Glenn Dranoff, MD
Two of the most powerful approaches to cancer treatment — a stem cell
transplant and an immune system-stimulating vaccine — appear to
reinforce each other in patients with an aggressive, hard-to-control
form of leukemia, Dana-Farber Cancer Institute scientists have found.
In a study to be published in the online early edition of the Proceedings of the National Academy of Sciences
the week of Aug. 24, the researchers report that patients with
high-risk acute myeloid leukemia (AML) or advanced myelodysplasia (a
blood disorder) who received a cancer vaccine shortly after a stem cell
transplant not only had few complications but also mounted a strong
immune system attack on the disease.
Particularly encouraging was the fact that rates of graft-versus-host
disease (GVHD), a potentially severe aftereffect of immune system-based
therapies, were no higher than with stem cell transplants alone.
The key to the technique's success was the timing of the vaccine,
explained the study's co-senior author, Glenn Dranoff, MD, of
"In previous studies that have combined stem cell transplantation
with a cancer vaccine, the vaccine wasn't given until a significant
amount of time after the transplant," said Dranoff. "In research with
animal models, we found the approach works best if the vaccine follows
the transplant by just a few weeks."
The study involved 28 patients with advanced myelodysplasia or
high-risk AML ("high-risk" meaning their disease did not respond to
standard chemotherapy treatment). Twenty-four underwent a transplant of
hematopoietic (blood-making) stem cells: after receiving chemotherapy to
reduce the number of diseased blood-forming cells in their bone marrow,
they received an infusion of healthy stem cells from a matched donor.
The transplanted cells settled in the bone marrow, where they began
to regenerate patients' blood supply, including white blood cells and
other agents that constitute the immune system.
Between 30 and 45 days after transplant, 15 of the patients began
receiving a cancer vaccine. The vaccine was made by surgically removing
cancerous or myelodysplasic tissue from patients and genetically
altering the diseased cells so they would produce a protein called
GM-CSF. When these modified cells were injected into patients as a
vaccine, the cells began pumping out GM-CSF. Just as a matador's cape
provokes the bull to attack, GM-CSF spurred the immune system to attack
cancer cells throughout the body.
Ten of the participating patients completed the full course of six
vaccinations (the others had to drop out of the trial because of rapidly
advancing disease). All of the patients who received even a single
vaccination had a better survival rate than people with these diseases
Of the 10 who received the entire vaccine course, nine are alive and in full remission up to four years after treatment.
Although the only way to determine whether the combined
transplant/vaccine approach is superior to transplant alone is to
compare them head-to-head in a clinical trial, the results of the
current study are highly encouraging, says co-senior author Robert
Soiffer, MD, of Dana-Farber. Historically, only about 20 percent of
similar high-risk AML and myelodysplasia patients who receive a
transplant survive for at least two years.
Researchers believe the new approach takes advantage of the unique
conditions that exist within the body shortly after a stem cell
"It usually takes several months following a transplant for the new
tissue to take root in the bone marrow and fully reconstitute the blood
supply," said Soiffer, who is also a professor of medicine at Harvard
"The period while that reconstitution is taking place is special. The
initial chemotherapy has depleted much of the patient's immune system,
and the body is trying to restore its previous state of function. That
'unsettled' condition seems to be a very opportune moment for an
intervention such as a cancer vaccine."
One of the pleasant surprises of the study was that GVHD rates among
study participants varied little from those of transplant-only patients.
As part of the transplant process, patients receive Tracrolimus, a
medication that inhibits the newly implanted tissue from launching an
immune system attack on the recipient's body. Researchers speculated
that the drug might dampen the vaccine's ability to spark an immune
response against diseased cells, but that turned out not to be a
Researchers also have strong evidence that the transplant and vaccine
complement each other in fighting AML and myelodysplasia cells. By
analyzing the blood of patients who received the combined therapy,
investigators found a sharp drop in a telltale protein, indicating
cancer cells were being killed by the immune response triggered by the
The study, though small in size, provides a solid indication that the
future of cancer therapy may involve combinations of treatments — such
as chemotherapy, radiation, and surgery — that directly kill cancer
cells, and other agents — such as cancer vaccines — that mobilize the
immune system against the malignancy.
"Where we currently have effective cancer therapies, they almost
always involve the combination of treating the disease and the host,"
said Dranoff, who is also an associated professor of medicine at Harvard
Medical School. "Chemotherapy and 'smart' drugs have a crucial role to
play, but when cancer cells find a way around them, immune-based
treatments offer another line of defense."
The study's lead author is Vincent Ho, MD, of Dana-Farber. Other
contributors include: Matthew Vanneman, Haesook Kim, PhD, Tetsuro
Sasada, MD, PhD, Yoon Joong Kang, PhD, Mildred Pasek, RN, Corey Cutler,
MD, John Koreth, DPhil, Edwin Alyea, MD, Stefanie Sarantopoulos, MD,
Joseph Antin, MD, Jerome Ritz, MD, and Christine Canning, PA-C, of
Dana-Farber; Jeffrey Kutok, MD, PhD, of Brigham and Women's Hospital;
and Martin Mihm, MD, of Massachusetts General Hospital.
Support for the study was provided by the Ted and Eileen Pasquarello
Research Fund, the Leukemia and Lymphoma Society, the National
Institutes of Health, and Bayer Pharmaceuticals.