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
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."