LentiGlobin Gene Therapy Possibly Safe for Severe
Sickle-Cell Disease
Interim data from a phase I study of LentiGlobin BB305 in
patients with severe sickle cell disease (SCD) suggest that
the gene therapy was safe and allowed for the production of
increased amounts of anti-sickling hemoglobin (HbA T87Q ). The
data were presented at the 23rd Congress of the European
Hematology Association by lead author Julie Kanter, MD, of
the Medical University of South Carolina.
”Gene therapy may have
a potential curative role ...
but I don’t believe we’ve
reached the point for the
routine use.” —JULIE KANTER, MD
LentiGlobin BB305 is an investigational gene therapy manu-
factured using a new process in which autologous CD34-pos-
itive hematopoietic stem cells (HSPCs) are transduced with
a lentiviral vector (BB305) that encodes for HbA T87Q . After a
patient’s HSPCs are modified ex vivo, the cells are then infused
back into the patient’s blood. In this protocol, investigators
revamped the process with plerixafor mobilization to increase
the percentage of patient stem cells that carry the corrected,
functional gene.
This early-phase trial enrolled patients with severe SCD
(age range = 18-42 years), defined as a history of recurrent
vaso-occlusive crises, acute chest syndrome, stroke, or tricuspid
regurgitant jet velocity of >2.5 m/s.
Patients were categorized into three patient groups, each
with their own collection protocol:
• Group A: bone marrow harvesting–derived HSPCs for back-
up and LentiGlobin BB305 manufacturing
• Group B: ≥2 months of red blood cell transfusions before
plerixafor mobilization/apheresis for backup HSPC collec-
tion (with retained bone marrow–harvesting HSPCs for
LentiGlobin BB305 manufacturing)
The investigators measured adverse events (AEs), cell engraft-
ment, vector copy number (VCN), and HbA T87Q production after
infusion.
A total of 10 patients received LentiGlobin BB3305 at a
median dose of 2.1x10 6 cells/kg (range = 1.6×10 6 -5.1×10 6
cells/kg).
After a median follow-up of 21.6 months (range = 17.8-26.7
months), the investigators reported the following:
• median peripheral blood VCN (copies per diploid genome):
0.1 (range = 0.1-0.2)
• total hemoglobin: 9.7 g/dL (range = 7.5-10.9 g/dL)
• HbA T87Q levels: 0.7 g/dL (range = 0.5-2.0 g/dL)
In group C (the group that received LentiGlobin BB3305 with
the amended study protocol), six of 11 patients completed the
plerixafor mobilization/apheresis process, with a high trans-
duction success rate: 78 to 88 percent of CD34-positive were
successfully transduced. By three months post-infusion, four of
these patients were producing 3 to 6 g/dL of HbA T87Q , “making
over 30 percent anti-sickling HbA T87Q ,” the researchers wrote.
Following bone-marrow harvesting, investigators observed
17 grade 3-4 AEs in five patients; another five grade 3-4 AEs
were observed in three patients following plerixafor mobili-
zation/apheresis. At last follow-up, there were no observed
incidences of graft failure or grade 3-4 infusion-related toxici-
ties associated with LentiGlobin BB305. Also, according to the
researchers, the rate of grade 3-4 AEs following LentiGlobin
BB3305 was consistent with those observed after myeloablative
conditioning.
Limitations of the study include its relatively small patient
population and the short follow-up.
While these results were encouraging, Dr. Kanter noted
that these results are still early. “Considering this is an interim
evaluation of an ongoing study, I don’t think we’re yet ready
to say the se findings will play a role in current clinical care,”
she told ASH Clinical News. “At the moment, gene therapy
may have a potential curative role for severe cases of SCD, but
I don’t believe we’ve reached the point for the routine use of
gene therapy for reversing some of the abnormal findings in
SCD, such as cardiac or renal dysfunction, any time soon.” ●
The researchers reported no conflicts of interest.
REFERENCE
• Group C: autologous CD34-positive HSPCs transduced with
the BB305 lentiviral vector and backup using plerixafor-
mobilized HSPCs
Kanter J, Thompson A, Mapara M, et al. Recent progress in gene therapy for severe
sickle cell disease: updated interim results from a phase 1 clinical study of lentiglobin
gene therapy. Abstract #S836. Presented at the 23rd Congress of the European
Hematology Association, June 16, 2018; Stockholm, Sweden.
October 2018
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