A series of advancements in genetically engineered cell
therapies demonstrate early efficacy and safety in patients with blood
disorders for whom standard treatments have been unsuccessful, according to
data showcased today during the 55th American Society of Hematology (ASH)
Annual Meeting and Exposition in New Orleans.
Today, many patients with newly diagnosed
blood disorders – ranging from cancer to rare genetic conditions – respond well
to modern treatment regimens. However, for more than half of newly treated
patients, therapies fail to work or patients experience a relapse that may
negatively affect their prognosis. Thankfully, an emerging field, dubbed
“precision medicine,” aims to improve success rates by attacking the specific
targets that are responsible for a patient's disease. Using a patient's own
re-engineered cells to attack their disease is an example of this approach.
Building on the existing concept of turning the immune system into a
disease-fighting weapon, this new field of medicine adds innovative
technologies that transform healthy cells into “super” cells that can more
effectively combat disease.
Several studies presented during the
meeting detail results using one method known as chimeric antigen receptor
(CAR) cell engineering. The CAR process starts when T cells (naturally
occurring immune cells) are extracted from the blood of an individual and
outfitted with two powerful features: a receptor on the outer cell surface that
recognizes a protein called CD19 present on most leukemic cells and a powerful
mechanism inside the cell that triggers it to expand and proliferate once
attached to the targeted protein. With these new engineered features, the T
cells are injected back into the patient, now primed to seek and destroy cancer
cells.
Studies on the CAR approach provide data on
both adult and pediatric patients with leukemia who have responded well to this
treatment strategy. In addition to the abstracts detailed below, two additional
data sets are being presented on this research program during the meeting
Preliminary studies have found that this
process may generate responses in as many as two-thirds of cases in which all
other treatment options have failed. Further, because the cells are derived
from the patient, there is an inherently lower risk of toxicity because the
cells are less likely to attack the host tissue than cells introduced from a
foreign body.
Other advances in cell engineering reported
today include a new generation of gene “vector” therapy that self-destructs
once it delivers critical, missing genetic material to a patient, solving the
issue of T cell overgrowth observed in previous studies. Finally, genetic
modifications of haploidentical (or half-matched) stem cells prior to
transplant could expand the utility of this treatment approach to a much wider
range of patients in the coming years by reducing the risk of transplant
infections.
“It’s exciting to see these encouraging
initial results with engineered immune cells, particularly such a durable
response among patients who have very aggressive disease that has relapsed
after standard treatments,” said Laurence Cooper, MD, of The University of
Texas MD Anderson Cancer Center in Houston. “With the right technology and
laboratory expertise, the process of cell engineering is feasible for many
patients. One remaining challenge is determining why some patients benefit and
others have less durable responses. Does ‘one size fits all’ therapy work or do
we need personalized or individualized T cell treatments? Further, we need to
extend these studies to other tumor types, particularly solid tumors, to
evaluate their potential in other clinical settings.”
This press conference will take place on Saturday, December 7,
2013 at 8:00 a.m. CST.
Removal of Alpha/Beta+ T Cells and of CD19+ B Cells From the
Graft Translates Into Rapid Engraftment, Absence of Visceral Graft-Versus-Host
Disease and Low Transplant-Related Mortality in Children With Acute Leukemia
Given HLA-Haploidentical Hematopoietic Stem Cell Transplantation [157]
Transplants of haploidentical, or
half-matched, blood-forming stem cells may be an effective option for patients
in need of a transplant without a fully matched donor; however, in the past, in
comparison to transplant from a fully matched donor, this treatment has been
associated with an increased risk of infection and disease recurrence. This
study tested the effectiveness of manipulating in the lab these half-matched
donor stem cells.
In this process, the team selectively
removed the alpha/beta-positive T cells and CD19-positive B cells from the
donor graft, as those are more likely to trigger donor cells to attack
recipient cells, resulting in a dangerous complication known as
graft-versus-host disease (GVHD). At the same time, the process preserved
healthy, mature, immune-active cells known as natural killer and
gamma/delta-positive T cells that help prevent disease relapse and protect
against infection. A total of 45 patients with acute leukemia were treated with
genetically engineered stem cells from one of their parents. Transplants
engrafted in 44 of the 45 patients, with a 29 percent cumulative incidence of
mild GVHD. One month after transplant, follow-up analyses showed that
transplanted cells had persisted in the patients and demonstrated potential
anti-leukemic activity, which continued to increase over time.
“Our results, which demonstrate that
transplantation of selectively modified, half-matched donor stem cells boasts
success rates equivalent to those of a fully matched transplant, preventing
GVHD and reducing transplant-related death, help continue to establish this
approach as a viable option for patients without a matched donor,” said study
author Alice Bertaina, MD, of the Bambino Gesu Children’s Hospital in Rome,
Italy. “This has the potential to make this lifesaving treatment more
accessible to a much larger population of patients who may not have a perfect
donor match.”
Dr. Bertaina will present this study during an oral presentation
at 5:00 p.m. CST on Sunday, December 8, in Rooms 208-210 of the Ernest N.
Morial Convention Center.
Immune Reconstitution and Preliminary Safety Analysis of 9
Patients Treated With Somatic Gene Therapy for X-Linked Severe Combined
Immunodeficiency (SCID-X1) With a Self-Inactivating Gammaretroviral Vector
Previous studies have investigated the potential for gene therapy using
a retroviral vector to treat children with the fatal inherited disease,
X-linked severe combined immunodeficiency (SCID-X1, or “bubble boy disease”).
The vector works by latching to the surface of the T cell and injecting genetic
material that helps “train” the cells to properly produce their own immune
cells. While successful in earlier studies, in some cases the children
developed leukemia when new corrective genetic material was inserted near a
trigger in the children’s DNA, predisposing T cells to turn into cancer cells.
Aiming to overcome this challenge and
achieve immune recovery in these patients without provoking the development of
leukemia, investigators considered an approach with a modified version of the
vector that was designed to insert the genetic material but not encourage
overgrowth of the cells. Enrolling nine boys with SCID-X1, investigators
removed some of the boys’ bone marrow stem cells and engineered them with this
new version of the vector and infused the engineered cells back into the
bloodstream. After the cell infusion and adequate observation, eight of the
nine boys remained alive and healthy; one patient died of advanced viral
infection that was present when he entered the study. Seven are showing signs
that their bodies are properly producing healthy T cells. Analysis of insertion
pattern in the blood of these children shows much less insertion of the
corrective gene near trigger points for cancer compared to children enrolled on
the previous trial.
“We have preliminary evidence that using
this new vector approach is just as effective but may eliminate the long-term
risk of leukemia in these children,” said study author Sung-Yun Pai, MD, of
Dana-Farber/Boston Children’s Cancer and Blood Disorders Center in Boston,
Mass. “We will need to closely monitor these patients to evaluate their long-term
risks, but at this point we are hopeful given the excellent response so far.”
Dr. Pai will present this study during an oral presentation at
4:30 p.m. CST on Monday, December 9, in Riverside Rooms R04-R05 of the Ernest
N. Morial Convention Center.
Long-Term Functional Persistence, B Cell Aplasia and
Anti-Leukemia Efficacy in Refractory B Cell Malignancies Following T Cell
Immunotherapy Using CAR-Redirected
T Cells Targeting CD19
T Cells Targeting CD19
These research results provide an overview of patient response in a
clinical research program evaluating treatment of pediatric and adult leukemia
patients with experimental CAR genetically engineered T cells. A series of
treatment cohorts were included in the analysis, including pediatric and adult
patients with high-risk, treatment-resistant acute lymphocytic leukemia and
adult patients with advanced relapsed and/or treatment-resistant chronic
lymphocytic leukemia. The focus of this research effort was to understand how
the engineered cells responded in patients with time, and how that response
correlated with anti-leukemia activity. To accurately estimate the quantity,
lifespan, and activity of the engineered cells in the patients, researchers
developed a number of highly accurate tests. The researchers observed
that those patients with the greatest expansion of T cells (above 5% of the
total of all of their T cells) were very likely to achieve complete response;
those with less robust, but still detectable, cell expansion were partial
responders; and those who had no detectable T cell expansion did not respond to
treatment. In complete responders, the engineered T cells were usually
detectable many months after the infusion and continued to show functional
activity in the body.
“These new and expanded data provide
significant proof that T cells engineered to express cancer-targeting chimeric
antigen receptors not only work, but work dramatically and in a sustained
manner in patients with relapsed, treatment-resistant leukemia, and further
demonstrate the potential of this approach to help these patients achieve
complete response,” said study author Michael Kalos, PhD, of the University of
Pennsylvania Perelman School of Medicine in Philadelphia. “Further, our results
show that we can potentially measure and track the activity of these engineered
cells in the body as a way to monitor treatment, an exciting finding
considering that this treatment is often the last hope for these patients.”
Dr. Kalos will present this study during an oral presentation at
5:00 p.m. CST on Sunday, December 8, in Riverside Rooms R02-R03 of the Ernest
N. Morial Convention Center.
T Cells Engineered With a Chimeric Antigen Receptor (CAR)
Targeting CD19 (CTL019) Produce Significant In Vivo Proliferation,
Complete Responses and Long-Term Persistence Without GVHD in Children and
Adults With Relapsed, Refractory ALL
This study report, which provides select
results from a group of cell therapy trials conducted by investigators at the
Children’s Hospital of Philadelphia and the University of Pennsylvania, used
the chimeric antigen receptor (CAR) cell engineering approach to manipulate the
T cells of 22 children and five adults with relapsed, treatment-resistant acute
lymphocytic leukemia. After treatment with their own cells re-engineered to
seek, attack, and kill leukemic cells, 24 patients (19 children, five adults)
achieved a complete response (CR). One patient has remained in remission for a
year and had detectable engineered cells at 18 months post infusion, indicating
that the cells show potential to persist in the body. Of those who achieved CR
at one month, six (five children, one adult) have since relapsed. No patients
experienced immediate infusion-related toxicities or graft-versus-host disease.
The most significant toxicity each patient experienced was a complication known
as delayed cytokine release syndrome, characterized by high fever, muscle pain,
and nausea, which developed as a result of successful T cell expansion, driven
by the interaction between engineered T cells and the patients’ leukemic cells.
“Our results serve as another important
milestone in demonstrating the potential of this treatment for patients who
truly have no other therapeutic options,” said study author Stephan Grupp, MD,
PhD, of the Children's Hospital of Philadelphia, Abramson Cancer Center and the
Perelman School of Medicine at the University of Pennsylvania in Philadelphia.
“These data also demonstrate that these engineered hunter cells greatly expand
and then persist in patients, allowing for long-term disease control. This
allays previous concerns that infused cells only survive for a limited time. In
the relatively short time that we’ve observed these patients, we have reason to
believe that this treatment could become a viable therapy for their relapsed,
treatment-resistant disease and we look forward to continuing to evaluate their
long-term response.”'
Dr. Grupp will present this study during an oral presentation at 5
p.m. CST on Sunday, December 8, in La Nouvelle Ballroom C of the Ernest N.
Morial Convention Center.
Effective Treatment of Chemotherapy-Refractory Diffuse Large
B Cell Lymphoma With Autologous T Cells Genetically-Engineered to Express an
Anti-CD19 Chimeric Antigen Receptor
This abstract reports on the treatment of
15 patients with anti-CD19 CAR-expressing T cells, all of whom had advanced B
cell malignancies, and eight of whom had large B cell lymphomas.
This is the first report of successful treatment in patients with chemotherapy-refractory
primary mediastinal B cell lymphoma and diffuse large B cell lymphoma. In the
trial, the 15 adult patients with varying types of lymphoma or leukemia
received an infusion of their own genetically modified T cells following a
chemotherapy conditioning regimen of cyclosphamide and fludarabine. Six
patients achieved complete remission and six achieved partial remission. Acute
toxicities such as fever, low blood pressure, focal neurologic deficits, and
delirium resolved in less than three weeks.
“Our data provide the first true glimpse of
the potential of this approach in patients with aggressive lymphomas that,
until this point, were virtually untreatable,” said study author James
Kochenderfer, MD, of the Experimental Transplantation and Immunology Branch of
the National Cancer Institute at the National Institutes of Health in Bethesda,
Md. “We are particularly encouraged by the partial and complete responses that
we observed in a number of patients with diffuse large B cell lymphomas who had
exhausted all other treatment options. This approach offers an option for
patients with chemotherapy-refractory large B cell lymphomas who are not
generally thought to be good candidates for hematopoietic stem cell
transplantation. This approach is still an early-stage experimental therapy,
and we will continue our research to further improve the protocol and evaluate
its value in additional patients with treatment-resistant disease.”
Dr. Kochenderfer will present this study during an oral
presentation at 6:15 p.m. CST on Sunday, December 8, in Riverside Rooms R02-R03
of the Ernest N. Morial Convention Center.
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