Experimental Gene Therapy Studies Show Promising Outcomes for Patients with Rare Blood Disorders and Cancer
Published on: December 05, 2015
(ORLANDO, December 5, 2015) – New research adds to a
growing body of evidence that gene therapy, an experimental technique that
involves correcting or replacing a person’s mutated or malfunctioning genes,
may improve health outcomes for patients with inherited bleeding and immune
disorders as well as some forms of blood cancer. Studies showcasing these
advances will be presented today at the 57th American Society of Hematology
(ASH) Annual Meeting and Exposition.
Patients with severe blood
diseases may have no other therapeutic options but to depend on life-long blood
transfusions or a stem cell transplant. For these patients, experimental gene
therapies have demonstrated promise in improving outcomes and even curing
diseases with otherwise grim prognoses. While past efforts were associated with
toxicities and susceptibility to treatment-associated leukemia – in some cases
the treatment being worse than the illness – pioneering hematologists have made
great progress in correcting these issues. As a result, current methods have
demonstrated improved safety and long-term efficacy in treating a number of
Research presented today shows the continued promise of
lentiviral gene therapy, an approach in which healthy genetic material is
delivered to a cell via a non-communicable virus. One study shares follow-up
data on patients who can forgo blood transfusion after receiving lentiviral
gene therapy to treat beta-thalassemia. Another two studies demonstrate the
promise of gene therapy using a lentiviral vector to rebuild the immune systems
of patients who suffer from two rare blood diseases, Wiskott-Aldrich Syndrome
and severe combined immunodeficiency (SCID-X1), also known as “Bubble Boy
disease.” A fourth study to be presented today presents an exciting first
clinical trial using engineered donor immune cells to prevent progressive
cancer after stem cell transplant. Finally, a late-breaking study demonstrates
promising early outcomes of a first-in-human trial using a patient’s own
genetically modified immune cells to eradicate multiple myeloma.
research presented today pertains to some of the most severe and hard-to-treat
blood diseases, which have a devastating impact on patients and families, and
until now could not be effectively treated or cured,” said George Daley, MD,
PhD, Boston Children’s Hospital. “We are encouraged by the results and advances
in the field of gene therapy, which appears to be effective in a range of
This press conference will take place on Saturday,
December 5, 2015, at 7:30 a.m. in Room W208AB of the Orange County Convention
Gene Therapy for Patients with Severe Beta-Thalassemia
May Reduce or Eliminate Life-Long Need for Blood Transfusions
Update of Results from the Northstar Study (HGB-204): A Phase I/II Study
of Gene Therapy for Beta-Thalassemia Major via Transplantation of Autologous
Hematopoietic Stem Cells Transduced Ex-Vivo with a Lentiviral Beta AT87Q-Globin
Vector (LentiGlobin BB305 Drug Product) 
- Beta-thalassemia is a blood disorder caused by a
mutation in the HBB gene and characterized by reduced production of
the protein hemoglobin, which affects the blood’s ability to transport
oxygen and is associated with life-threatening complications such as severe
anemia and organ damage.
- Patients with more severe forms of
beta-thalassemia require frequent blood transfusions to replace their
unhealthy blood with healthy blood. However, transfusion-related
complications such as iron overload can be deadly.
- To provide an
alternative to life-long transfusions, researchers developed LentiGlobin
BB305, which uses a non-communicable virus to deliver a fully functioning
HBB gene to a patient’s own blood-producing stem cells. Researchers
hypothesized that hemoglobin production from the modified stem cells might
reduce or eliminate the need for blood transfusions in patients with
- This Phase I/II study examined if using
LentiGlobin BB305 to introduce a fully functioning hemoglobin gene into a
patient’s stem cells was a safe and effective treatment. Investigators
collected stem cells from transfusion-dependent beta-thalassemia major
patients, inserted the healthy gene, and then infused the cells back into
the patient after first giving high-dose chemotherapy to destroy the
thalassemia-producing blood cells.
- As of October 28, 13
transfusion-dependent beta-thalassemia major patients received LentiGlobin
BB305 therapy. The modified gene is in all patients and producing the
corrected hemoglobin. Of the nine patients who were treated more than six
months ago, five are transfusion-free, including three patients treated
longer than a year ago. These five all have HBB gene mutations that are
associated with reduced, but not totally absent, production of functional
- The other four patients have had transfusion needs
reduced but not entirely eliminated. These four patients have two copies of
a specific type of HBB gene mutation known as beta 0
(β0/β0) and appear to need a higher level of
corrected hemoglobin to reliably eliminate the RBC transfusions. However,
all patients demonstrated a reduction in transfusion volume ranging from 33
percent to 100 percent. Two serious adverse events, skin infection and
veno-occlusive liver disease, have been reported during the study but were
not related to treatment with the genetically modified cells.
results indicate that gene therapy is a promising option for reducing or
eliminating blood transfusions and limiting long-term complications in
patients with this disease.
Mark C. Walters, MD, UCSF
Benioff Children’s Hospital Oakland, Oakland, Calif., will present this study during an
oral presentation on Sunday, December 6, at 8:00 a.m. in room Tangerine 3
(WF3-4), level 2 of the Orange County Convention Center.
Five-Year Follow-Up of Gene Therapy in Patients with Rare Immune Disease Shows
Continued Improved Clinical Outcomes
Safety and Clinical Benefit
of Lentiviral Hematopoietic Stem Cell Gene Therapy for Wiskott-Aldrich Syndrome
- Wiskott-Aldrich Syndrome (WAS) is a rare genetic
disease of the immune system characterized by low platelet counts,
recurrent infections, easy bruising, bleeding, eczema, autoimmune
disorders, and high susceptibility to cancer. The disease is caused by a
mutation in the WAS gene.
- Stem cell transplant is the most
effective treatment for WAS but is associated with potentially
life-threatening complications, particularly in the absence of matched
- This Phase I/II clinical trial, initiated in April 2010,
examined whether engineering patients’ own stem cells with the correct
WAS gene could directly improve the severe complications associated
with this disease.
- Researchers extracted blood-forming stem cells
from patients with a mutated WAS gene and used a lentiviral vector
to engineer the cells to express the normal form of WAS.
of October 2015, eight patients have been treated at a median age of 2.2
years. All patients were alive after a median follow up of 3.3 years after
treatment (range: 0.1 – 5.4 years). No adverse reactions to gene therapy
were observed after infusion.
- Notably, six patients with a follow-up
period of more than two years after receiving treatment experienced a
marked reduction in the rate of severe infections and bleeding events after
treatment, as compared with before gene therapy.
- While continued
patient follow-up is needed to understand the long-term safety and efficacy
of this treatment, this form of gene therapy appears to be well tolerated
and may lead to sustained clinical benefit for these patients.
Francesca Ferrua, MD, San Raffaele Telethon Institute for Gene Therapy
(TIGET), San Raffaele Scientific Institute, Milan, Italy, will present this
study during an oral presentation on Sunday, December 6, at 12:00 noon in room
W230, level 2 of the Orange County Convention Center.
Presents Evidence That Gene Therapy Can Rebuild Immune System in Children,
Adolescents and Young Adults With Rare Immunodeficiency
Lentiviral Hematopoietic Stem Cell Gene Therapy for Older Patients with
X-Linked Severe Combined Immunodeficiency 
- X-linked severe combined immunodeficiency (SCID-X1), also
known as “Bubble Boy disease,” is a rare, inherited disorder of the immune
system affecting almost exclusively males. SCID-X1 is caused by mutations in the
IL2RG gene. Boys with SCID-X1 are born with poorly functioning immune
systems and are prone to life-threatening infections.
treatment of choice for infants with SCID-X1 is a stem cell transplant from a
matched sibling donor. For infants without a matched sibling donor, use of
partially matched stem cells from a parent without using pre-transplant
conditioning with chemotherapy to assist engraftment is lifesaving but only
partially restores their immune system, improving T cell immunity but not
correcting B and natural killer (NK) immune cell functions. These patients
require life-long treatment with immune globulin, a complex mix of antibodies
derived from donated blood plasma.
- Researchers sought to
demonstrate that a combination of gene therapy to insert a normal form of the
IL2RG gene into patients’ own stem cells and use of low-dose marrow
conditioning to enhance engraftment of the patients’ own gene-corrected stem
cells would successfully restore both B cell immunity and antibody
- Study participants included five patients 23, 24,
7, 16, and 10 years of age with worsening immune systems and complex medical
problems despite one or more previous transplants from a partially matched
parental donor. Patients have been treated with follow-up periods of three
months to three years.
- Researchers extracted blood-forming
stem cells from the patients and delivered a normal IL2RG gene to the
cells using a lentiviral vector. The stem cells were infused back into the
patients after a low dose of busulfan chemotherapy marrow conditioning.
- The two older patients with significantly longer follow-up
demonstrated increasing percent of immune cells with corrected genes,
specifically T cells (13-55%), B-cells (38%), and NK cells (56-76%), and
restoration of antibody production.
- This is the first study
of gene therapy in older SCID-X1 patients, including those well into late
adolescence and early adult stages of life demonstrating broad restoration of
immunity that includes full restoration of antibody production. Results
demonstrate that this approach can salvage failed stem cell transplants by
rebuilding the immune system.
Suk See De Ravin, MD, PhD,
National Institute of Allergy and Infectious Diseases, National Institutes of
Health, Bethesda, Md., will present this study during an oral presentation on
Sunday, December 6, at 12:30 p.m. in room W230, level 2 of the Orange County
Engineered Donor T Cells May Eradicate
Progressive Disease After Stem Cell Transplant
T-Cells Expressing an Anti-CD19 Chimeric Antigen Receptor Cause Remissions of
B-Cell Malignancies after Allogeneic Hematopoietic Stem Cell Transplantation
without Causing Graft-Versus-Host Disease 
- Stem cell transplant, a form of cell replacement therapy
in which the diseased stem cells are replaced with healthy donor cells, is a
potential curative therapy for patients with treatment-resistant blood
- Progressive disease is a leading cause of death after
stem cell transplant. If a patient’s cancer continues to spread after
transplant, the current standard treatment is to infuse the patient with
unmanipulated donor white blood cells to fight the disease. However, this
procedure is often ineffective and increases risk of graft-versus-host disease
(GVHD), a complication that occurs when the new cells attack the patient’s
- Instead of unmanipulated white blood cells, researchers
hypothesized that an infusion of genetically engineered donor T cells would
eradicate progressive disease after stem cell transplant in patients with
B-cell malignancies, which include types of leukemia and non-Hodgkin lymphoma.
- Researchers conducted a clinical trial in which donor T cells
were engineered to express a chimeric antigen receptor (CAR). CAR T cells are
programmed to first recognize CD19, a protein on the surface of most B-cells,
and then attack the targeted cell.
- Patients who experienced
resurgence of B-cell malignancies after stem cell transplant received a single
infusion of CAR T cells obtained from each recipient’s stem cell donor. No
chemotherapy or other therapies were administered.
- Eight of
the 20 total patients obtained remissions, including six complete remissions
and two partial remissions. Response rates were highest for patients with acute
lymphocytic leukemia, with four of five patients achieving complete remission.
- The longest ongoing complete remission is more than 30 months
in a patient with chronic lymphocytic leukemia.
- No patient
developed GVHD after infusion with CAR T cells.
- The findings
support the hypothesis that infusing anti-CD19 donor CAR T cells is a promising
method for treating B-cell malignancies that emerge after stem cell transplant.
James N. Kochenderfer, MD, Center for Cancer Research,
National Cancer Institute, Bethesda, Md., will present this study during an
oral presentation on Saturday, December 5, at 12:30 p.m. in room W314, level 3
of the Orange County Convention Center.
Using Engineered Cells to Target Multiple Myeloma Shows Early Promise
Remissions of Multiple Myeloma during a First-in-Humans Clinical Trial of
T Cells Expressing an Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor
- Multiple myeloma (MM) is a cancer of the plasma cells. The
disease is incurable in most cases and new therapies are urgently needed.
- The B-cell maturation antigen (BCMA) is a protein expressed by both
normal and malignant plasma cells. Because BCMA is only expressed by plasma
cells and a small fraction of B-cells, it is a promising target for treating
- In this Phase I clinical trial, researchers
extracted immune T cells from patients and genetically engineered the cells to
express an anti-BCMA chimeric antigen receptor (CAR-BCMA) to recognize and kill
the myeloma cells. Patients received one round of chemotherapy before their own
engineered cells were infused back into their bodies at one of four dose
- As of November 2015, 11 patients with advanced MM and a
median of seven previous failed therapies have participated in the trial.
- One month following infusion, the two patients treated at the
highest dose level demonstrated the strongest anti-cancer responses. One patient
achieved a stringent complete remission at two months following the CAR-BCMA T
cell infusion. The other patient had undetectable myeloma in the bone marrow
plasma cells but has not yet reached complete remission status.
- Of the six patients treated on the lowest two dose levels, one patient
experienced a short partial remission of two weeks and the other five remained
stable, their disease neither improving nor worsening.
patients on the second-highest dose level maintained stable disease, and one
patient obtained a very good partial response.
- Toxicity and
side effects were mild for patients who received the lowest dose levels.
Patients who received the highest doses experienced cytokine release syndrome,
a severe and potentially fatal side effect of therapy characterized by high
fever, muscle pain, and heart and kidney problems.
CAR-BCMA T cells were detected in the blood of all 10 patients assessed to
date. Toxicities were similar to those observed in leukemia patients treated
with similar therapies.
- These findings suggest that CAR-BCMA
is a promising option for advanced multiple myeloma patients who have failed
several previous therapies.
James N. Kochenderfer, MD,
Center for Cancer Research, National Cancer Institute, National Institutes of
Health, Bethesda, Md., will present this study during the Late-Breaking
Abstracts Session on Tuesday, December 8, at 7:30 a.m. in Hall D, level 2 of the
Orange County Convention Center.
American Society of
Hematology 57th Annual Meeting
The study authors and press program
moderator will be available for interviews after the press conference or by
telephone. Additional press briefings will take place throughout the meeting on
precision medicine, supportive care for patients with blood diseases, sickle
cell disease, and novel therapies for blood cancers. For the complete annual
meeting program and abstracts, visit www.hematology.org/annual-meeting.
Follow @ASH_hematology and
#ASH15 on Twitter and like
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The American Society of Hematology (ASH)
(www.hematology.org) is the world's largest professional society of
hematologists dedicated to furthering the understanding, diagnosis, treatment,
and prevention of disorders affecting the blood. For more than 50 years, the
Society has led the development of hematology as a discipline by promoting
research, patient care, education, training, and advocacy in hematology. The
official journal of ASH is Blood (www.bloodjournal.org), the most
cited peer-reviewed publication in the field, which is available weekly in
print and online and has been serving the hematology community for 70 years.
Amanda Szabo, ASH
(407) 685-5410; email@example.com
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