A study by a University of Nebraska Medical Center researcher has shown
that gene therapy can kill tumor cells that otherwise are returned to cancer
patients following high-dose chemotherapy, while keeping the good cells
intact.
In a report published in December in Cancer Gene Therapy, James Talmadge,
Ph.D., announced that his group was able to purge tumor cells without affecting
the stem cells needed to make the high-dose chemotherapy patient healthy
again.
“When cancer patients turn to transplantation for treatment, oftentimes
the stem cells that are reinserted into their body aren’t completely cancer-free,”
said Dr. Talmadge, professor of pathology and microbiology at the UNMC
and principal investigator on the study. “Treating stem cells with adenovirus
protects the numbers of healthy cells replaced in the body and reduces
cancer cell numbers to levels researchers never have seen before.”
Dr. Talmadge’s group used adenovirus vectors, a common virus naturally
found in the lungs, to carry a gene to breast cancer cells. The gene, p53,
inhibits tumor growth. The adenovirus vectors, or delivery systems, used
in these studies were replication incompetent, meaning they are unable
to cause infection.
In adult stem cell transplantation, a large number of stem cells are
removed from the body before a patient is given a high-level dosage of
chemotherapy. While the cells are outside the body, they can be treated
with a process called “purging” to reduce the number of tumor cells contaminating
the stem cell product. Generally, purging kills most of the tumor cells
and as many as 30 to 50 percent of the stem cells, a problem Dr. Talmadge
and his collaborators were able to overcome using adenovirus gene therapy.
“It is clear that the cells within the stem cell products used in transplants
can cause cancer, based on retrovirus studies reported previously by other
researchers,” Dr. Talmadge said. “At this time, there isn’t a good, clear
way to purge stem cells completely of cancer. Either you miss some tumor
cells or you lose healthy stem cells, which is a problem because reinserting
healthy cells in the point of transplant protocol.”
Dr. Talmadge, working with Canji, Inc., a biotechnology company in San
Diego that is affiliated with Schering-Plough Corporation, sought to find
a way to limit tumor cells from being re-inserted in humans. Through his
research, Dr. Talmadge found that incubating stem cells with adenovirus
for a four-hour period kills tumor cells without having an impact on stem
cells.
“In a further test we re-inserted these human steam cells into a mouse
without an immune system,” Dr. Talmadge said. “The human hematopoietic
stem cells in those mice grew, while the tumor cell levels were reduced
to all-time lows.”
Hematopoietic cells are found in bone marrow and help red blood cells,
white blood cells and platelets regenerate after stem cell transplants.
Normally, these cells are weakened severely by chemotherapy, causing cancer
patients to become anemic, neutropenic and to develop life-threatening
infections.
In this study, scientists purged the stem cell products used to rescue
patients following high-dose chemotherapy of the contaminating tumor cells.
These stem cells were then used to treat severe combined immunodeficient
mice and allow them to generate human blood cells. The unique aspect of
these studies was that adult human stem cells were used to reconstitute
these myelosuppressed mice, demonstrating that the human stem cells remained
fully functional. Earlier in vitro studies examining this dilemma were
encouraging, but in those experiments it was not possible to determine
if the purged stem cells were unable to produce all of the blood elements
needed for recovery following high-dose chemotherapy.
To prove that the hematopoietic cells were regenerating after transplant,
Dr. Talmadge took hematopoietic cells out of the mice and used them to
rescue another group of mice, again with no immune system. Multiple tests
on mice produced the same results, proving that these cells were self-renewing
and would not exhaust themselves following transplantation and so could
continue to produce cells throughout the lifespan of the transplanted patient,
in this case a mouse.
Initial testing focused on breast cancer, but Dr. Talmadge said other
types of cancer, such as ovarian cancer, have been targeted for further
studies. The Nature Publishing Group published the research in Cancer Gene
Therapy, a month scientific journal highlighting the latest cancer and
gene therapy discoveries.
Clinical trials won’t be starting any time soon, Dr. Talmadge said.
Adenovirus vectors received an undeservedly bad reputation from an incident
in Philadelphia, he said, and transplantation for breast cancer has yet
to demonstrate a significant prolongation of survival. Dr. Talmadge said
that as the use of adenovirus in gene therapy becomes better accepted,
he hopes human trials will be initiated.