, Trescowthick Research Laboratories, Melbourne, Australia. Research: "The Potential Role of Hyaluronic Acid in Ex Vivo Stem Cell Expansion and Its Utility in the Prognosis of Childhood ALL"

Peter Parham, Ph.D., Stanford University School of Medicine, Department of Structural Biology, Stanford, CA. Research: "Impact of KIR and LILR Variation on Allogeneic Hematopoietic Cell Transplantation for Leukemia, Lymphoma and Myeloma"

Shahin Rafii, M.D., Weill Medical College of Cornell University, Department of Hematology/Oncology, New York, NY. Research: "Therapeutic Modulation of Acute Leukemias with Anti-Angiogenic Agents" (renewal grant)

Aaron Schimmer, M.D., Ph.D., F.R.C.P.C, Princess Margaret Hospital, Ontario Cancer Institute, Department of Cellular and Molecular Biology, Toronto, Ontario, Canada. Research: "Defects in Caspase Activation as Prognostic Markers and Therapeutic Targets"

Donald Small, M.D., Ph.D., Johns Hopkins University, Department of Oncology, Baltimore, MD. Research: "The Investigation of FLT3 TK Inhibitors as Specific Therapy for AML" (renewal grant)

Lloyd Stoolman, M.D., University of Michigan, Department of Pathology, Ann Arbor, MI. Research: "Lymphoma/Leukemia Therapies Using Dendritic Cells Engineered to Overexpress Lymph-Node Homing Receptors"

Roger Strair, M.D., Ph.D., University of Medicine and Dentistry of New Jersey, The Cancer Institute of New Jersey, New Brunswick, NJ. Research: "Phorbol Ester Administration to Patients with Acute Myelogenous Leukemia"

Moshe Talpaz, M.D., University of Texas, MD Anderson Cancer Center, Department of Bioimmunotherapy, Houston, TX. Research: "Subtypes of Gleevec Resistance Among CML Patients and Their Response to a Novel Bcr-Abl Inhibitor - BMS354825"

Max Topp, M.D., University of Tübingen, Department of Hematology, Tübingen, Germany. Research: "Adoptive Immunotherapy with T-cells Rendered to Express Chimeric Immunoreceptor Targeting Antigens Expressed by Multiple Myeloma"

Joseph Tuscano, M.D., University of California at Davis, Department of Internal Medicine Hematology/Oncology, Sacramento, CA. Research: "Anti-CD22 Antibodies to Treat Lymphoma"

Xiao-Feng Yang, M.D., Ph.D., Baylor College of Medicine, Immunology Section, Houston, TX. Research: "Novel Antigen Targets for Immunotherapy of Myeloproliferative Diseases"

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