Like brainy bookworms unprepared
for the rough and tumble of post-graduation life, white blood cells trained by
scientists to attack tumors tend to fade away quickly when injected into cancer
patients. Dana-Farber Cancer Institute scientists, however, have developed a
technique that can cause such cells to survive in patients’ bloodstreams for
well over a year, in some cases, without the need of other, highly toxic
treatments, a new study shows.
a paper published in the Apr. 27 issue of Science
Translational Medicine, the researchers report the results of a small,
Phase I study in which the technique – a form of “adoptive immunotherapy” – was
tested in nine patients with advanced melanoma.
Ten weeks after
starting the therapy, seven of the nine patients had more of the specially
trained, tumor-hunting cells than they had started with. Three of the patients
had stable disease – neither advancing nor retreating – and one had shrinkage
of a tumor that had spread to the lung.
experienced a complete remission, with no tumors visible on CT or PET scans. Today,
25 months after receiving the one-time therapy, he has no evidence of cancer.
results represent the longest that the injected cells – known as anti-tumor T
cells – have ever endured in cancer patients without the use of supplemental
treatments – treatments that, while effective, often have harsh side effects.
Marcus Butler MD
demonstrates it is possible to maintain high levels of anti-tumor T cells in
patients over a long period of time while avoiding the complications of conventional
approaches,” says the study’s lead author, Marcus Butler, MD, of Dana-Farber’s
Early Drug Development Center. “Our technique opens the way to therapies that
produce less-toxic, long-lasting immune system attacks on cancer cells.”
technique’s promise was further illustrated when researchers combined it with
whose disease had progressed after T cell infusions were treated with
ipilimumab, a drug that boosts the cells’ anti-tumor response. Three of the
patients had long-term shrinkage of their tumors, and two others had their
disease stabilize. Patients who received the drug after the completing clinical
trial had sizable increases in the number of anti-tumor T cells in their blood.
skin cancers were diagnosed in more than 68,000 Americans in 2010, according to
the American Cancer Society, and the numbers have been rising for more than 30
If detected and
removed at an early stage, melanomas can usually be cured, but once the disease
has spread to distant sites, the median survival time for patients is less than
a year. Scientists are developing an array of novel treatment approaches to
improve those odds.
immunotherapy involves collecting T cells – natural infection- and
cancer-fighters of the immune system – from a patient and exposing them to
protein “antigens” found only on tumor cells. The T cells learn to recognize
the antigens and to attack tumor cells that carry them.
these “educated” T cells with a growth stimulator to increase their number and
then inject them back into the patient, where they fan out to obliterate tumor
normal conditions, the re-injected T cells die off in a matter of days. Doctors
can increase their staying power by depleting patients’ blood of certain
regulatory T cells that dampen the anti-tumor T cells’ response to cancer or by
using Interleukin 2, which spurs the growth of T cells.
can cause a host of health problems, including nausea, fever, muscle weakness,
a drop in certain kinds of white blood cells, as well as other, more severe
technique developed at Dana-Farber aims to reduce those problems while giving
anti-tumor T cells the stamina to persevere in the body.
It involves an
artificial version of cells known as antigen-presenting cells. Such cells act
like tiny “FBI Most Wanted” posters: by displaying tumor cell antigens, they
inform the immune system that cancer is present and needs to be eliminated.
scientists engineered antigen-presenting cells to produce a key molecule, known
as CD83, which ensures that T cells persist for a long period of time.
They also used Interleukin
15 to educate the T cells to be survivors. These educated T cells, known as
memory cells, use their “knowledge” of tumor antigens to prepare them to launch
a swift, powerful attack on tumor cells.
exams of study participants showed that blood levels of educated anti-tumor T
cells remained elevated many months after treatment and congregated inside the
By observing how
the cells function, investigators confirmed that they were indeed memory cells —
and therefore the descendants of the ones that had been educated in the lab —
not untrained T cells that had yet to encounter cancer cell antigens.
researchers found that patients with the highest post-treatment levels of
anti-tumor T cells did not necessarily fare better than those with lower
levels. This wasn’t surprising, they say, because many tumors have developed an
ability to blunt a T cell attack.
a phase I trial, the study was primarily concerned with the safety of the
technique and with its ability to produce long-lasting anti-tumor T cells in
results in the patient who is cancer-free two years after completing therapy
were unexpected, the authors say, but offer a glimpse of the technique’s
effectiveness when refined and combined with other agents.
next step will be to study this technique in conjunction with other therapies
that can boost the numbers and effectiveness of these memory T cells,” says the
study’s senior author, Naoto Hirano, MD, PhD, of Dana-Farber and the Ontario
Cancer Institute, in Toronto. “We will be beginning a series of clinical trials
to learn which combinations work best in which patients.”
study was funded by grants from the National Institutes of Health,
Immunotherapy Fund 1, the S. Craig Lindner Fund for Cancer Research, the Rudolf
E. Rupert Foundation for Cancer Research, the Cancer Research Institute/Ludwig
Institute for Cancer Research Cancer Vaccine Collaborative, Friends of the Dana-Farber
Cancer Institute, the Dunkin’ Donuts Rising Stars Program, and the American
Society of Hematology Scholar.
T cells were generated in Dana-Farber’s Connell and O’Reilly Families Cell
Manipulation Core Facility. The study and scientific analysis was conducted in
the laboratory of Lee Nadler, MD, senior vice president of Experimental
Medicine at Dana-Farber.
co-authors of the study are Matthew Milstein, Mary Mooney, Genita Metzler,
Andrew Murray, Alla Berezovskaya, Linda Drury, Lisa Brennan, RN, BSN, Marisa
Flavin, Donna Neuberg, ScD, and Kristen Stevenson, Dana-Farber; Philip
Friedlander, MD, Makito Tanaka, PhD, Osamu Imataki, PhD, Stephen Hodi, MD,
Martin Mihm, MD, and Lee Nadler, MD, Dana-Farber and Brigham and Women’s Hospital;
Elsa Velazquez, MD, Brigham and Women’s and Tufts University School of
Medicine; Michael Jaklitsch, MD, and Sara Russell, MD, Brigham and Women’s; and
Donald Lawrence, MD, Massachusetts General Hospital.