CLINICAL NEWS
On Location 2014 ASH Annual Meeting
CAR T Therapies: Engineering a Breakthrough
in Lymphoma and Leukemia Treatment
Novel therapies that harness the body’s own immune cells to attack cancer
cells took center stage at
this year’s annual meeting.
Across a variety of settings,
genetically engineered
chimeric antigen receptor
T (CAR T) cells demonstrated safe and durable
responses in patients with
Stephan A. Grupp, MD, PhD
relapsed and treatmentresistant blood cancers.
“CARs are living drugs,” Carl H. June, MD, from the
Abramson Cancer Center at the University of Pennsylvania
Perelman School of Medicine in Philadelphia, said during
the standing-room-only “Special Scientific Symposium
on Chimeric Antigen Receptor T-Cell Therapy.” Dr. June
and other speakers discussed the mounting enthusiasm for
these “natural born killers,” as well as some of the novel settings in which CAR T therapy is being investigated.
“What we have is an ability to target cancer cells based
on an antigen that is expressed on the surface of B cells,”
Stephan A. Grupp, MD, PhD, director of translational
research for the Center for Childhood Cancer Research at
The Children’s Hospital of Philadelphia, said during a press
briefing discussing novel immunotherapeutic approaches.
“In theory, anything that you can build a monoclonal antibody to, you might be able to target with a CAR.”
Two studies presented at this year’s annual meeting
highlight CAR T therapies’ promise in two difficult to-treat
disease settings: pediatric acute lymphocytic leukemia
(ALL) and treatment-resistant, relapsed Hodgkin lymphoma (HL).
Can CAR T Replace Transplant in Pediatric ALL?
While that is his “fondest hope” for this promising new
treatment approach, we are not there quite yet, Dr. Grupp
said during a discussion of the results from his research
group’s study of CD19-targeting CAR T in pediatric patients with acute lymphocytic leukemia (ALL). However,
long-term disease control may be a possibility.
In their long-term follow-up of CAR T-cell therapy in
39 children and young adults with relapsed, treatmentresistant ALL, Dr. Grupp and colleagues reported that 36
patients (92%) achieved a complete response after being
treated with CLT019 – the T-cell therapy tested in this trial.
In July 2014, CTL019 was awarded Breakthrough Therapy
designation from the Food and Drug Administration in
both pediatric and adult ALL.
Importantly, CTL019 can persist for more than two
years – leading to durable remission in these study patients,
Dr. Grupp added. Six months after treatment, 70 percent
of children enrolled in the study remained cancer-free,
and 75 percent have survived. Only three of the 39 patients
eventually underwent stem cell transplantation.
Notably, the response induced by CAR T therapy occurred independently of disease burden, except in the case of
patients with high disease burden, such as the highly-treatable cytokine-release syndrome. Several of the study patients
experienced other toxicities (including encephalopathy and
B-cell aplasia) which were eventually resolved without incident or long-term complications, Dr. Grupp explained.
“With this longer follow up, we now have children who
remain in remission a year or more after treatment solely
because of this T-cell therapy,” said Dr. Grupp. For the first
time, “we are beginning to see the picture of longer-term
persistence and longer-term disease control in ALL.”
Clearly, this individualized approach demonstrated a
benefit for the 39 patients in this study, but can the treatment approach – harvesting and engineering T cells for
every individual – feasibly be implemented on a larger
scale? According to Dr. Grupp, the next step is to conduct
a phase 2, multicenter trial to assess the safety, efficacy,
and feasibility of this treatment in multiple centers across
the United States – with the ultimate goal of evaluating its
long-term potential to become a replacement for stem cell
transplant in this setting.
Targeting CD123: New Hope for Relapsed/Refractory HL
For the 10 to 15 percent of HL patients who relapse or are
refractory to first-line therapy, CART123 approaches may
improve their typically poor prognosis, according to mice
model data presented by Marco Ruella, MD.
Dr. Ruella, of the Abramson Family Research Cancer
Institute at the University of Pennsylvania, and others
previously demonstrated the efficacy of CD123-targeting
CART123 in treating refractory B-cell malignancies. With
their latest research, the investigators attempted to translate
these findings to patients with refractory HL, using a combined approach of CART123 and rescue autologous bone
marrow transplantation.
In a group of 10 mouse models of HL, Dr. Ruella and
colleagues searched for a cell membrane antigen associated
with HL that could be targeted by CAR T cells – ideally one
expressed on neoplastic cells and infiltrating immune cells
to provide robust stimulation of the CAR T cells. This target
was found in CD123, the alpha chain of the receptor for
interleukin-3, an important cytokine that has been shown to
promote HL growth. Immunohistochemistry revealed that
CD123 was expressed in five out of 10 patients’ HRS cells.
After defining the role of IL-3 signaling in HL in in
vitro models of the disease, Dr. Ruella and investigators
confirmed these results in in vivo models, where, approximately six weeks after injection, mice were treated with
1.5 million CART123 cells or control T cells. “CART123
induced complete and durable eradication of disseminated
tumor within 14 days, leading to 100 percent relapse-free
and 100 percent overall survival at six months,” the investigators reported. Tumor elimination was also associated
with extensive CAR T-cell expansion.
“We developed anti-CD123 chimeric antigen receptor
T cells and demonstrated that they are highly effective in
a preclinical in vivo model of Hodgkin lymphoma,” Dr.
Ruella told ASH Clinical News. “Since neoplastic cells in
Hodgkin lymphoma comprise only 1 to 2 percent of the
tumor mass, targeting both the tumor and microenvironment can be particularly important for the long-term
eradication of the disease.”
So, given the promising safety and durable efficacy data
of CAR T in these difficult-to-treat diseases, where else will
these CARs take us? “We’re hoping for a fleet of CARs,” Dr.
June predicted. ●
References
1. Ruella M, Kenderian SS, Shestova O, et al. Novel Chimeric Antigen
Receptor T Cells for the Treatment of Hodgkin Lymphoma. Abstract #806.
Presented at the 2014 ASH Annual Meeting. December 9, 2014.
2. Grupp SA, Maude SL, Shaw P, et al. T Cells with a Chimeric Antigen Receptor
(CAR) Targeting CD19 (CTL019) Have Long Term Persistence and Induce
Durable Remissions in Children with Relapsed, Refractory ALL. Abstract
#380. Presented at the 2014 ASH Annual Meeting. December 8, 2014.
Joseph Alvarnas, MD
HSCT Could
Become Standard
of Care for HIVPositive Patients
with Lymphoma
Results from a multi-institutional trial
presented at ASH 2014 debunk the common myth that HIV-positive patients
with lymphoma might not be suitable for
autologous hematopoietic stem cell transplants (HSCT).
Until now, HIV-positive patients
have been excluded from this therapy
due to concerns about higher risks of
infection and poorer graft function
because of their need for HIV medications. But, according to the study’s lead
author, Joseph Alvarnas, MD, “This
trial confirms that HIV-associated
lymphoma patients may successfully
undergo autologous transplants with
favorable outcomes.”
Dr. Alvarnas, associate clinical
professor at the City of Hope National
Medical Center in Duarte, California,
presented results from the single-arm,
multi-institutional clinical trial, which
included 40 patients with treatable
HIV-1 infection who underwent HSCT
for HIV-associated lymphoma (HAL);
all were aged 15 years or older and had
failed prior therapy.
Lymphoma subtypes included diffuse
large B-cell lymphoma (40%), plasmablastic lymphoma (5%), Burkitt/Burkitt-like
lymphoma (17.5%), and Hodgkin lymphoma (37.5%). All patients underwent
a pre-transplant regimen of carmustine,
etoposide, cytarabine, and melphalan (or
a modified BEAM regimen) followed by
autologous HSCT.
Investigators measured response rates
before transplant and at 100 days after
transplant (TABLE, page 36). At 100 days,
one patient had died after undergoin g
HSCT. Response to transplant in the remaining 39 patients was overwhelmingly
positive – 36 achieved complete remission and one achieved partial remission,
while two patients experienced relapse or
progressive disease.
Continued on page 36
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ASH Clinical News
January 2015