Major breakthrough in treatment of chronic lymphocytic leukaemia
Protocol offers roadmap for treatment of other cancers
In a cancer treatment
years in the making, researchers from the
University of Pennsylvania’s Abramson
Cancer Center and Perelman School of
Medicine have shown sustained remissions
of up to a year among a small group of
advanced chronic lymphocytic leukaemia
(CLL) patients treated with genetically
engineered versions of their own T cells.
The protocol, which involves removing
patients’ cells and modifying them in Penn’s
vaccine production facility, then infusing
the new cells back into the patient’s body
following chemotherapy, provides a tumour-attack roadmap for the treatment of
other cancers including those of the lung
and ovaries and myeloma and melanoma.
The findings, published simultaneously 10
August 2011 in the New England Journal of
Medicine and Science Translational Medicine,
are the first demonstration of the use of
gene transfer therapy to create “serial killer”
T cells aimed at cancerous tumours.
“Within three weeks, the tumours had
been blown away, in a way that was much
more violent than we ever expected,” said
senior author Carl June, MD, director of
Translational Research and a professor of
Pathology and Laboratory Medicine in the
Abramson Cancer Center. “It worked much
better than we thought it would.”
The results of the pilot trial of three
patients are a stark contrast to existing therapies
for CLL. The patients involved in the
new study had few other treatment options.
The only potential curative therapy would
have involved a bone marrow transplant, a
procedure which requires a lengthy hospitalisation
and carries at least a 20% mortality
risk – and even then offers only about a 50%
chance of a cure, at best.
“Most of what I do is treat patients with
no other options, with a very, very risky
therapy with the intent to cure them,” says
co-principal investigator David Porter,
MD, professor of Medicine and director of
Blood and Marrow Transplantation. “This
approach has the potential to do the same
thing, but in a safer manner.”
Dr June thinks there were several “secret
ingredients” that made the difference
between the lacklustre results that have
been seen in previous trials with modified
T cells and the remarkable responses seen
in the current trial. The details of the new
cancer immunotherapy are detailed in
Science Translational Medicine.
After removing the patients’ cells, the
team reprogrammed them to attack tumour
cells by genetically modifying them using a
lentivirus vector. The vector encodes an
antibody-like protein, called a chimeric
antigen receptor (CAR), which is expressed
on the surface of the T cells and designed to
bind to a protein called CD19.
Once the T cells start expressing the
CAR, they focus all of their killing activity
on cells that express CD19, which includes CLL tumour cells and normal B cells. All
of the other cells in the patient that do not
express CD19 are ignored by the modified
T cells, which limits side effects typically
experienced during standard therapies.
The team engineered a signalling molecule
into the part of the CAR that resides
inside the cell. When it binds to CD19,
initiating the cancer-cell death, it also tells
the cell to produce cytokines that trigger
other T cells to multiply – building a
bigger and bigger army until all the target
cells in the tumour are destroyed.
“We saw at least a 1,000-fold increase in the
number of modified T cells in each of the
patients. Drugs don’t do that,” Dr June says.
“In addition to an extensive capacity for
self-replication, the infused T cells are serial
killers. On average, each infused T cell led
to the killing of thousands of tumour cells –
and overall, destroyed at least two pounds of
tumour in each patient.”
The importance of the T cell self-replication
is illustrated in the New England
Journal of Medicine paper, which describes
the response of one patient, a 64-year-old
man. Prior to his T cell treatment, his blood and marrow were replete with tumour cells.
For the first two weeks after treatment,
nothing seemed to change. Then on day 14,
the patient began experiencing chills,
nausea, and increasing fever, among other
symptoms. Tests during that time showed
an enormous increase in the number of T
cells in his blood that led to a tumour lysis
syndrome, which occurs when a large
number of cancer cells die all at once. By
day 28, the patient had recovered from the
tumour lysis syndrome – and his blood and
marrow showed no evidence of leukaemia.
“This massive killing of tumour is a
direct proof of principle of the concept,”
Dr Porter says.
The Penn team pioneered the use of the
HIV-derived vector in a clinical trial in
2003 in which they treated HIV patients
with an antisense version of the virus.
That trial demonstrated the safety of the lentiviral vector used in the present work.
The cell culture methods used in this trial
reawaken T cells that have been suppressed
by the leukaemia and stimulate the generation
of so-called “memory” T cells, which the
team hopes will provide on-going protection
against recurrence. Although long-term
viability of the treatment is unknown, the
doctors have found evidence that months
after infusion, the new cells had multiplied
and were capable of continuing their seekand-
destroy mission against cancerous cells
throughout the patients’ bodies.
The team plans to test the same CD19
CAR construct in patients with other
types of CD19-positive tumours, including
non-Hodgkin’s lymphoma and acute
lymphocytic leukaemia. They also plan to
study the approach in paediatric leukaemia
patients who have failed standard therapy.
Additionally, the team has engineered a
CAR vector that binds to mesothelin, a
protein expressed on the surface of
mesothelioma cancer cells, as well as on
ovarian and pancreatic cancer cells.
of upload: 18th Oct 2011