Professional Documents
Culture Documents
Inside:
THE NEW JAMES
IMMUNE THERAPY
OHIO STATE UNIVERSITY COMPREHENSIVE CANCER CENTERJAMES CANCER HOSPITAL AND SOLOVE RESEARCH INSTITUTE
UPFRONT
The Directors Perspective
Director, Comprehensive Cancer Center Physician-in-Chief Vice President, Medical Center EDITORIAL BOARD
Chief Executive Officer, James Cancer RICHARD GOLDBERG, MD Expansion and Outreach Stephen Chaykowski
Hospital and Solove Research Institute Medical Director, Expansion William Carson III, MD
MICHAEL A. CALIGIURI, MD Distinguished University Professor Campaign
Jennifer Carlson
OSU Cancer Scholar and Senior Adviser DAVID E. SCHULLER, MD
Jeffrey Fowler, MD
Senior Executive Director CLARA D. BLOOMFIELD, MD
Interim Chief Communications Officer Melissa Hall
JEFF A. WALKER, MBA
Electra Paskett, PhD, MSPH
cancer.osu.edu
FEATURES
Immune Boosters
14 22
THE NEW JAMES IMMUNE BOOSTERS
A 21st-century facility for collaborative, Research on immune therapy for cancer
subspecialized and precision cancer care turned a corner a few years ago, resulting in
treatment strategies that show real promise
04 F R O N T L I N E 12 O F N O T E
Recent grants, awards and honors, new faculty and
THREE PERSPECTIVES
program developments
The new James Cancer Hospital and Solove
Research Institute
06 B R E A K T H R O U G H 29 B E N C H T O B E D S I D E
EVASIVE ACTION WILLIAM E. CARSON, MD
Survival Molecule Helps Cancer Cells Hide From A Phase I/II Trial of Cetuximab in Combination
Immune System with Interleukin-12 Administered to Patients with
Unresectable Primary or Recurrent Squamous
RISK POTENTIAL Cell Carcinoma of the Head and Neck
Researchers Find Possible Link Between Breast Cancer
and Salivary Gland Cancer
EXAMINING ERLOTINIB
30 NEED TO KNOW
Study May Explain Why Targeted Drug Doesnt Benefit THE CELL THERAPY LABORATORY
Patients with Early-Stage Lung Cancer
EXPANDING EFFICACY
Low Doses of Targeted Drug Might Improve Cancer-Killing TURNING CANCER DISCOVERIES INTO TREATMENTS
Neck Cancer
CURBING COST ON THE COVER:
Study Suggests Dopamine is a Safe Antiangiogenic Drug The New James Cancer Hospital
and Solove Research Institute
OHIO STATE UNIVERSITY COMPREHENSIVE CANCER CENTERJAMES CANCER HOSPITAL AND SOLOVE RESEARCH INSTITUTE 03
Read Frontiers online or download an issue at http://cancer.osu.edu/Frontiers.
FRONTLINE
The Researchers Voice
and comforting. The standardized department that will open access to the latest research and
room-design supports quality this spring. This new facility technologies that we are using in
care and promotes better patient should enhance patient care and the fight against cancer.
outcomes. Disease-specific units satisfaction. In the end, that is what Im also impressed about the
foster evidence-based practice and nursing is all about. level of thought that went into
innovative care. effective floor planning. All the
Relationship Based Care AMBER GORDON, MLS operating rooms are on the same
underpins the practice of nursing Senior Clinical Research Coordinator floor, which allows for quick
at The James. It focuses on care of James Cancer Hospital and Solove
equipment transfer, and the clinical
patients, care of colleagues and care Research Institute
trials processing laboratory shares
of self. All inpatient rooms include As a clinical research coordinator, the same floor as the units that
patient lifts to decrease work-related I constantly look for ways to bring administer experimental therapies
injuries, and all units include respite the laboratory and the clinic closer to patients. This will facilitate good
areas for patients, family members together. I am very excited that the communication, ensure accurate
and staff. integration of research and clinical sample collection and expedite
The research space on all care is an important focus of the specimen processing, all critical
inpatient units encourages new James. Each inpatient floor has factors when developing safe and
professional team building and translational laboratory space so efficient novel therapeutics.
professional development. that we can, quite literally, close the Overall, the design features of
In addition, multiple spaces are gap between bench and bedside. the new James Cancer Hospital
designated for multidisciplinary Im excited to see how these and Solove Research Institute
teams to meet, which should spaces will help push translational will increase the efficiency of our
enhance communication, safety research at The James to a new level. clinical and translational research,
and quality. Terrace gardens located The new building, equipped with which in turn should accelerate the
on the north and south sides of the the latest technology, along with the discovery and development of novel
building further enhance this caring growing incorporation of genomic therapeutics and their delivery to
and healing environment. medicine and stong emphasis on the patients who need them. Its an
Other exciting innovations targeted-drug development and exciting time for cancer research at
include an oncology emergency clinical trials, will improve patient Ohio State! F
05
BREAKTHROUGH
The Frontiers of Cancer Research
CANCER IMMUNOLOGY
Evasive Action
Survival Molecule Helps Cancer Cells Hide From the
Immune System
James) showed that a molecule Guttridge, who also co-leads
called nuclear factor kappa B (NF- the Translational Therapeutics
kB) helps cancer cells suppress the Program at the OSUCCC James.
immune systems ability to detect Therefore, inhibiting NF-kB might
and destroy them. The molecule make tumor cells more vulnerable
regulates genes that suppress to elimination by the immune
immune surveillance mechanisms system.
and that lead to the production Guttridge credits the papers
of cells that inhibit the immune first author, David J. Wang, for
response. developing many of the studys
The findings suggest that concepts.
immune therapy for cancer might
be more effective if combined with Published in the journal Cell
drugs that inhibit NF-kB. They Reports
also provide new details about how
interactions between cancer cells
To refer a patient, please call
and noncancer cells assist tumor
The James Line New-Patient
growth.
Referral Center toll free:
DENIS GUTTRIDGE, PHD, Weve long known that NF-kB
1-800-293-5066
professor in the Department of Molecular promotes cancer development by
Virology, Immunology and Medical Genetics subverting apoptosis, an internal
and the Department of Molecular and safety mechanism that otherwise
Cellular Biochemistry at Ohio State would cause cancer cells to self-
destruct, says principal investigator
A molecule that helps cancer Denis Guttridge, PhD, a professor
cells evade programmed self- in the Department of Molecular
destruction might also help Virology, Immunology and Medical
malignant cells hide from another Genetics and the Department
source of death: the immune of Molecular and Cellular
system. Biochemistry at Ohio State.
A study by researchers at This study shows that NF-kB
The Ohio State University might coordinate a network of
Comprehensive Cancer Center immune-suppressor genes whose
James Cancer Hospital and Solove products enable tumor cells to
cancer.osu.edu
S A L I VA R Y G L A N D C A N C E R
Risk Potential
Researchers Find Possible Link Between Breast Cancer and
Salivary Gland Cancer
07
LUNG CANCER
Examining Erlotinib
Study May Explain Why Targeted Drug Doesnt Benefit
Patients with Early-Stage Lung Cancer
The drug erlotinib is highly Oncologists use erlotinib to Carbone, co-corresponding
effective in treating advanced-stage treat lung cancers that have author Stacey Huppert of
lung cancer patients whose tumors a mutation in a gene called Cincinnati Childrens Hospital
have a particular gene change, but epidermal growth factor receptor and their colleagues conducted
when the same drug is used for (EGFR). The mutation causes the study using several cell lines
patients with early-stage tumors EGFR to run like it has a stuck of non-small-cell lung cancer to
with the same gene change, they accelerator, and erlotinib blocks learn if inhibiting EGFR enhances
fare worse than if they had taken the overactive molecule. the activity of the Notch signaling
nothing at all. The study shows that while pathway.
A study by researchers at erlotinib causes tumors to We found that the activated,
the OSUCCC James and at shrinksuggesting that the mutated EGFR directly inhibits
Cincinnati Childrens Hospital drug is helping a patientit also Notch signaling, Carbone says.
might explain why. increases the aggressiveness of the Inhibiting EGFR with erlotinib
tumor so that cancer-cell growth removes this restraint and activates
accelerates when therapy ends. Notch signaling, which suggests
The study found that this is due that combining an EGFR inhibitor
to a secondary and previously with a Notch inhibitor might
unknown effect of inhibiting overcome this adverse effect.
EGFR.
The researchers discovered Published in the journal Cancer
that when erlotinib blocks Research
EGFR, it activates a second
signaling molecule called Notch3.
Activating that pathway leads to
increased development of cancer To refer a patient, please call
stem cells among the surviving The James Line New-Patient
tumor cells and to accelerated Referral Center toll free:
tumor growth. 1-800-293-5066
Our findings might explain
why erlotinib in clinical trials
seems to worsen survival in
patients with early-stage lung
DAVID CARBONE, MD, PHD, cancer, says co-corresponding
professor in the Division of author David Carbone, MD, PhD,
Medical Oncology at Ohio State a professor in the Division of
Medical Oncology at Ohio State
and co-leader of the OSUCCC
cancer.osu.edu
Expanding Efficacy
Low Doses of Targeted Drug Might Improve Cancer-Killing
Virus Therapy
of proteasomes, structures in
cells that break down and recycle
09
HEAD AND NECK CANCER
Influencing Outcome
Experience Counts With Radiation Therapy for Head and
Neck Cancer
When it comes to specialized for head and neck cancer, says
cancer surgery, its generally true Wuthrick, the papers first author.
that the more experienced the They indicate that patients do
surgeon, the better the outcome. better when treated at centers
The same might be true for where more of these procedures are
radiation therapy used to treat performed versus centers that do
head and neck cancer, according fewer.
to a study by researchers at the Radiation therapy for head and
OSUCCC James. neck cancer requires complex
The study was co-led by Evan treatment planning that can vary
Wuthrick, MD, assistant professor considerably among institutions
of Radiation Oncology at Ohio and physicians. In addition,
State, and Maura Gillison, MD, significant short- and long-term
PhD, professor of Internal Medicine side effects can occur that require
EVAN WUTHRICK, MD,
and Epidemiology at Ohio State, management by a carefully
assistant professor of Radiation
where she also is a member of the coordinated multidisciplinary care
Oncology at Ohio State
Cancer Control Program at the team.
OSUCCC James. National Comprehensive Cancer
The study compared survival Network guidelines recommend
and other outcomes in 470 patients that head and neck cancer patients
treated with radiation therapy at receive treatment at experienced
101 treatment centers through a centers, but whether provider
clinical trial held from 2002 to experience affects outcomes was
2005. The trial was sponsored by previously unknown.
the National Cancer Institute and
organized by the Radiation Therapy Published in the Journal of
Oncology Group (RTOG). Clinical Oncology
The findings indicated that
patients treated at the less-
experienced centers were more
likely to have cancer recurrence
MAURA GILLISON, MD, PHD,
(62 percent versus 42 percent at
professor of Internal Medicine
five years) and had poorer overall
and Epidemiology at Ohio State
survival compared with those at
the highly experienced centers (51
percent versus 69 percent five-year
survival, respectively).
Our findings suggest that
cancer.osu.edu
Curbing Cost
Study Suggests That Dopamine is a Safe Antiangiogenic Drug
11
OF NOTE
Recent Recognition of OSUCCC James Physicians and Researchers
GRANTS
MICHAEL A. CALIGIURI, MD, director of NORMAN LEHMAN, MD, PHD, associate
The Ohio State University Comprehensive professor-clinical and director of the
Cancer Center and CEO of The James Division of Neuropathology, has received
Cancer Hospital and Solove Research a $1.8 million, five-year grant from the
Institute, has received a five-year, $2.56 National Institute of Neurological Disorders
million Oncology Training Grant renewal and Stroke (NS081125) to study Aurora-A,
(CA009338) from the National Cancer Institute (NCI) to support a protein that helps drive cell division, as a novel therapeutic
Ohio States postdoctoral oncology training program. target in glioblastoma.
RAMIRO GARZON, MD, associate professor STEVEN CLINTON, MD, PHD, professor, Division of Medical
in the Division of Hematology, was Oncology, College of Medicine; PURNIMA KUMAR, MDS,
awarded a five-year, $1.59 million NCI grant PhD, associate professor, Division of Periodontology, College
(CA188269) to develop a new class of drugs of Dentistry; STEVEN SCHWARTZ, PhD, professor of Food
called CRM1 inhibitors for treatment of acute Science and Technology, College of Food, Agricultural and
leukemia. Environmental Sciences; and CHRISTOPHER WEGHORST,
PHD, professor and associate dean for research, Division of
BALVEEN KAUR, PHD, professor of Environmental Health Sciences, College of Public Health,
Neurological Surgery and associate have received a five-year, $3.1 million NCI grant (CA188250)
director for shared resources at the to investigate the interactions between black raspberry
OSUCCC James, has received a five-year, phytochemicals and tobacco on the oral microbiome and how
$1.7 million grant from the National Institute they influence early oral carcinogenesis.
for Neurological Disorders and Stroke
(NS064607) for a study evaluating changes
in the tumor microenvironment induced by oncolytic viruses AWARDS AND HONORS
(OV) and their effect on OV therapy.
DONALD BENSON, MD, PHD, associate
FEN XIA, MD, PHD, professor of Radiation Oncology, and professor, Division of Hematology, has
ARNAB CHAKRAVARTI, MD, professor and chair of Radiation been elected a member of the Henry
Oncology, have received a five-year, $2.09 million NCI grant Kunkel Society, which is dedicated to
(CA188500) to study the molecular mechanisms involved in fostering patient-oriented research,
the response of glioblastoma multiforme (GBM) cells and brain particularly in the field of immunology.
neurons to DNA damage caused by radiation therapy. The goal
is to improve the therapeutic index in GBM treatment. CLARA D. BLOOMFIELD, MD,
Distinguished University Professor, and
RAMESH GANJU, PHD, professor of Pathology, has received a cancer scholar and senior adviser to the
five-year, $1.23 million NCI grant (CA109527) OSUCCC James, has been honored
to further characterize the role of several as one of 50 American Society of Clinical
chemokine-receptor pathways in regulating Oncology (ASCO) Oncology Luminaries.
breast tumor growth, angiogenesis and Bloomfield was recognized for her years of practice-changing
metastasis. leukemia and lymphoma research.
METIN GURCAN, PhD, associate professor of Biomedical BLOOMFIELD and CARLO CROCE, MD, professor and chair
Informatics and director of the Clinical Image Analysis Lab, of the Department of Molecular Virology, Immunology and
and GERARD LOZANSKI, MD, associate professor-clinical of Medical Genetics, and director of Human Cancer Genetics at
Pathology, have received a four-year, $1.09 million NCI grant the OSUCCC James, are among 14 faculty and staff at Ohio
States Wexner Medical Center to appear on the 2014 list of
(CA134451) for a computer-based assessment of the tumor
Highly Cited Researchers presented by Thomson Reuters, a
microenvironment in follicular lymphoma.
mass media and information firm.
12
OF NOTE
FRONTIERS
WINTER 2015
13
14
cancer.osu.edu
F E AT U R E : T H E N E W J A M E S
FRONTIERS
WINTER 2015
15
ARNAB We do have the latest and best equipment...But its really
CHAKRAVARTI, MD the physicians, therapists, nurses and staff who make this a
professor and chair of
Radiation Oncology and special place.
co-director of the Brain
Tumor Program
To facilitate translational treatment and help speed research in the country in promoting and
research, a wet and a dry laboratory discoveries. championing precision oncology.
is located on alternating patient This approach, called precision The new hospital further
floors. We believe this proximity cancer medicine, uses next- integrates precision cancer
of bench to bedside is unique in generation sequencing and other medicine into patient care at the
the United States, and were really high-throughput technologies to OSUCCC James, applying it to a
proud of that, Caligiuri says. identify the gene and molecular growing number of malignancies.
changes that drive a patients
Precision Cancer Medicine Radiation Oncology Center
malignancy or increase the risk of
Each inpatient unit has its recurrence or resistance to therapy. The hospitals custom-designed
own cancer focussuch as Next-generation sequencing radiation oncology center features
gastrointestinal, head and can identify which of 200-plus seven linear accelerators and one
neck, breast, genitourinary and significant genes are altered in a brachytherapy vault. Top radiation
hematologic malignancies. The patients cancer, and we can use oncologists and radiation oncology
oncologists, nurses, pharmacists that information to guide therapy researchers at the center specialize
and genomic experts on each or match patients to clinical trials, in specific types of cancer, says
unit treat just that type of cancer, says Sameek Roychowdhury, MD, Arnab Chakravarti, MD, professor
collaborating with researchers to PhD, director of precision cancer and chair of Radiation Oncology
look at each patients genes and medicine at the OSUCCC James. and co-director of the Brain Tumor
tumor DNA to determine the best Ohio State is among the leaders Program.
cancer.osu.edu
Importantly, the centers second- Principles That Guided the Design of the New James
floor location distinguishes it from
Cancer Hospital and Solove Research Institute
most others worldwide and provides
soothing natural light to promote
Patient Care single-occupancy rooms, organized into neighborhoods
patient healing and comfort.
of 10-12 rooms
We do have the latest and best
equipment, says Chakravarti, who Allow family support 24/7
holds the Max Morehouse Chair Bedside technology point-of-care support
in Cancer Research and helped Patient safety through room design
design the center. But its really the
Support and facilitate caregiver efficiency and productivity
physicians, therapists, nurses and
staff who make this a special place. Research clinical research throughout inpatient facility
Education Two priorities:
A Standout Surgical Suite
Patient: Central family resource center with on-demand,
The expansive new OSUCCC patient-specific education
James surgical suite features Student: Dedicated meeting space
advanced technology and a forward-
Healing environment an interior design with natural light, soothing
thinking design. The 14 operating
rooms, including six interventional colors and various art forms
operating suites, are each equipped
cancer.osu.edu
17
The 14 operating rooms, including six interventional operating
RAPHAEL E.
POLLOCK, MD, PHD,
suites, are each equipped to perform minimally invasive robotic
director of Ohio States surgery and state-of-the-art microvascular reconstructive surgery.
Division of Surgical Oncology
and chief of surgical services
They were built intentionally large to accommodate future
at the OSUCCC James technology and equipment.
Retail pharmacy
Patient resource center
19
MICHAEL A. CALIGIURI, MD
We put a lot of thought into planning the new James...
director of The Ohio State This integration of patients, researchers, clinicians,
University Comprehensive
Cancer Center and CEO of The students and visitors is truly inspiring and we believe
James Cancer Hospital and
Solove Research Institute sets a model for 21st-century cancer care.
manufacturing standards (see Facilitating Clinical Care questions and schedule future
page 30). Located on the hospitals appointments.
Enhancing that sense of well-
14th floor, the unit features large Each inpatient floor has a
being, a patients electronic medical
windows that provide patient rooms pharmacist who is part of the care
records are available at the bedside.
and common areas with abundant team (oncology pharmacists also
Known as MyChart Bedside, the
natural light. staff the first-floor cancer specialty
bedside medical records result in
Steven Devine, MD, director of pharmacy), and patient medications
faster documentation, fewer errors
the Blood and Marrow Transplant carry barcodes that clinicians
and seamless sharing by members
Program, notes that these and other wirelessly scan prior to dispensing
of the medical team. Patients and
design elements can accelerate at bedside, to ensure accuracy.
family members can see names and
patient-recovery times and increase
photos of their doctors, primary Patient Rooms
patients sense of well-being.
nurse and other key care-team
members, along with test results, All inpatient rooms in the new
and they can ask non-urgent hospital are private, spacious,
cancer.osu.edu
cancer.osu.edu
21
Immune Boosters
Research on immune therapy for cancer turned a corner a few years ago,
activating the field and resulting in treatment strategies that show real promise
cancer.osu.edu
THOMAS MAGLIERY, PHD, DAVID P. CARBONE, MD, PHD, MIKHAIL DIKOV, PHD,
associate professor of Chemistry and professor of Medical Oncology, and associate professor of Medical
Biochemistry, and member of Ohio States Barbara J. Bonner Chair in Lung Oncology at Ohio State
Drug Development Institute Cancer Research at Ohio State
22
F E AT U R E : I M M U N E B O O S T E R S
FRONTIERS
WINTER 2015
BY DARRELL E. WARD
For more than 100 years doctors associate professor of Medical disease. One of the vaccines is in
and researchers have poked, Oncology at Ohio State and a clinical testing.
prodded and worked to coax the member of the OSUCCC James
immune system into eliminating Molecular Carcinogenesis and CANCER VERSUS THE
cancer. Then, in the last few Chemoprevention Program. The IMMUNE SYSTEM
years, scientists gained insights field is expanding rapidly.
Studies by Lesinski and his
into the mechanisms of immune These suppressive modulators
lab focus on how cancer alters
suppression. It was a breakthrough. include the programmed cell death
the immune system and how to
It brought true clinical successes protein 1 (PD1), a T-cell receptor
reverse immune suppression. He
and energized the field. Today, that inactivates T cells. Another is
collaborates with OSUCCC
immune therapy is one of the CTLA4 (cytotoxic T-lymphocyte-
James clinical researchers studying
hottest areas of cancer research. associated protein 4), a receptor
immune therapies in clinical
Clinically evident tumors must on T cells that downregulates the
trials, and he leads translational
have avoided an effective immune immune system.
mechanistic studies that could lead
response to have survived. But New classes of drugs have been
to new treatments.
initial attempts to generate a developed that inhibit both PD1
One long-standing interest is the
therapeutic immune response to and CTLA4, says William Carson
STAT3 protein. It is almost always
treat those tumors were not very III, MD, professor of Surgery at
turned on in cancer cells, where
successful because they attempted Ohio State and associate director
it promotes survival and inhibits
to induce immunity to cancer, for clinical research at the OSUCCC
death by apoptosis, Lesinski says.
says Mikhail Dikov, PhD, associate James. The success of these
Theyre learning its also important
professor of Medical Oncology agents has given immune therapy a
for the generation of myeloid-
at Ohio State and member of the tremendous boost.
derived suppressor cells (MDSCs),
Translational Therapeutics Program Simply by giving a drug that
a class of immune cells that curtail
at Ohio States Comprehensive stops one negative pathway on
immune responses in cancer
Cancer Center Arthur G. James T cells, were seeing impressive
patients.
Cancer Hospital and Richard shrinkage of tumors in melanoma
Our evidence suggests that
J. Solove Research Institute and other cancers. The thinking is
STAT3 promotes both tumor-cell
(OSUCCC James). Then that those cases can also be treated
survival and the downregulation
scientists discovered that, in with immune therapy, Carson says.
of anticancer immune responses
addition to overactive mechanisms A number of OSUCCC
we see in patients with advanced
of immune induction, there are James researchers are working
cancer, Lesinski says.
mechanisms that suppress the to improve immune therapy
Were investigating whether
immune system in cancer patients. for both solid tumors and
inhibiting the STAT3 pathway
Therapies that reverse that hematologic malignancies. Some
might be a novel way to enhance
suppression have been fruitful. are investigating mechanisms of
immune therapy against cancer. We
Patients with cancers that have immune suppression and how to
think that targeting STAT3 might
been refractory to everything thats inhibit them. Others are developing
have a dual effect, one on tumor
been tried, such as non-small-cell peptide vaccines and inhibitors
cells and another that restores a
cancer.osu.edu
23
GREGORY LESINSKI,
PHD, MPH,
associate professor of
Medical Oncology at
Ohio State.
with soy can lead to immunologic global phase III trial for the
changes, Lesinski says. Now drug nivolumab, an anti-PD-1
were addressing whether a simple monoclonal antibody. The trial
dietary intervention might alter (NCT02041533) compares
the immune response in a way that this immune therapy with
favors anticancer immunity. chemotherapy as first-line
In 2014, the researchers published treatment for lung cancer.
findings from a study of black Anti-PD1 therapy by itself is
raspberry extracts and metabolites. proving to be extremely important,
It showed that these compounds Carbone says. For decades, the
might downregulate suppressive paradigm in metastatic lung
immune cells, in part through cancer has been platinum-based
targeting STAT3. chemotherapy first line, with
They block the ability of experimental treatments later on.
STAT3 inhibitors are themselves proinflammatory cytokines But anti-PD1 immunotherapy
PRAVIN
KAUMAYA, PHD, immunotherapy because to expand the population of has generated so much excitement
professor and immune cells rely on the STAT3 immune suppressive cells that are and evidence of clinical benefit that
director of the pathway, he notes. We think upregulated in cancer, Lesinski its now being tested as first-line
Division of Vaccine that those inhibitors may have an says. The findings suggest that black therapy, as the sole therapy. This
Development in Ohio underappreciated effect on the raspberries might be a source of raises the possibility that some
States Department immune system. compounds for drugs that influence lung cancer patients may have
of Obstetrics and Similarly, his lab is exploring immune function or inhibit STAT3 durable remissions for metastatic
Gynecology pathways. disease that last a long time with
other pathways that are targeted
in cancer cells and also used by minimal toxicity and without ever
immune cells. Some of these LUNG CANCER having had chemotherapy. This
inhibitors might in reality work by PD-1 is a receptor present on large randomized trial compares
acting on immune cells rather than activated T cells and a potent nivolumab alone head to head
on tumor cells. Were exploring that mechanism of immune suppression. with platinum-based doublet
in-depth for several inhibitors. When tumor cells express one of chemotherapy for patients with
PD-Ls two ligandsPD-L1 or PD- newly diagnosed metastatic lung
DIETARY IMMUNE L2tumor cells can shut down cancer.
attacking T cells in the tumor This is fantastic by itself,
MODULATORS
microenvironment. Carbone says, but it also tells us
Lesinskis lab is also investigating that immunotherapy can work.
dietary and natural products Expression of PD-L1 on tumor
cells is associated with poor Now we need to look at the
as a novel means to reverse
prognosis in non-small-cell lung science and figure out all the other
immune suppression or to prevent
cancer and other tumor types, processes that are involved in
inflammatory immune changes that
says David P. Carbone, MD, PhD, suppressing the immune response
can produce smoldering chronic
professor of Medical Oncology to develop new therapies and new
inflammation and then cancer.
and Barbara J. Bonner Chair in combinations that might be even
One line of an NCI-supported
Lung Cancer Research at Ohio more effective or work in more
study (CA169363) examines
State. But tumors expressing these people.
whether dietary soy might
change the immune-cell profile ligands respond better to the new
in patients with prostate cancer. antibodies that target this pathway. NOTCH
Weve learned that isolated soy Carbone chairs the steering Carbone and collaborator
components and diets enriched committee for a 120-site, Mikhail Dikov are also investigating
a mechanism of immune T-cell changes and dramatically immune suppressor cells, which act
suppression very different from PD- slowed tumor growth. We believe to restrain the immune system. He
1. It involves an interesting pathway that if we can develop a drug that and his lab are investigating how
called Notch. works in humans to increase Notch myeloid-derived suppressor cells,
Notch is key for the development signaling, it will have a similar effect or MDSCs, affect antibody therapy
and differentiation of T cells in patients, Carbone says. (NCI grant CA095426). We want
and other immune cells, and for Carbone and Dikov are working to inhibit the cells that are braking
immune responses. When certain to develop this new drug for clinical the immune system, Carson says.
ligands bind with Notch receptors use. To be active, it will need to Its like cutting the brake line
on T cells, it activates the cells and consist of a multivalent form of things should go a lot faster and the
induces differentiation and immune DLL1, Carbone says. The idea cancers should shrink more.
responses. is to express multimers of the In many cancers, we can get a
Carbone and Dikov have shown DDL1 binding domain for optimal general idea of how well patients
that Notch signaling through a signaling. will do based on whether immune
molecule called DLL1 is reduced in The researchers are developing cells are infiltrating the tumor,
bone-marrow immune precursor the complex agent in collaboration he adds. That suggests that the
cells both in patients and tumor- with Ohio State biochemist Thomas immune system is working to
bearing animal models. Magliery, PhD, associate professor eliminate these cancers, and that
We believe that activating the of Chemistry and Biochemistry, its involved in the response to
Notch signaling pathway offers and a member of Ohio States Drug treatments like radiation and
a novel strategy for overcoming Development Institute. chemotherapy. This idea is also
cancer-induced immune This exciting partnership is supported by the effectiveness of
suppression, Dikov says. taking our findings in an animal anti-CTLA4 and anti-PD1 immune
That conclusion is based on model and using them to develop boosters.
the findings of a 2011 study led an agent we hope to use in the Carson has long had an
by Carbone showing that tumor clinic, Carbone says. interest in investigating the use
growth can inactivate the Notch Studies under way by Carbone of immune hormones to enhance
pathway and turn off T cells. This and Dikov will provide a deeper the effectiveness of monoclonal-
immune suppression protects understanding of Notch, DLL1 and antibody-based drugs.
tumor cells from destruction by other Notch ligands in antitumor He is principal investigator on
cytotoxic T cells. immunity and will help evaluate a phase I/II trial (NCT01468896)
The researchers found that their therapeutic and prognostic that combines the antibody-based
Notch is inactivated by high potential. The work is supported drug cetuximab with an immune
levels of circulating vascular by an NCI grant, Notch Ligands hormone called interleukin-12
endothelial growth factor (VEGF). in Regulation of Anti-Cancer (IL-12) in patients with head and
The high levels of VEGF inhibit Immunity (CA175370). The neck cancer. The drug binds to
the expression of two Notch findings will contribute to the EGFR receptors on the surface of
ligands called DLL1 and DLL4 development of the therapeutic malignant tumor cells. Patients are
by endothelial and other cells DLL1 agent and possible prognostic then given an injection of IL-12.
into the bloodstream. Low levels assays. Our thought is that immune cells
of those ligands shut down the like natural killer (NK) cells will
Notch pathway in use it or lose it ENHANCING ANTIBODY attack the antibody-coated cancer
fashion. THERAPIES cells, and that interleukin-12 will
They also showed that boosting provide an extra boost to the NK
cancer.osu.edu
25
works in the test tube, it works in
CAR T CELLS SHOW PRECLINICAL PROMISE
mice, and now we will learn if it
AS MULTIPLE MYELOMA THERAPY works in humans. (For more about
this clinical trial, see page 29.)
A recent study by OSUCCC James researchers provided A previous phase I trial
evidence that genetically modified immune cells might conducted by Carson evaluated
effectively treat multiple myeloma, a disease that remains the combination of IL-12 and
incurable and accounted for an estimated 24,000 new cases trastuzumab (Herceptin) in patients
and 11,100 deaths in 2014. with breast and gastrointestinal
The researchers modified T lymphocytes, or T cells, to target cancers. The study accrued 21
a molecule called CS1, which is found on more than 95 percent patients with metastatic HER2-
of myeloma cells. The modified cellstechnically called chimeric positive tumors. The findings,
antigen receptor (CAR) T cellswere able to identify myeloma published in the journal Molecular
CRAIG HOFMEISTER, cells and kill them.
MD, MPH, assistant Cancer Therapy, showed that IL-12
The researchers grew the modified T cells in the lab to in combination with trastuzumab
professor of medicine
and a member of the increase their numbers and then injected them into an animal and paclitaxel is safe and has
OSUCCC James model where they again killed human myeloma cells. activity in patients with HER2-
Leukemia Research The findings were published in the journal Clinical Cancer overexpressing cancers.
Program Research.
Despite current drugs and use of bone marrow
ANTICANCER PEPTIDE
transplantation, multiple myeloma remains incurable, and almost
VACCINES
all patients eventually relapse, says co-principal investigator
OSUCCC James researcher
and multiple myeloma specialist Craig Hofmeister, MD, MPH,
Pravin Kaumaya, PhD, professor
assistant professor of medicine and a member of the OSUCCC
and director of the Division of
James Leukemia Research Program.
Vaccine Development in Ohio
This study presents a novel strategy for treating multiple
States Department of Obstetrics
myeloma, and we hope to bring it to patients as part of a phase I
and Gynecology, is leading the
clinical trial as soon as possible, Hofmeister says.
development of five anticancer
In particular, our study shows that we can modify T
peptide vaccines and related peptide
lymphocytes to target CS1, and that these cells efficiently
inhibitors.
destroy human multiple myeloma cells, says principal
The vaccines and inhibitors target
investigator Jianhua Yu, PhD, assistant professor of
EGFR, HER-2, HER-3, VEGF and
medicine and a member of the OSUCCC James Molecular
IGF-1R receptors. The molecules
Carcinogenesis and Chemoprevention Program.
JIANHUA YU, PHD, play key roles in cancer-cell growth,
An important possible advantage to this approach is that
assistant professor proliferation and survival, and they
of medicine and a these therapeutic T cells have the potential to replicate in the
are often overexpressed in breast
member of the OSUCCC body. Therefore, they might suppress tumor growth and prevent
cancer, including triple-negative
James Molecular relapse for a prolonged period, Yu says.
Carcinogenesis and breast cancer, and in pancreatic,
Yu, Hofmeister and their colleagues used cell lines and fresh
Chemoprevention esophageal and colon cancers.
myeloma cells from patients to produce genetically engineered
Program HER-2 overexpression, for example,
T cells with a receptor that targets CS1. The researchers then
occurs in 15-25 percent of breast
tested the capacity of the modified cells to kill human multiple
cancers and is associated with
myeloma cells in laboratory studies and an animal model.
aggressive tumor behavior.
Kaumayas peptide vaccines are
Funding from the National Institutes of Health (CA155521, OD018403),
Multiple Myeloma Opportunities for Research and Education, the National Blood
designed to provoke an antibody
Foundation, and an OSUCCC James Pelotonia Idea Grant supported this response to the target molecules on
research. tumor cells and to generate memory
26
F E AT U R E : I M M U N E B O O S T E R S
FRONTIERS
WINTER 2015
that will enable the immune system combining two peptide vaccines,
to respond quickly should the two inhibitors, one of each or
cancer recur. combined with chemotherapy
The peptide inhibitors target the might further improve the agents
same set of cell-surface receptors. effectiveness.
They bind with and inactivate We believe that strategies that
the target molecule, leading selectively target both IGF-1R
to programmed cell death, or and HER-3 hold great promise
apoptosis. for overcoming mechanisms of
The agents have completed resistance to HER-1- and HER-
preclinical testing; the HER- 2-targeted agents and facilitating
2 vaccine is in phase I testing tumor regression in a range of
(NCT01376505) in patients with tumor types, Kaumaya says.
metastatic solid tumors. More broadly, we believe
Innovative immune-based our novel immune-stimulatory
therapies that target these receptors strategies using peptide vaccines
are particularly important, and inhibitors hold the promise of
Kaumaya says, because they might durable clinical benefit for high-
offer long-term control in several risk, recurrent, refractory and
tumor types without the toxicities metastatic cancers, he adds.
associated with current FDA-
approved regimens. HEMATOLOGIC CANCERS
HER-2-positive patients Immune therapy is a long-term
are treated with humanized focus of the OSUCCC James
monoclonal antibodies such as Leukemia Research Program. Our
trastuzumab, he adds, but they goal is to develop immune therapies
often develop resistance within a for hematologic malignancies as
year, rendering the drug ineffective. one component of a move away
Prolonged treatment can also lead from chemotherapy altogether, says
to serious side effects, and the drugs Jeffrey Jones, MD, MPH, section
are very expensive. head for CLL/Hairy Cell Leukemia.
A standard one-year course of Its an attainable target made
treatment with trastuzumab, for possible, he says, by recent advances
example, can cost $70,000, he notes. in technology that enable new
We believe our new peptide treatment strategies. He notes three
immune-based therapies and approaches to immune therapy for
strategies will overcome these hematologic malignancies: JEFFREY JONES, MD, WILLIAM CARSON III,
problems, he says, noting that the Monoclonal-antibodies and section head for CLL/Hairy MD, professor of Surgery and
many advantages of peptides over other agents that stimulate both Cell Leukemia associate director for clinical
monoclonal antibodies include the adaptive and innate immune research at the OSUCCC
lower cost, high specificity and response; James
potency, ability to penetrate the cell Monoclonal antibodies tagged
membrane, low immunogenicity with a toxin or a radioactive isotope
and greater overall safety. that kills targeted cells;
cancer.osu.edu
28
BENCH TO BEDSIDE
FRONTIERS
WINTER 2015
BENCH TO BEDSIDE
From the Laboratory to the Pharmacy
HYPOTHESIS: More than macrophages and T cells to sites of The phase II study will determine
90 percent of squamous cell inflammation. the response rate to the two agents.
carcinomas (SCC) that originate NK cells express an Fc receptor Additional correlative studies
in the oropharynx overexpress the called FcRIIIa, which enables will provide information on the
epidermal growth factor receptor them to interact with antibody- antitumor mechanism of IL-12 and
(EGFR, or HER1). Cetuximab is an coated tumor cells and to mediate establish biomarkers for predicting
anti-HER1 monoclonal antibody antibody-dependent cellular patient responsiveness.
that binds to HER1-overexpressing cytotoxicity (ADCC) and the Along with characterizing the
tumor cells and has activity as a secretion of IFN- and TNF-. immunologic effects of IL-12 in
single agent when administered to The presence of IL-12 markedly combination with cetuximab,
patients with HER1-positive SCC enhances this antitumor activity. this study will provide a better
of the oropharynx. We hypothesize This protocol evaluates whether understanding of the NK-cell
that IL-12 administration will administration of IL-12 will response to antibody-coated
enhance the antitumor activity enhance the antitumor activity tumor cells and of how to improve
of cetuximab by activating innate of cetuximab in patients with the regimens effectiveness. The
immune cells that recognize inoperable HER1-overexpressing information gained from this
antibody-coated tumor cells. SCCs of the head and neck. study should also apply to other
The phase I portion of the study monoclonal antibodies currently in
RATIONALE: This novel protocol will identify a tolerable dose of IL- use or under development.
exploits the fact that innate immune 12 plus cetuximab;
cells bear specialized receptors
for the Fc region on monoclonal
antibodies. Evidence suggests that
Fc-receptor-dependent mechanisms AT A GLANCE
contribute substantially to the Trial no.: ClinicalTrials.gov identifier: NCT01468896
activity of monoclonal antibodies PI: WILLIAM E. CARSON III, MD
directed against tumor antigens,
Phone: 614-293-6306
and that co-administration of
Email: william.carson@osumc.edu
immune stimulatory cytokines
might enhance their effects. This is Eligibility: age 18 or older, histologically proven recurrent
particularly true for natural killer or metastatic squamous cell carcinoma of the head and
(NK) cells. neck that is unresectable (patients in the phase II portion of the trial must have
Once activated, NK cells release measurable disease), ECOG performance status less than 2 (Karnofsky greater
cytokines that have antitumor than 60%), life expectancy greater than 6 months, normal organ and marrow
cancer.osu.edu
activity and help coordinate innate function, ability to understand and willingness to sign a written informed consent
and specific immune responses. document.
They also release factors that recruit
29
NEED TO KNOW
At the OSUCCCJames
It is equipped with cell-selection devices, automated processors, a bioreactor, an eight-parameter flow cytometer, and
cryopreservation and storage equipment.
The lab maintains extensive cleaning and sanitization, environmental monitoring, batch production, materials management
and process-validation records.
30
NEED TO KNOW
U P D AT E : T H E N E W J A M E S FRONTIERS
WINTER 2015
31
OHIO STATE UNIVERSITY Non Profit Org.
COMPREHENSIVE CANCER CENTER U.S. Postage
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RICHARD J. SOLOVE RESEARCH INSTITUTE Columbus, OH
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Columbus, OH 43210-1240
UPCOMING EVENTS
PELOTONIA 15
August 7-9
Pelotonia is an annual bicycling event that takes riders through the bucolic Ohio countryside on routes of varying length. The event
attracts thousands of cyclists from across the nation and world, and 100 percent of the funds raised supports cancer research at the
OSUCCC James.