Pancreas Center News - UCSF Helen Diller Family Comprehensive

SPRING/SUMMER 2015
Pancreas
Center
News
Andrew Ko, MD, associate professor, UCSF Department of Medicine
CAR T Cell Therapy: Engineering the
Immune System to Treat Cancer
Penn research collaborator Robert Vonderheide, MD, DPhil,
(above left) with colleague Carl June, MD
If the strategy works
well, it could have a
significant impact on
patients’ longevity.
Andrew Ko
As clinicians and researchers race to bring immunotherapy’s
recent successes in other cancers to pancreatic cancer,
chimeric antigen receptor (CAR) therapy is one approach
generating interest.
Carl June, MD, and his colleagues at University of Pennsylvania (Penn)
have been developing CAR T cell therapy to treat blood cancers.
In this process, clinicians collect patients’ T cells (a type of lymphocyte
or white blood cell that can infiltrate and attack tumors) from their
blood, modify the cells to detect cancer cells, and then reintroduce the
modified T cells into the patients to improve their immune systems’
anti-cancer responses.
Now, as part of a joint Phase I-Phase II clinical trial, June’s collaborators
at Penn – Gregory Beatty, MD, PhD, and Robert Vonderheide, MD, DPhil,
– are working with UCSF pancreatic cancer experts Alan Venook, MD,
and Andrew Ko, MD, to modify the CAR T cell concept for patients with
pancreatic ductal adenocarcinoma.
(continued on page 3)
From the Director
Building on the Promise of
Immunotherapy
In 2013, the magazine Science called cancer
immunotherapy the breakthrough of the
year. Since that time, immunotherapy has
recorded impressive results for a subset
of patients with blood, skin, prostate, and
lung cancers. A few of these therapies are
already in regular clinical use.
The question is whether we can apply
similar tools and technologies to get
the same or better results in a cancer
notoriously resistant to treatment. With our
“Dream Team” project – funded by a grant
from Stand Up to Cancer (SU2C) – and
a series of other trials, we are racing to
see if we can harness the immune system
to promote tumor control and transform
pancreatic ductal adenocarcinoma into a
manageable disease.
It won’t be easy. It never is with pancreatic
cancer, which is the fourth leading cause
of cancer-related death in both men and
women in the United States. Yet we have
reason for hope.
First, advances in chemotherapy have
improved our ability to rapidly force
pancreatic cancer into remission. This is
especially important with the advent of these
powerful immunotherapies, which need
some time to take effect; in more cases than
ever, chemotherapy can provide that time.
Second, the team science approach we
reported on last year – increasingly close
collaborations among leading institutions
that leverage diverse talent and disciplines
from the bench to the bedside – are
generating new ideas and speeding the
sharing of knowledge. As you will read about
in this issue, we are working with experts
from the University of Pennsylvania on CAR
T cell approaches, Johns Hopkins on cancer
2
Margaret Tempero, MD
vaccines, and Oregon Health & Science
University on a drug designed to free up the
body’s immune system to do its work. All of
these efforts proffer genuine hope that we
can improve outcomes across all stages of
the disease.
In addition, innovative funders are facilitating
these remarkably productive collaborations.
Whether it is SU2C, government- or
industry-sponsored research programs or
the contributions of dedicated individuals
like John Sobrato who we profile herein,
these determined supporters play an
instrumental role in advancing the science
and ensuring we provide ever more precise
and sensitive care to our patients.
For more than a decade, a few visionary
researchers at leading institutions – including
UCSF – have been working to unleash the
body’s immune system for the fight against
cancer. These researchers are beginning to
see the fruits of their labor. For those of us
battling pancreatic cancer, it’s imperative
that we seize this moment.
Sincerely,
Margaret Tempero, MD
Director, UCSF Pancreas Center
Rombauer Family Distinguished Professor
in Pancreas Cancer Clinical and
Translational Science
CAR T Cell Therapy (continued)
“The hope is that because we
have proof of principle in leukemias
we can make this work in solid
tumors,” says Venook, who leads the
gastrointestinal oncology program
at the UCSF Helen Diller Family
Comprehensive Cancer Center.
To sustainably prime the body’s
immune system to fight pancreatic
cancer, address patient safety
concerns associated with the original
trials, and advance the science,
the new trial combines two CAR
T cell therapies.
COMBINING THERAPIES: One
CAR T cell therapy is a version of
the original therapy, which enables
T cells to target CD19, a protein
associated with the body’s B cells;
in pancreatic cancer, B cells can
have an immunosuppressive function
that prevents T cells from doing their
tumor-fighting work. The second
formulation creates CAR T cells
that target mesothelin, a protein
overexpressed in many tumors,
especially pancreatic cancer.
As with all
trials, the devil
is in the details
– perhaps no
detail more
important
than patient
selection.
“This is a
Gregory Beatty, MD, PhD,
high risk,
Penn
but potentially
high reward type of treatment plan,”
says Ko. “If the strategy works well,
it could have a significant impact on
patients’ longevity, but it’s a matter
of selecting the right individuals.
We have to be extremely cautious
and methodical…there’s a lot we
still need to learn.”
belief that breakthroughs in cancer
treatment come from cooperative
groups, because only they can
test therapies across large patient
populations. “Uniting research teams
with distinct expertise could allow the
field to move forward at a more rapid
pace,” says Vonderheide.
Venook believes that’s critical – that
at this point, new trials should aim
for significant leaps forward rather
than just inching ahead. He says,
“We appreciate any advances, but
we need to be bold and look to make
bigger differences for patients.” n
TEAM SCIENCE: Venook notes that
the trial is part of an immunotherapy
network that will bring together
UCSF, Penn, and other leading
institutions. The network reflects the
1
2
Alan Venook, MD,
professor,
UCSF Department
of Medicine,
Madden Family
Distinguished
Professor in
Medical Oncology
and Translational
Research
3
“Eliminating B cells may lead to a
more efficacious treatment, because
they can make antibody responses
to the engineered T cells, which
causes their elimination over time,”
says Beatty. “By depleting B cells
and using CAR T cells that recognize
CD19, we hope the mesothelinspecific CAR T cells will live longer in
patients after infusion allowing them
to be more efficacious in attacking
the cancer.”
Clinicians 1 collect patients’ T cells from their blood, 2 modify
the cells to detect cancer cells, 3 and then reintroduce the
modified T cells into the patients to improve their immune
systems’ anti-cancer responses.
3
I trust that the best researchers
in the world here at UCSF –
working with others across the
nation – will ultimately find
solutions if given the needed
resources.
John M. Sobrato
Abby and John M. Sobrato
Donor Snapshot
Personal Loss Drives Support for Translational Research Efforts
In 2010, John M. Sobrato lost his wife, Abby,
to pancreatic ductal adenocarcinoma. The
tragedy made him painfully aware of the fact
that even as treatments for many other cancers
have achieved remarkable leaps in survival,
pancreatic cancer continues to claim the lives
of more than 90 percent of patients within five
years of diagnosis.
As chief executive officer of a renowned Silicon
Valley real estate firm that through its Sobrato Family
Foundation is one of the Bay Area’s largest corporate
philanthropies, Sobrato felt he might be able to help
researchers accelerate their progress in the fight against
pancreatic cancer. Over the past five years, he has
given generously to the UCSF Pancreas Center in both
time and financial support.
“My interest and motivation is very simple,” he says.
“Dr. [Margaret] Tempero gave my wife very personalized
and compassionate care – and I want to see a
significant improvement in outcomes for the vast
majority of pancreatic cancer patients.”
Sobrato knows all too well that researchers are still
trying to understand why pancreatic cancer remains
stubbornly resistant to treatments that work in other
forms of cancer.
4
Aside from providing financial support, Sobrato is a
member of the UCSF Pancreas Center’s SPORE Advisory
Group. SPORE (Specialized Programs of Research
Excellence) grants are part of a National Cancer Institute
program that fosters collaborative, interdisciplinary
translational research among basic and clinical scientists.
If the UCSF Pancreas Center is successful in achieving
a coveted SPORE grant for pancreatic research,
Sobrato, as a member of the Advisory Group, will play an
important role in that program. Such research, Sobrato
says “takes some of the most promising basic science
coming out of the laboratory and moves it to early
testing with humans to see whether there are tangible
therapeutic benefits.”
He feels this is where hope lies. “One of the most
frustrating aspects of pancreatic cancer has been
that therapies that appeared to work in the lab have
not ended up having the same favorable outcomes in
human trials,” he says. “Hopefully, someday, thanks to
accelerated translational efforts, improvements in survival
will be measured in years, not weeks, as is often the case
for most treatments available today.”
Thanks in part to Sobrato’s generosity, that day may
come soon. n
Research Profile
Vaccines Aim to Ignite the Body’s Anti-Cancer Fight
“Pancreatic cancer is not
typically considered to be an
immunogenic malignancy, which
means that the body does not
react to the tumors with an
immune response,” says UCSF
oncologist Andrew Ko, MD.
The goal with vaccines, therefore,
is to get the body’s immune system,
particularly the T lymphocytes, to
better recognize and attack the tumors.
Ko is working with fellow oncologist
Dung Le, MD, of the The Sidney
Kimmel Comprehensive Cancer
Center at Johns Hopkins on three
clinical trials that test vaccines
for metastatic pancreatic ductal
adenocarcinoma (PDAC).
COMBINATION VACCINES: One
trial – a large, Phase II randomized
study known as ECLIPSE – will
enroll approximately 240 PDAC
patients who have progressed on
prior chemotherapy. The study tests
a combination of GVAX pancreas
vaccine – an irradiated cellular vaccine
that has shown efficacy in earlier
trials at Johns Hopkins, the center of
cancer vaccine development – and
CRS 207, a vaccine derived from a
genetically modified bacteria called
Listeria. One arm of the study will
receive both vaccines, one arm will
receive CRS 207 alone, and the third
will receive standard chemotherapy
as the control group.
Last year, the U.S. Food and Drug
Administration granted Breakthrough
Therapy designation – which
expedites the development and
review of a particularly promising
drug candidate – for the GVAX/CRS
207 combination.
A second Phase II trial is for patients
with metastatic PDAC who have
had one prior chemotherapy regimen;
this trial adds the immune checkpoint
inhibitor nivolumab to the GVAXCRS 207 combination. Checkpoint
inhibitors block the interactions
between T cells and cancer cells
that normally inhibit the T cells and
allow cancer cells to evade the host
immune system. The randomized,
controlled trial – called STELLAR –
will give one group the full combination; the other will receive only the
GVAX/CRS 207 pancreas vaccine.
A third trial, also for patients with
metastatic PDAC, will enroll those
whose tumors have first responded
to or stabilized with a common frontline combination chemotherapy
regimen called FOLFIRINOX. Patients
in this study are randomized to
either receive ipilimumab – another
checkpoint inhibitor – in combination
with the GVAX vaccine or continue
with standard chemotherapy.
CLINICAL IMPACT: The idea is
that after chemotherapy shrinks the
tumor, immunotherapy can then be
more successful in helping the body
fend off recurrence or additional
tumor growth.
“This multipronged approach
is more likely to have a clinical
impact than treating with a single
immunotherapeutic agent,” says Ko,
who also notes that patient selection
will be especially important, because
immunotherapies take some time
before they show effect. “Only a
subset of relatively robust patients is
likely to derive substantial benefit.”
“Nevertheless, we now have access
to novel agents to test in combination strategies that make sense
scientifically,” Le says. “Collaboration
allows us to bring together a team
of researchers skilled in the care of
pancreatic cancer patients, who can
use clinical and scientific judgment to
attempt to move the field forward for
this devastating disease.” n
Andrew Ko, MD,
associate professor,
UCSF Department of
Medicine
We now have
access to novel
agents to test
in combination
strategies that
make sense
scientifically.
Dung Le
Dung Le, MD,
Johns Hopkins
5
Clinical Care
Helping Cancer Nurses Care for Patients and Their Families
Through the Rigors of Treatment
Taking advantage of a
generous gift from patient
Stu Rickerson, Elizabeth
Dito, RN, is spearheading a
nurses’ educational program at
the UCSF Helen Diller Family
Comprehensive Cancer Center.
It will provide more thorough
and individualized palliative
care for patients.
Though many people still associate
palliative care only with end-of-life
care, these days palliative care
teams holistically manage the
physical, psychological, and spiritual
symptoms associated with any
life-limiting illness and its treatment.
EDUCATIONAL PROGRAM:
The Pancreas Center’s educational
program will have two primary
components, which Dito is
developing in consultation with
the Cancer Center’s Symptom
Management Service.
The first component is a series of
classes that will certify interested
cancer center nurses in palliative
care. Oncology nurse Nancy
Shepard Lopez, NP, of the UCSF
Symptom Management Service is
a certified instructor for the course,
which the comprehensive cancer
center at City of Hope developed.
taught at the UCSF School of
Nursing inspired Dito to make the
content accessible to nurses at the
cancer center, who typically form
close attachments to their patients
and want to provide fully integrated,
holistic care.
The second component will be
an ongoing series of evening
programs aimed at discussing
various aspects of palliative care –
anything from nutrition to managing
symptoms associated with a
particular type of cancer therapy
and caring for caregivers.
Having worked with pancreatic
cancer patients for 17 years,
Dito believes the opportunity to
deepen her understanding of
palliative care is a valuable addition
to her practice. “I spend a lot
of time listening to my patients
and managing their disease or
treatment to improve their quality
of life,” she says. “This program
can be a real help in my treatment
planning role.”
STARTING 2015: Both components
will begin this year and initially
target the 20 to 30 cancer nurses
working in the ambulatory setting at
UCSF Medical Center. Eventually,
Dito hopes to expand the classes to
inpatient nurses as well.
“My practice has always had a
palliative care emphasis, but we
wanted to do something more indepth,” says Dito. Attending a course
that palliative care nursing expert
Doranne Donesky, RN, PhD, NP,
Moving ahead, Dito would like the
program to integrate cancer center
physicians and advanced practice
nurses, because palliative care is a
team-based concept that involves
multiple disciplines. “Over time,
we will fine tune what we’re doing
based on feedback from the people
who attend,” Dito says. n
We want to become a
resource for centralized
information about
palliative care that
is tailored to our
particular patients.
Elizabeth Dito
6
Elizabeth Dito, RN, UCSF Pancreas Center
clinical research nurse
Research Profile
Freeing the Body’s Immune
System To Fight PDAC
Before Lisa Coussens, PhD, joined the Oregon
Health & Science University, she served as
co-director of UCSF’s Program in Cancer
Immunity working closely with Pancreas Center
director Margaret Tempero, MD. She and
Tempero have been working on a groundbreaking manuscript that aims to define the
role B cells play in inflammation associated with
pancreas cancer development.
Coussens has used mouse models of pancreas
cancer to study the role of immune cells, in particular
B cells, in cancer development; these studies led her
to examine an FDA-approved lymphoma drug named
ibrutinib. Coussens and team revealed that the drug
could neutralize cancer growing pathways facilitated
by immune cells, while also opening the door for
T cells to attack tumors.
Lisa Coussens, PhD,
associate director
of Basic Research,
Knight Cancer Institute,
Oregon Health &
Science University
Now, Coussens, Tempero, and
UCSF cancer immunotherapy
specialist Lawrence Fong, MD,
are initiating a Phase II clinical trial
– funded by Stand Up to Cancer
and Pharmacyclics, a biotech drug
development company – that will
test ibrutinib in combination with
chemotherapy for patients suffering
from metastatic pancreatic
ductal adenocarcinoma (PDAC).
The trial begins at a time when immunotherapy – an
approach that stimulates or frees the body’s immune
system to fight cancer – has begun to demonstrate
exciting outcomes in a subset of patients with a variety
of cancers.
“We are finally seeing some durable responses in solid
tumors,” says Fong, who has spent the last 15 years
working on tumor immunology. “Some prostate cancer
patients now have [inactive] disease six or seven
years out.”
Though ibrutinib has not been tested in solid tumors
to date – and has never been combined with the
chemotherapies that will be used in this new trial –
Lawrence Fong, MD, professor,
UCSF Department of Medicine
Margaret Tempero, MD
Our center is
particularly strong on
the clinical side. We
have [a number of]
people well-versed in
supporting patients
through trials.
Margaret Tempero
the pre-clinical research and other immunotherapy trials
offer hope that pancreatic cancer patients could benefit.
“If it works, it will be phenomenal,” says Coussens.
Tempero’s vast experience treating PDAC patients
provides reassurance for patients enrolling in the trial.
“Our center is particularly strong on the clinical side,”
she says. “We have [a number of] people well-versed in
supporting patients through trials.”
As part of that process, the team will monitor closely
any safety concerns related to how the ibrutinib and
chemotherapy interact. From an efficacy standpoint,
some patients will undergo biopsies before and after
treatment. Then, the researchers will deploy next
generation sequencing to determine whether neutralizing
the pro-tumorigenic B and myeloid cells did, indeed,
induce T cells to attack the tumors. Fong adds that learning from other immunotherapy trials
in progress could eventually make it possible to use
different combination approaches – ibrutinib, vaccines,
CAR T cells (see p.1) – for different patient types.
“We need to build on our successes so we can
move beyond helping only a small subset of patients,”
he says. n
7
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Pancreas Center News | SPRING /SUMMER 2015
Jennifer Matz with children
Tobias and Madeleine Matz
(courtesy of Tobias and Madeleine
Matz and Race with Jennifer)
Zeny, Kiana and Shawn Correa
Don Ritchie’s granddaughter Violet
Titan’s Cage and the Correa Family
Race with Jennifer
Thanks to the Correa family and Titan’s Cage
for raising more than $11,000 for the UCSF
Pancreas Center at Mixed Martial Arts events
throughout Northern California, in memory
of family member Cora Claro, who passed
away in 2013.
When Jennifer Matz was diagnosed with pancreatic cancer in
2013, she bravely and gracefully responded to the challenge.
She recognized that decades of innovative research were having
a huge impact on care, and she wanted to do something that
would further benefit other pancreatic cancer patients.
Don Ritchie 5K Run/Walk
The Don Ritchie annual 5K run/walk is
dedicated to the memory of Don Ritchie, a
long time runner and Marin County educator,
who died in 2009. The event has raised almost
$25,000 for pancreatic cancer research at
UCSF. Thanks to Don’s wife Jane and everyone
who participates. For more information, visit
marinraces.com.
In September 2014, she helped organize and participated in the
Race with Jennifer. In just a few months, the race organizers
collected more than $350,000 for research at the UCSF Pancreas
Center. To honor such a remarkable woman, 325 friends and
family ran, biked, and swam; 55 people volunteered; and more
than 1,220 individuals donated to the race.
After a courageous battle, Jennifer passed away on Dec. 5, 2014.
Her friends and family as well as the entire UCSF community
mourn her passing. We thank them for their support.
For more information on the UCSF Pancreas Center, email [email protected] or call 415-502-3362.
ucsfpancreascenter.org or cancer.ucsf.edu/research/pancreas
Pancreas Center News Managing Editor: Susan Godstone | Writer: Andrew Schwartz | Design: Laura Myers Design
Photography: Steve Babuljak, Elisabeth Fall, RCL Portrait Design | Illustration: Caron A. Jacobson and Jerome Ritz/Wikimedia Commons
© Regents of the University of California 2015
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