CAR T Cell Therapy: Engineering the Immune System to Treat Cancer 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.

Pancreas Center News

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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

SPRING/SUMMER 2015

Andrew Ko, MD, associate professor, UCSF Department of Medicine

From the DirectorBuilding on the Promise of ImmunotherapyIn 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

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, MDDirector, UCSF Pancreas Center

Rombauer Family Distinguished Professor in Pancreas Cancer Clinical and Translational Science

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Gregory Beatty, MD, PhD, Penn

“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.

“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 mesothelin-specific CAR T cells will live longer in patients after infusion allowing them to be more efficacious in attacking the cancer.”

CAR T Cell Therapy (continued)

As with all trials, the devil is in the details – perhaps no detail more important than patient selection. “This is a high risk, 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.”

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

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

Alan Venook, MD, professor, UCSF Department of Medicine, Madden Family Distinguished Professor in Medical Oncology and Translational Research

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.

1 2 3

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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.

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

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

Donor Snapshot Personal Loss Drives Support for Translational Research Efforts

Abby and John M. Sobrato

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“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 GVAX-CRS 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 combina-tion; 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 front-line 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 combina-tion 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

Research ProfileVaccines Aim to Ignite the Body’s Anti-Cancer Fight

We now have access to novel agents to test in combination strategies that make sense scientifically.

Dung Le

Andrew Ko, MD, associate professor,

UCSF Department of Medicine

Dung Le, MD, Johns Hopkins

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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

Clinical CareHelping Cancer Nurses Care for Patients and Their Families Through the Rigors of Treatment

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.

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.

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 in- depth,” says Dito. Attending a course that palliative care nursing expert Doranne Donesky, RN, PhD, NP,

We want to become a resource for centralized information about palliative care that is tailored to our particular patients. Elizabeth Dito

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.

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.”

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

Elizabeth Dito, RN, UCSF Pancreas Center clinical research nurse

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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 ground-breaking 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.

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 –

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

Our center is particularly strong on the clinical side. We have [a number of] people well-versed in supporting patients through trials.

Margaret Tempero

Lisa Coussens, PhD, associate director of Basic Research, Knight Cancer Institute, Oregon Health & Science University

Margaret Tempero, MD

Lawrence Fong, MD, professor, UCSF Department of Medicine

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Zeny, Kiana and Shawn Correa

Jennifer Matz with children Tobias and Madeleine Matz (courtesy of Tobias and Madeleine Matz and Race with Jennifer)

Don Ritchie’s granddaughter Violet

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For more information on the UCSF Pancreas Center, email UDARCC@ucsf.edu or call 415-502-3362. ucsfpancreascenter.org or cancer.ucsf.edu/research/pancreasPancreas 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

Race with JenniferWhen 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.

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.

Titan’s Cage and the Correa FamilyThanks 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.

Don Ritchie 5K Run/WalkThe 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.

Pancreas Center News | SPRING/SUMMER 2015