New Approaches Aim to Enhance CAR T-Cell Therapy
products may overcome resistance, reduce toxicity, simplify treatment
Published on: December 07, 2019
(Orlando, FL, Dec. 7, 2019)
–– Four early-phase studies being presented today during the 61st American
Society of Hematology (ASH) Annual Meeting and Exposition spotlight the rapid
advances being made in cellular immunotherapy for blood cancers. Researchers
will present the results of early-phase studies of emerging “second-generation”
cellular immunotherapy products that strive to overcome the limitations of
Cellular immunotherapy uses
genetic engineering to enhance the ability of the immune system – the body’s
defense system against infection and disease – to kill malignant cells in the
blood, the bone marrow, and other sites, in order to keep cancer from coming
back. Chimeric antigen receptor T-cell (CAR-T) therapies are developed by
harvesting a patient’s own T cells (the immune system’s primary cancer-killing
cells), engineering them to target proteins specific to the surface of cancer
cells, and reintroducing these modified T cells back into the patient’s immune
system to kill the cancer cells.
First-generation CAR T-cell
therapies primarily target CD-19, a protein found on the surface of most normal
and malignant B cells in B cell cancers such as lymphoma. These therapies have
been shown to produce long-term remissions in about one-third of patients with
B-cell lymphomas that have not responded to prior therapies.
“We are now seeing efforts to:
1) enhance the effectiveness of CAR T-cell therapy by designing products
capable of attacking multiple targets; 2) expand the availability of cellular
immunotherapy to other blood cancers such as multiple myeloma; and 3) replace
the complex manufacturing process required for CAR T-cell therapy with a uniform
off-the-shelf product,” said press briefing moderator Gary Schiller, MD,
One phase I study to be
presented today evaluates an off-the-shelf cellular immunotherapy product that
targets two proteins found on the surface of lymphoma cells, including its
potential to “revive” previously administered CAR T cells that have stopped
working. Another study presents preclinical results for one of the first
cellular immunotherapies to be based on off-the-shelf natural killer (NK) cells
and the first, according to its manufacturer, to be genetically engineered to
contain three active anti-tumor components.
The other two studies, also phase
I studies, assess novel CAR T-cell therapies for multiple myeloma that test
different dual-target strategies. One product is genetically engineered to
contain two proteins that attach to BCMA, a protein found almost exclusively on
the surface of plasma cells, the immune-system cells that become cancerous in
multiple myeloma. The other is designed to target both BCMA and CD-38, another
protein found on the surface of plasma cells. In both studies, many patients
achieved minimal residual disease (MRD) negativity, which means that using highly
sensitive testing fewer than one myeloma cell per 100,000 cells was identified in
the bone marrow. Previous studies have shown that patients who achieve this milestone
have a lower risk of relapse after more than three years of follow-up.
The three phase I studies
also hint at the possibility that dual-targeted CAR T-cell therapies might
result in fewer patients experiencing moderate to severe cytokine release
syndrome (CRS), a known adverse effect caused by an immune response in the body
to the activated T cells that are attacking the cancer. CRS causes flu-like
symptoms such as fever, body aches, and fatigue, and in severe cases can be
life-threatening. Treatment with the drug tocilizumab can reduce CRS symptoms.
This press conference will take place on Saturday, December 7, at 7:30 a.m. in the
ASH press briefing room W221DE.
Antibody Elicits Durable Responses in Poor-Prognosis non-Hodgkin Lymphoma (NHL)
#6 Mosunetuzumab Induces Complete
Remissions in Poor Prognosis Non-Hodgkin Lymphoma Patients, Including Those Who
Are Resistant to or Relapsing after Chimeric Antigen Receptor T-Cell (CAR-T)
Therapies, and Is Active in Treatment through Multiple Lines
Patients with B-cell NHL that had returned after or failed to respond to
a median of three prior therapies showed complete responses and durable
remissions after being treated with an investigational drug called
mosunetuzumab. Among patients whose lymphoma progressed after treatment with
CAR T-cell therapy, 22% had complete remissions when treated with
mosunetuzumab. This new drug targets two proteins, one on the surface of tumor
cells and the other on the surface of the recipient’s Tcells.
“Unlike CAR T-cell therapy, mosunetuzumab is an off-the-shelf
immunotherapy product that can be given to patients without having to
genetically modify their T cells,” said lead author Stephen J. Schuster, MD,
of Abramson Cancer Center at the University of Pennsylvania in
Philadelphia. “Mosunetuzumab generates
long-lasting responses with a very tolerable safety profile in patients with
B-cell non-Hodgkin lymphomas for whom multiple prior treatments have failed and
whose prognosis is poor. Of particular interest, we are seeing durable complete
remissions in patients whose lymphomas progressed after CAR-T.”
Many remissions continue after patients stop receiving the drug. “I have
stopped therapy in some patients after six months and they have remained in
remission. Some patients have remained in remission without additional therapy
for more than a year,” Dr. Schuster said.
New treatment options are needed not only for patients in whom CAR
T-cell therapy has failed, but also for those patients whose lymphomas are
getting worse so quickly that they cannot wait for CAR T cell manufacturing,
which takes several weeks, Dr. Schuster said.
Mosunetuzumab is a synthetic antibody designed to bind to a specific
marker on tumor cells. It works by activating the patient’s own T cells, stimulating
them to attack and kill cancerous B cells to which they have been introduced by
the novel antibody. The drug could potentially be given to patients before,
after, or in combination with CAR-T, which needs to be further tested and
explored, researchers explained.
Data were presented for 270 patients (median age 62, 172 men) enrolled
in the phase I trial in seven countries (the United States, Australia, Canada,
Germany, South Korea, Spain, and the United Kingdom). All had B-cell lymphomas
that had come back or not responded to a median of three prior therapies.
Two-thirds of patients (67%) had fast-growing lymphomas; 85 (31%) patients had
more slow-growing forms of the disease. In 30 patients (11%), the cancer was
resistant to or returned after an initial response to CAR T-cell therapy; in 77
patients (29%), the disease had progressed after a stem cell transplant.
All patients were treated with mosunetuzumab by intravenous infusion.
They had an imaging test at either six weeks or three months after starting
therapy to assess the initial response to treatment, and responses continued to
be followed every three months thereafter.
Forty-six of 124 patients with fast-growing lymphomas (37%) had
measurable decreases in the extent of their cancer (objective response); 24 of
124 patients (19%) saw all detectable tumors disappear (complete response). A
higher response rate was observed in patients with higher exposure to
mosunetuzumab. Among patients with slow-growing lymphomas, 42 of 67 (63%) had
objective responses and 29 of 67 (43%) had complete responses. Both objective
response rate and complete response rate were maintained in subgroups of
patients at high risk for relapse.
Complete remissions appear to be long lasting, Dr. Schuster said. With a
median follow-up of six months since first complete remission, 24 of 29 patients (83%) who achieved complete
remissions of their slow-growing lymphomas and 17 of 24 patients (71%) who
achieved complete remissions of their fast-growing lymphomas remain free of
disease. In some patients whose cancers progressed after receiving CAR T-cell
therapy, highly sensitive molecular testing showed that the previously
administered CAR T cells increased in number. This suggests that, in addition
to its ability to kill cancerous B cells, mosunetuzumab may also help augment
the effect of the prior CAR-T treatment, Dr. Schuster said.
In this study, 29% of patients treated with mosunetuzumab experienced
cytokine-release syndrome that was mostly mild. In 3% of patients, CRS was
treated with tocilizumab. Four percent of patients experienced moderately
severe neurologic side effects. Patients who received higher doses of
mosunetuzumab were no more likely to have CRS or neurologic side effects than
patients treated at lower doses.
A study of a higher dose of mosunetuzumab is now enrolling patients, Dr.
Schuster said. Long-term follow-up of these patients will ultimately help to
better evaluate the durability of response data.
“Larger, randomized trials are needed to further confirm these promising
data and determine whether the treatment benefit of mosunetuzumab is enhanced
when it is used earlier in the course of lymphoma therapy or in combination
with other agents,” Dr. Schuster said.
This study was supported by Genentech, Inc.
Stephen J. Schuster,
MD, Abramson Cancer Center, University of Pennsylvania will present this study
during the plenary session on Sunday, December 8, at 2 p.m. in Hall D.
Novel Off-the-Shelf CAR NK Product Overcomes CD19 Antigen
Escape in Preclinical Studies
Translation of First-of-Kind Multi-Antigen Targeted Off-the-Shelf CAR NK Cell
with Engineered Persistence for the Treatment of B Cell Malignancies
Preclinical studies provide
the first evidence that cellular immunotherapy for B cell cancers could
ultimately become an off-the-shelf product, capable of being uniformly
manufactured in large quantities as prescription drugs are.
“We have taken the concept of
traditional pharmaceutical drug development and applied it to cellular
therapy,” said senior author Bob
Valamehr, PhD, of Fate Therapeutics, a San Diego biopharmaceutical company.
The product, dubbed FT596, is
among the first cellular immunotherapies to be based on off-the-shelf NK cells
– the “first line of defense” of the immune system – and is the first cellular
immunotherapy to be genetically engineered to contain three active anti-tumor
components, according to Dr. Valamehr.
FT596 demonstrated comparable
ability to kill cancerous white blood cells as standard CAR T cells and, when
combined with the drug rituximab, killed cancerous white blood cells that were
no longer responding to standard CAR T-cell therapy due to loss of the CD19
The U.S. Food and Drug
Administration (FDA) approved Fate Therapeutics’ Investigational New Drug
Application for FT596 in September and the company hopes to begin a
first-in-human phase I clinical trial for the treatment of B-cell lymphoma and
chronic lymphocytic leukemia in the first quarter of 2020. The primary purpose
of this trial will be to assess the safety and activity of FT596 in patients.
The process of creating FT596
begins with human induced pluripotent stem cells (iPSCs) that are uniquely
capable of unlimited self-renewal and can differentiate into more than 200
types of human cells. The iPSCs are genetically engineered, after which a single
clone (genetically engineered cell) is selected and multiplied in the
laboratory to create a master engineered cell line that can be repeatedly used
to generate cancer-fighting immune-system cells such as NK and T cells.
NK cells are part of the innate
immune system, the body’s first line of defense against infection and disease.
Unlike T cells, which have to be trained to recognize their target and can kill
only cells that display that target on their surface, NK cells do not need
special preparation before going on the attack and can kill many different
types of transformed or infected cells.
“NK cells are multifaceted
and can be viewed as a ‘jack-of-all-trades’ when it comes to protecting the
host, whereas T cells can act in only one way,” explained Dr. Valamehr.
But NK cells are unlike T
cells in a couple of other ways: They are inherently limited in their capacity
to multiply and expand when infused into patients, and they have a shorter
Dr. Valamehr and his
colleagues used genetic engineering to address these shortcomings. In addition
to engineering FT596 to carry a CAR targeting the CD19 protein – which is
produced by nearly all B-cell lymphomas and leukemias – they inserted two other
novel proteins: CD16, which boosts and broadens the NK cells’ ability to kill
cancer cells, and IL15, which stimulates FT596 to proliferate and persist.
FT596 has been designed to
address two other limitations of CAR T-cell therapy, said Dr. Valamehr.
- As an
off-the-shelf product, it significantly improves the current patient-by-patient
CAR-T treatment paradigm by eliminating the time-consuming and costly process
that is currently required to treat a patient with CAR T cells (harvesting the
patient’s own T cells, sending those cells to a manufacturing site to be
genetically engineered, processing the manufactured product for shipment back
to the treating hospital, and finally infusing the CAR T cells into the
- The addition of
the CD16 protein gives FT596 broader therapeutic activity and versatility. In
combination with a drug such as rituximab, FT596 has the potential to lead to
deeper and more durable responses and overcome resistance that hampers the
long-term efficacy of CAR T-cell therapy.
“Eliminating the high
production cost, weeks of manufacturing time, and complex manufacturing process
required for CAR T-cell therapy and replacing it with a mass-produced,
off-the-shelf product promises to expand access to effective cell-based cancer
immunotherapy to many more patients who may benefit from it,” said Dr.
This study was supported by
Fate Therapeutics, Inc.
Jode P. Goodridge, PhD, Fate Therapeutics, will
present this study during an oral presentation on Saturday, December 7 at 4 p.m.
in Valencia A (W415A).
High Response Rate Seen With BCMA-Directed CAR T-Cell
Therapy for Multiple Myeloma
#577 Results from
CARTITUDE-1: A Phase 1b/2 Study of JNJ-4528, a CAR T-Cell Therapy Directed
Against B-Cell Maturation Antigen (BCMA), in Patients with Relapsed and/or
Refractory Multiple Myeloma (R/R MM)
Patients with multiple
myeloma who had received a median of five prior therapies, and for whom
standard-of-care treatments were no longer working, had a high response rate
when treated with the investigational CAR T-cell therapy JNJ-4528, which
targets BCMA, a protein commonly found on the surface of multiple myeloma
“We are seeing a high
response rate, with most patients achieving MRD negativity,” said lead study
author Deepu Madduri, MD, of The
Tisch Cancer Institute at Mount Sinai in New York. “Considering these patients
have all received multiple prior therapies, these results are extremely
All evaluable patients
receiving this CAR T-cell therapy have achieved MRD-negative disease state and
27 of 29 patients are progression free at a median follow-up of six months, Dr.
Multiple myeloma is a cancer
of plasma cells, which are found in the bone marrow and are part of the immune
system, the body’s defense system against infection. Typical signs and symptoms
of multiple myeloma may be bone pain or fractures, high levels of calcium in
the blood, kidney damage, and anemia. Multiple myeloma affects an estimated
160,000 people each year, occurs most often in people over 60, and is slightly
more common in men than in women.
Although new therapies for
multiple myeloma have recently become available that can extend patients’ life
expectancy, a cure for the disease remains elusive, Dr. Madduri said. “We can
get the disease into remission, but most patients unfortunately relapse, and
outcomes are very poor for patients who have relapsed multiple times,” she
Researchers said that JNJ-4528
is a novel CAR T-cell therapy featuring two molecules that bind to BCMA, a
protein found on the surface of multiple myeloma cells. “We are learning that
every CAR T-cell therapy is different,” said Dr. Madduri. “JNJ-4528 has a
unique CAR T cell composition in patients, preferentially enriched in CD8 T cells,
which are believed to be one of the most important T cells in killing cancer
This phase Ib/II trial is
continuing to enroll patients. Dr. Madduri reported results for the first 29
patients enrolled. Patients’ T cells were collected and sent to a laboratory
where they were genetically engineered to express JNJ-4528. Prior to reinfusing
these CAR T cells, the patients received three days of chemotherapy to “make
room” in their immune systems for the engineered T cells. Following
chemotherapy, each patient received a single infusion of the JNJ-4528 CAR T
cells. They had blood and bone marrow exams at a minimum at 28 days, six
months, and one year after treatment to assess their response. The primary aims
of the trial are to assess the therapy’s safety and to confirm the dose to be
tested in a larger, phase II trial.
The median follow-up time in
the current analysis is six months. Overall, 100% of patients had a clinical
response to JNJ-4528. Moreover, 66% had a stringent complete response, meaning
that sensitive laboratory and microscopic tests found no evidence for myeloma
proteins or cells in blood, urine, or bone marrow.
Most patients (93%)
experienced CRS; one patient had severe (grade 3) CRS, and one patient died
from its complications 99 days after the CAR T cell infusion. In 76% of
patients, CRS was treated with tocilizumab.
“To see some patients in this
heavily pretreated population surviving for a year or more with a one-time
treatment and a manageable safety profile is remarkable,” Dr. Madduri said.
“These patients feel that they have their quality of life back. They no longer
have to come into the clinic for weekly treatments and some are well enough to
The phase II portion of this
study is ongoing to evaluate the overall response rate of patients treated with
JNJ-4528. Additional clinical studies are evaluating the safety and efficacy of
JNJ-4528 in different multiple myeloma treatment settings.
This study was supported by
Janssen Research & Development, LLC.
Deepu Madduri, MD, Tisch Cancer Institute, Mount Sinai
will present this study during an oral session on Monday, December 9, at 6:15
p.m. in Valencia A (W415A).
Encouraging Results for
Dual-Targeted CAR T-Cell Therapy in Hard-to-Treat Multiple Myeloma
#930 A Bispecific CART-Cell Therapy Targeting BCMA and CD38 for
Relapsed/Refractory Multiple Myeloma: Updated Results from a Phase I
More than three out of four patients with multiple myeloma that returned or
did not respond to at least two therapies remained in remission seven months
after treatment with a novel CAR T-cell therapy targeting two proteins that are
frequently found on myeloma cells. Those experiencing sustained remissions
include nine patients with a difficult-to-treat form of multiple myeloma in
which the disease has spread beyond the bone marrow.
one in 10 patients with multiple myeloma develop tumors in the organs or soft
tissues such as the blood vessels, muscles, and nerves. These so-called
extramedullary tumors respond poorly to treatment, and patients who develop
them have a poor outlook and poor quality of life, said study author Yu Hu, MD, PhD, of Union Hospital,
Huazhong University of Science and Technology in Wuhan, China.
results show that this CAR T-cell product can effectively achieve elimination
of extramedullary tumors,” said Dr. Hu. “Although these are preliminary data,
they are encouraging for patients with multiple myeloma who have not responded
to other therapies.”
study treatment is the first CAR T-cell therapy to be genetically engineered to
target BCMA and CD38, two proteins found on the surface of plasma cells.
Multiple myeloma is a cancer of plasma cells, which are found in the bone
marrow and are part of the immune system, the body’s defense system against
infection and disease.
thinking was that targeting both of these proteins would improve treatment
efficacy without increasing toxicity, and induce deeper, more durable
remissions,” said Dr. Hu.
first-in-humans phase I trial enrolled 22 patients whose average age was 59, of
whom 11 were men. All had multiple myeloma that had returned or not responded
to at least three therapies. Nine of the 22 patients had extramedullary tumors.
The study aims were to determine the safest and most effective dose of the CAR
T-cell therapy as well as to initially evaluate its effectiveness.
received three days of chemotherapy to “make room” in their immune systems for
the engineered T cells. Then each patient was infused with the dual-targeted
CAR T cells. Patients were divided into five groups, with each group receiving
a higher dose than the previous one. Depending on the cell dose, patients
received either one or two infusions.
median of 36 weeks of follow-up, 18 patients (90.9%) had MRD-negative disease.
Twelve patients (54.5%) had a stringent complete response, meaning that no
plasma cells were detected in the bone marrow. Seven patients (31.8%) had a
good or very good partial response, meaning that the level of M-protein (an
abnormal protein produced by cancerous plasma cells) in the blood or urine was
reduced but still detectable. In eight of the nine patients with extramedullary
lesions, these tumors were undetectable on their computed tomography scans. For
the 17 patients who remained in remission at seven months after treatment, the
median duration of response was 28.8 weeks.
observed some side effects: 20 patients experienced CRS, of whom six needed
treatment. No serious adverse neurologic effects such as seizures, movement
impairment, difficulty speaking or understanding speech, or fatal swelling in
the brain were reported.
this dual-targeted CAR T-cell therapy, we have demonstrated a high response
rate, especially a higher rate and longer duration of stringent complete
response, compared with other therapies, as well as effective elimination of
extramedullary lesions, with no serious neurologic adverse effects and
manageable levels of other adverse effects,” said Dr. Hu.
investigators will continue to follow the patients for two years. They are also
planning to conduct a phase II trial in both China and the United States to
test the treatment’s effectiveness in a larger number of patients.
study was supported by the National Natural Science Foundation of China, the
Major Technological Innovation Special Project fund of Hubei Province of China,
and Cellyan Therapeutics Co., Ltd.
Yu Hu, MD, PhD, Union
Hospital, Huazhong University of Science and Technology, will present this
study during an oral presentation on Monday, December 9, at 6:15 p.m. in Hall
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 VTE, sickle cell disease, inclusive medicine, and late-breaking
abstracts. For the complete annual meeting program and abstracts, visit
www.hematology.org/annual-meeting. Follow @ASH_hematology and #ASH19 on Twitter
and like ASH on Facebook for the most up-to-date information about the 2019 ASH
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 60 years, the
Society has led the development of hematology as a discipline by promoting
research, patient care, education, training, and advocacy in hematology. ASH
publishes Blood (www.bloodjournal.org), the most cited peer-reviewed
publication in the field, which is available weekly in print and online. In
2016, ASH launched Blood Advances (www.bloodadvances.org), an online,
peer-reviewed open-access journal.
Adam Silverstein, FleishmanHillard
Leah Enser, ASH
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