Adaptimmune Announces Preliminary Results from an Early Phase Trial of Gene Engineered T Cells Targeting Cancer Testis Antigens in Multiple Myeloma
Study reports encouraging response rates, and data support
safety and preliminary proof of mechanism
(Atlanta, GA and Oxford, UK) 10 December, 2012. Adaptimmune today
announces the release of preliminary results from an early phase
clinical study using patients’ own T cells that have been
genetically altered to attack multiple myeloma (MM) cells. Lead
investigators for the study presented today in three separate
sessions at the annual meeting of the American Society of
Hematology (ASH).
The clinical study was designed as a single arm open label study
where patients are given standard of care (autologous stem cell
transplant) in conjunction with engineered T cells. The critical
step in this new approach is that the infused T cells have been
genetically engineered to carry receptors that help the T cells
recognize and attack a tumor, while sparing healthy tissue.
Study objectives are to evaluate the safety, bioactivity and
anti-tumor effect of infusion of patients’ own T cells that
have been genetically modified to express a high affinity T cell
receptor (TCR) specific for a type of tumor antigen (protein) known
as a cancer testis antigen (CT antigen). The target CT antigens in
the study are NY-ESO-1 and LAGE-1.
The initial six patient phase is complete and, based on the
encouraging preliminary results, the study was extended to a target
enrollment of 26 patients. To date, a total of 15 patients have
been enrolled and have received the engineered T cells; of these,
13 have been assessed at day 100 and 11 patients have reached a
minimum of six month follow-up for assessment of tumor response to
the treatment.
Multiple myeloma is a hematologic cancer localized to the bone
marrow, and is currently incurable in most patients. With standard
therapy, long-term response rates are low, and the median survival
for patients with this disease is three to five years.
The clinical study focuses on this unmet medical need and includes
patients who have received prior treatment for their myeloma or who
have disease considered to be high risk, and who are eligible for
an autologous stem cell transplant (auto-SCT). Auto-SCT is the
transplant of a patient’s own stem cells, which is a standard
of care for treatment of multiple myeloma in the U.S. Infusion of
the gene modified T cells occurs just following auto SCT.
Dr. Aaron Rapoport, the Chair of the clinical study, presented
abstract 472 entitled “Adoptive Transfer of Gene-Modified
T-Cells Engineered to Express High-Affinity TCRs for Cancer Testis
Antigens (CTAs) NY-ESO-1 or Lage-1, in MM Patients Post
Auto-SCT”. He reports that infusions of engineered T cells
have been well tolerated. The overall best response rate at 100
days is 77%, which is encouraging when compared to the rate
expected from auto-SCT alone (33%-69% as reported in contemporary
published studies). Of the 15 patients treated to date, 10 have
ongoing responses, and 5 have progressed. In cases of disease
progression, a concomitant loss or reduction of engineered T cells,
or a loss of antigen positivity on recurring tumor, has been
observed. Consequently, the protocol has been modified to allow for
additional infusions provided the patient’s tumor continues
to express target antigen. These infusions will be administered
outside of the transplant setting.
“I am encouraged by the clinical data, particularly after
having the opportunity to carry out a detailed review ahead of this
meeting,” says Dr. Rapoport. “I look forward to
continuing this research and having the opportunity to evaluate the
engineered cells outside of the transplant setting.”
Dr. Michael Kalos, the lead correlative scientist on the study,
presented abstract 755 entitled “Prolonged T Cell
Persistence, Homing to Marrow and Selective Targeting of Antigen
Positive Tumor in Multiple Myeloma Patients Following Adoptive
Transfer of T Cells Genetically Engineered to Express an
Affinity-Enhanced T Cell Receptor against the Cancer Testis
Antigens.” He reports robust persistence of engineered T
cells; in all cases cells are detectable at least six months post
infusion, and expression of the engineered TCR on T cells is
detected up to one year post infusion. Engineered T cells also
traffic to the bone marrow, the site of tumor in MM, and have been
detected in the marrow of all patients. The ratio of tumor antigen
to tumor cells remains below baseline in all patients, except in
cases where loss of engineered T cells occurs.
“The preliminary data to date support the anticipated
mechanism of action for the engineered cells,” says Dr.
Kalos. “The engraftment data, particularly the trafficking to
marrow, is very encouraging, and the disappearance of antigen in
responding patients and its correlation with engineered cell
persistence supports the concept that the engineered T cells are
providing an additive effect to the transplant.”
In addition, Dr. Carl June, study sponsor and recipient of the
prestigious 2012 Ernest Beutler Award for major translational
advances, also presented a summary of the study findings at the
Beutler Lecture today. “This study is an important
contribution to a growing field of genetic therapies showing
exciting promise both as a therapy for myeloma patients and also
patients with other hematological and solid malignancies,”
states Dr. June.
Enrollment is expected to complete in Q2 2013, with 9 month
follow-up and final study analysis completed by Q1 2014. A second
early phase study, designed to evaluate the safety and anti-tumor
effect of the engineered T cells outside of the transplant setting,
is expected to open in Q2 2013.
Mr. James Noble, CEO of Adaptimmune, also commented, “It has
been a privilege to work with this translational team and we are
very encouraged by progress to date. We look forward to presenting
further data on this and other studies in due course.”
Additional study details and contact information for patients
interested in finding out more about participation can be found at
clincialtrials.gov, under trial identifier number
NCT01352286.
Dr. Carl H. June at the University of Pennsylvania (UPenn) Abramson
Cancer Center and Dr. Aaron Rapoport of the University of Maryland
Marlene and Stewart Greenebaum Cancer Center, developed the study.
Dr. June is the regulatory sponsor (FDA representative) for the
study, Dr. Rapoport is the lead clinical investigator at the
University of Maryland and protocol Chair, and Dr. Michael Kalos is
the Director of the Translational and Correlative Sciences
Laboratory at UPenn, and leads the correlative analyses for the
study. Other investigators include Dr. Edward Stadtmauer who is the
lead clinical investigator at the UPenn Abramson Cancer Center, and
Dr. Dan Vogl who is a sub-investigator also at UPenn. Adaptimmune
Ltd is the financial sponsor and owns the core T cell receptor
technology. T cell manufacturing is performed at the Clinical Cell
and Vaccine Production Facility at the University of Pennsylvania
directed by Dr. Bruce Levine.
Ends
Contact
Margaret Henry
PR Consultant
Adaptimmune Ltd, UK
T: +44 (0) 1865 261491
Mobile: +44 (0) 7771 377363
E: m.henry@oxin.co.uk
Images available on request:
1. T cell (blue) killing a tumor cell (red)
2. Adaptimmune laboratory – Scientist cloning a T cell
receptor
3. Adaptimmune laboratory – Scientists growing research
cells
4. Adaptimmune laboratory – Scientists growing a cell therapy
product
Notes for editors
About Adaptimmune
Adaptimmune is focused on the use of T cell therapy to treat HIV
and cancer. It aims to utilize the body’s own machinery
– the T lymphocyte cell – to target and destroy
cancerous or infected cells.
Established in July 2008 with a research base in Oxford, UK and
clinical base in Philadelphia, US, Adaptimmune was set up to a
develop unique T cell receptor engineering technology for adoptive
T cell therapy exclusively licensed from Immunocore Ltd (formerly
Avidex/MediGene). Specifically, Adaptimmune makes use of the
body’s ability to recognize infected or cancerous cells by
enhancing the power of the T cell receptor (TCR) on killer T cells.
All cells, including cancerous cells, will typically present small
parts or peptides of internal proteins on their surface as part of
the natural protein processing pathway. This offers a "molecular
fingerprint" of the protein called an epitope for killer T-cells
from the immune system to identify and destroy. However, since
cancer proteins are usually derived from self proteins against
which naturally selected TCRs in the body do not respond, the
Adaptimmune technology uniquely enhances the natural TCR affinity
to these cancer-specific epitopes enabling targeted killing of the
cancer cells.
Adaptimmune has undertaken significant preclinical development with
a number of pipeline TCRs to demonstrate their potency and
specificity in vitro. The TCR in the current myeloma study
specifically recognizes two cancer testis antigen targets: NY-ESO-1
157-165 and LAGE-1 (HLA A2; SLLMWITQC), and was engineered using
Adaptimmune’s proprietary TCR engineering platform. Myeloma
is the lead indication for the therapy, with related trials in
melanoma and sarcoma also recruiting patients and further trials in
ovarian and hepatic cancer scheduled to open in 2013.
http://www.adaptimmune.com
Posted: December 2012
