NY-ESO-1 targeting immunotherapies are seeing
renewed clinical development interest as the antigen is widely expressed in
certain solid tumors and sarcomas, experts said. They noted recent checkpoint
inhibitor approvals and modified T cell receptor (TCR) research underscore the
enthusiasm, experts said.
Combinations with checkpoint inhibitors and
other immune modulators have the potential to increase response rates seen with
existing NYESO-1 directed vaccines, and TCR approaches offer newer strategies
to exploit the NY-ESO-1 antigen over-expression in cancers. There is some
caution on how well the approaches will pan out. Furthermore, experts expressed
the need to target multiple additional antigens besides NY-ESO-1 to induce
significant immune responses.
While Adaptimmune (NASDAQ:ADAP) and Immune
Design (NASDAQ:IMDZ) are using a modified TCR approach with a Phase I/II NYESO
TCR, and Phase I LV305 with CMB305, respectively, for multiple cancers, Celldex
(NASDAQ:CLDX) is exploring a vaccine approach in different cancers with the
Phase II CDX-1401, an NY-ESO-1-targeting vaccine. Early trials at academic
centers like Memorial Sloan Kettering, New York and Roswell Park Cancer Institute
are also underway.
Adaptimmune, Immune Design, Celldex did not
respond to a request for comment.
NY-ESO-1
antigen expression
NY-ESO-1 expression in normal tissues is
relatively narrow and from an antigen standpoint, it is a wonderful antigen to
start research with, said Dr Paul Sabbatini, deputy physician-in-chief for
clinical research, Memorial Sloan Kettering Cancer Center, New York.
The NY-ESO-1 antigen is widely expressed in
synovial sarcoma (SS), myxoid round-cell liposarcoma (LPS), melanoma, ovarian
cancer, glioblastoma (GBM) and other tumors, but it has the most potential in
sarcomas and melanoma due to their being immunogenic in nature, experts said.
NY-ESO-1 is expressed highly in SS and myxoid
round-cell LPS in about 60-70% of tumors, said Dr Sant Chawla, director,
Sarcoma Oncology Center, Santa Monica, California. NY-ESO1-targeting seem to
especially benefit SS, and there have been remissions observed in these
patients, said Dr Sebastian Bauer, professor of medicine, West German Cancer
Center, Germany.
Among 24 patients in a Phase I study of Immune
Design’s LV305 in sarcomas, one had a partial response, and 13 had stable disease
(SD), with a median progression-free survival (PFS) of 4.6 months, according to
data presented at the ASCO annual meeting. Among 14 patients receiving CMB305,
10 had SD, with a median 5.5-month PFS.
NY-ESO-1 expression in ovarian cancer is said
to be in the range of 42- 60%, said Sabbatini and Dr Oliver Dorigo, associate
professor, obstetrics and gynecology, Stanford University Medical Center, Palo
Alto, California. The NYESO-1 antigen has been of particular interest in
ovarian cancer since as patients have had their ovaries removed, NY-ESO-1
expression in normal ovarian tissue is not a clinical issue, added Dorigo.
However, it’s not necessarily the expression
of the antigen, but also the tumor immunogenicity that’s important, said Dr
Brent Hanks, assistant professor of medicine, Duke University School of
Medicine, Durham, North Carolina. Melanomas are just more responsive to
immunotherapies than gastric or colon cancer, he added. NYESO-1 expression in
melanoma can range from 25-50+%, depending on which research study is
considered, he added.
Though melanomas do overexpress the antigen,
it is unknown if that is enough to drive T cell responses, cautioned Dr Jason
Luke, assistant professor of medicine, University of Chicago. Therapies that
target NY-ESO-1 have been around for many years, he and Dr Anthony Olszanski,
co-director, cutaneous oncology and melanoma, Fox Chase Cancer Center,
Philadelphia agreed. Luke noted most researchers would find it unlikely that
targeted NY-ESO-1 would be a particularly efficacious way to move forward.
Previous studies have not shown any significant response rate in melanoma,
Olszanski added. However, now with the introduction of PD-1 inhibitors, the
hope is that a combination approach can capitalize on the antigen recognition
and improve the efficacy of these therapies, he said.
Across indications, it still needs to be
explored if the ideal patient population would be one in remission with a lower
disease burden, or those with active disease and a higher antigenic load, said
Sabbatini.
Promising
combinations
NY-ESO-1 vaccinations have induced mild immune
responses in a disease like ovarian cancer, but the question is always on how
to enhance those responses across all tumor types, said Sabbatini. If the focus
is on just one antigen and the induced immune response is not potent enough to
generate T-cell responses to other antigens, then the tumor can simply
downregulate the expression or processing of those antigens, agreed Hanks and
Dorigo. NY-ESO-1 expression in ovarian cancer is more heterogeneous and patchy
than in others, and it might be necessary to target a second or third antigen
or add another other antitumor treatment for a clinical response, Dorigo
explained.
New co-stimulatory molecules and checkpoint
inhibitors could modulate these immune responses, said Sabbatini. Ultimately,
future research will focus on combination approach in the form of a vaccine
with the checkpoint inhibitor, agreed Hanks. Other agents that have been
designed to reverse immune suppression or reverse immune invasion by the cancer
could be combined as well, he added. The next generation of therapies is
looking at the addition of these immune molecules to elicit a robust immune
response, said Sabbatini.
Immune Design is studying (NCT02609984)
CMB305, a dendritic cell-targeting vector that expressed NY-ESO-1 and a
NY-ESO-1 recombinant protein in combination with Roche’s (VTX:ROG) Tecentriq
(atezolizumab). An investigator sponsored Phase I trial (NCT02737787) at MSKCC
will explore Bristol-Myers Squibb’s (NYSE:BMY) Opdivo (nivolumab) in
combination with a dual NY-ESO-1 and WT1-directed vaccine. Celldex is also
evaluating CDX-1401 in a Phase I/ II (NCT02413827) study in Stage III/IV
melanoma patients in combination with its anti-CD27 antibody, varlilumab, and
BMS’ anti-CTLA4 antibody Yervoy (ipilimumab).
However, it is not clear if there’s a role for
NYESO-1-based vaccines and combination with checkpoint inhibitors have not
proven to be particularly efficacious, differed Luke.
TCRs or vaccines the best way to target the
antigen may depend on the host immune response, said Liau, adding that TCRs or
vaccines could be potential strategies to use NY-ESO-1. For patients who are
able to mount an active immune response, a vaccine may be optimal, while
adoptive immunotherapy with engineered T cells may be preferable for those who
cannot, she added.
By tailoring the antigen-targeting treatment
to each patient, researchers can look at individual tumor presentation and
customize T cell directed therapy, said Dorigo. One reason for the recent focus
on TCRs is that chimeric antigen receptor T-cells (CAR-Ts) haven’t been shown
to be effective in solid tumors yet, said Dorigo, though they could be in the
future. Adaptimmune is running multiple clinical trials where a patient’s T
cells are extracted and modified to identify NY-ESO-1 in ovarian cancer and
certain sarcomas. However, with a TCR approach, the impact of induced
myelosuppression on heavily pretreated ovarian cancer patients is not yet
known, said Dorigo.
Modifying T cells is a newer approach than
vaccines, but vaccines have not been studied in combination with
immune-modulating agents before, said Sabbatini. It is still too early to
determine which approach would work best or how effective it would be, said
Dorigo.
Alaric DeArment
Reporter, New York
Alaric DeArment covers cancer drug
development for BioPharm Insight. He served as associate editor of Drug Store
News from 2008 to 2014, covering branded and generic drugs from development to
distribution, retail and specialty pharmacy and regulatory affairs. In
2011-2012, he edited the book Contestation and Adaption: The Politics of
National Identity in China. A native of Seattle, he graduated with honors with
a bachelor’s degree in journalism from Ball State University and also lived in
China from 2001-2004. Follow Alaric on Twitter @AlaricD_BPI
Indrani Datta
Reporter, New York
Indrani Datta covers cancer drug
development for BioPharm Insight. She holds a B.E. in Biochemical Engineering,
a BS in Computer Science and a master’s in journalism with a concentration in
Health and Science Reporting from CUNY Graduate School of Journalism. Prior to
joining BioPharm Insight, Indrani performed experimental lab work in a startup
biotech company, worked as a bioinformatics statistician in academia and a LIMS
(laboratory information management system) developer for various pharmaceutical
companies. She also built interactives for The New York Times before founding a
news web startup. Indrani has written about hospital finance and politics for
various publications.
Manasi Vaidya
Reporter, New York
Manasi Vaidya has a master’s degree
in biotechnology. After a stint in a research lab, she spent two years as
correspondent in India for BioSpectrum, a publication focused on the Asian
biotechnology industry. She then moved to the United States to pursue a master’s
degree in science, Health and Environmental Reporting at New York University.
Manasi has reported primarily on topics that combine health and policy, and her
work has appeared in Nature Medicine, Nautilus and Scienceline. Her coverage at
BioPharm Insight focuses on cancer.