City of Hope: Boldly Traversing the "Valley of Death"

City of Hope

Founded in 1913 as a tuberculosis sanatorium, City of Hope today enjoys a reputation as a leading research, treatment, and education center for those with cancer, diabetes, and other life-threatening diseases.

The Duarte, California, center, which is designated as a comprehensive cancer center by the National Cancer Institute (NCI) and is a founding member of the National Comprehensive Cancer Network, is well known for research and treatment protocols that advance care throughout the nation, as well as the compassion that drives those innovations. Indeed, it was recombinant DNA techniques patented at City of Hope that led to the development of synthetic human insulin, and it was City of Hope scientists who developed monoclonal antibody technology, a breakthrough that led to one of the dominant patents in the field for “smart” cancer drugs.

As an independent medical and research institution, City of Hope embraces a culture that breaks through the barriers that have traditionally stood between scientists and physicians, accelerating the application of laboratory findings to more effective treatments. Central to this commitment are City of Hope’s on-campus good manufacturing practices (GMP) facilities.

On-Site GMP

Despite great promise, many new drugs enter the early stages of drug research (before large-scale human trials) never to be seen again–forever lost in the so-called “valley of death.” This phenomenon often has less to do with lack of efficacy than with a lack of resources and infrastructure needed to successfully transition new agents from the lab to phase I and II clinical trials. At City of Hope, however, a unique approach to drug development is enabling researchers to successfully usher novel therapies through the dreaded “valley of death,” into clinical trials and, ultimately, to the bedside.

City of Hope’s three on-site GMPs are critical to the success of this approach to translational medicine. The largest of these facilities, the Center for Biomedicine and Genetics (CBG), produces biologics, including viral and nonviral gene therapeutics, for on-campus testing while also providing services to outside institutions. The Cellular Medicines GMP facility provides on-site development of City of Hope’s stem cell—based therapy efforts, and the Chemical GMP Synthesis facility–the newest of the three–focuses on small molecules.

This enviable infrastructure arms scientists with everything they need to develop, test, and transition novel agents into clinical trials, and even includes an on-campus regulatory office to facilitate and expedite FDA review.

Even as an increasing number of academic centers jump on the manufacturing bandwagon, with some able to produce materials to meet their own needs, City of Hope remains unique in several ways, not the least of which are manufacturing capabilities that meet chemical, biologic, and viral needs. Also highly unusual is the center’s role as a national supplier, as evidenced by the CBG’s National Institutes of Health (NIH) grant to serve as primary supplier of biologic agents for NIH research at other institutions. City of Hope also shares its expertise with outside companies and institutions, helping to guide them through the regulatory process and sharing expertise about how best to manufacture products for the marketplace.

City of Hope scientists’ work with the imaging agent 64Cu-DOTA-trastuzumab and the breast cancer target known as cancer proliferating cell nuclear antigen (caPCNA) are just two of myriad examples of this unique approach to drug development.

Joanne Mortimer, MD

64Cu-DOTA-Trastuzumab: New Insights Into HER2-Positive Disease

One of the products developed by City of Hope scientists and synthesized in the new Chemical GMP Synthesis facility is 64Cu-DOTA-trastuzumab, a radiolabeled positron emission tomography (PET) imaging agent. Head of City of Hope’s Women’s Cancers Program and Phase I Clinical Trials Program Joanne Mortimer, MD, expects the agent to provide new insights into the biology of HER2-positive breast cancer while helping to identify women most likely to benefit from treatment with trastuzumab.

To this end, Mortimer and her team are assessing the ability of 64Cu-DOTA-trastuzumab PET scanning to accurately characterize HER2 expression by evaluating uptake of the agent in women with metastatic disease with varying degrees of HER2 expression. The team began by administering cold doses of the radiotracer prior to scanning to minimize its uptake in normal tissues, optimizing image quality and enabling determination of the optimal dose. The next step was for women to undergo 64Cu-DOTA-trastuzumab PET scanning, with a small dose of radiolabeled trastuzumab administered 48 and 24 hours prior to imaging.

Ten patients have been imaged since enrollment began in March 2011, and an additional 15 will undergo imaging by the study’s completion in 2013. “Rather than needing to perform repeat biopsies–something that is sometimes not even possible in this population–64Cu-DOTA-trastuzumab PET allows us to look at the biology of a malignancy in the ‘entire patient,’” said Mortimer, who stresses that such insights are key to developing effective treatments and identifying the best candidates for such treatments. Indeed, the team is now imaging women whose cancers are not strongly HER2-positive to identify additional patients who might benefit from trastuzumab. “Ultimately,” said Mortimer, “we might even find that trastuzumab benefits those with HER2-negative disease.”

Linda Malkas, PhD

caPCNA: Novel Breast Cancer Target

Also benefiting from collaborative efforts with GMP scientists is Linda Malkas, PhD, associate director for Basic Science and co-leader of City of Hope’s Molecular Oncology Program, whose work with the breast cancer target caPCNA may lead to development of novel compounds for treatment.

Years before coming to City of Hope, Malkas identified caPCNA, a previously unknown isoform of the protein PCNA, which is expressed in cancer cells but not in normal cells. The protein is involved in a number of DNA pathways, acting as a hub for replication and repair, and making it an excellent target.

Malkas was then able to identify several small molecules that recognize the protein and appear to block interaction between caPCNA and its protein partners. “Knowing that caPCNA physically interacts with at least an additional 100 proteins, we reasoned that finding molecules to block those interactions would allow us to shut down cancer cell replication and repair processes,” she explains. Malkas’s move to City of Hope provided the infrastructure needed to fully explore the action of those molecules at a cellular level, and to show that replication and repair can, indeed, be shut down. She also reports finding an additional small molecule that seems to works well in neuroblastoma.

The team is now working to define the mechanisms of action of compounds already identified as able to target caPCNA, while also searching for others. Preliminary animal testing on one such compound appears promising. Malkas explains that once identified, these compounds would probably be used in combination with conventional agents, but in reduced and better tolerated doses. “In animal models, we’ve already seen that compounds that shut down DNA repair act synergistically with much lower concentrations of agents such as cisplatin and doxorubicin, and without affecting normal cells.”

In the best possible scenario, Malkas envisions compounds being used to target novel molecules that appear not just in breast cancers but in all cancer cells. “It’s City of Hope’s uniquely collaborative infrastructure that allows this work to move forward,” she says.

“Already, I’m working with the people who will ultimately serve as phase I clinicians for our work some 3 years in the future. And when I need to find developmental therapeutic scientists who can produce analogues to help change a compound’s structure, or get advice on selecting the best animal models or finding clinical trial participants, I have only to walk across the street or down the hallway.”

City of Hope Timeline

 

1913

1976

1994

2009

 

City of Hope is founded as a tuberculosis sanatorium.

City of Hope performs one of the first successful bone marrow transplants in the country.

The Irell & Manella Graduate School of Biological Sciences is chartered, providing practical laboratory and research training for future scientists.

The Cellular Medicines GMP facility is opened to support manufacturing immunotherapies and stem-cell based therapies in development.

 

 

 

 

 

 

 

 

 

 

 

1949

1978

2000

2012

 

With tuberculosis now controlled, City of Hope expands its scope to address cancer and other serious illnesses.

City of Hope scientists develop monoclonal antibody technology and create synthetic human insulin.

The Center for Biomedicine & Genetics is established to ensure that City of Hope scientific discoveries are efficiently translated from the lab to the clinical setting.

The Chemical GMP Synthesis facility is opened, focusing on small-molecule manufacturing.

Marcia Grant, RN, DNSc

Nursing Considerations

As scientists, clinicians, and patients reap the rewards of such innovative work, treatments improve and numbers of survivors increase, creating the welcome but challenging task of providing comprehensive and effective survivorship care. Even so, many centers do not yet have the programs in place to deal with this “new normal.”

As the recipient of two NCI grants to disseminate information on development programs for survivorship care,City of Hope’s Director of Nursing Research and Education Marcia Grant, RN, DNSc, has trained multidisciplinary teams from 2006-2009, and is currently targeting nurses (2012-2016) through annual courses that draw participants from across the country.

The two-and-a-half-day courses cover the four components of survivorship care, as defined by the Institute of Medicine Report From Cancer Patient to Cancer Survivor: Lost in Transition.

• Prevention deals with what patients need to know about healthy living, focusing on “teachable moments” related to lifestyle-related issues, such as nutrition, exercise, and smoking cessation.
• Surveillance involves patient education related to monitoring for recurrences and development of new cancers.
• Intervention involves physical, psychological, social, and spiritual aspects of late and long-term effects of both cancer and its treatments.
• Coordination refers to the use of treatment summaries and survivorship care plans to manage appropriate care among patients, oncologists, and primary care practitioners.

The first four multidisciplinary courses, held in 2006-2009, were attended by 408 professionals from 204 institutions in 44 states. Most attendees were nurses, followed by social workers, administrators, and small numbers of physicians, psychologists, dieticians, and chaplains. The first course of the second series, scheduled for October 2012, targets 48 oncology nurses.

Course evaluation is accomplished with several techniques, including pre- and post-course institutional surveys to determine a center’s baseline and 1-year level of comfort and capability in implementing survivorship care. Upon arrival, attendees also are asked to share three goals, which are subsequently refined in an effort to make them as specific and achievable as possible before being presented to the participants’ administrative staff. Telephone follow-up is then conducted 6, 12, and 18 months after the course. “When they arrive, most participants haven’t begun work on a survivorship program,” says Grant, who adds that the courses prompt active sharing of ideas and valuable networking.

This wrought iron gate located in City of Hope’s International Garden of Meditation is inscribed with the comprehensive cancer center’s credo, “There is no profit in curing the body if in the process we destroy the soul.”

Challenges Remain

As with any institutional change, there has been some initial resistance to the idea of formal survivorship care, something Grant expects to lessen in light of the American College of Surgeons Commission on Cancer Standards mandate that cancer centers provide care plans to all cancer survivors by 2012. She also expects financial challenges to ease somewhat as centers complete implementation of electronic medical records and can free up more resources for other endeavors.

Not surprisingly, reimbursement poses its own unique challenges, says Grant. “We’re accustomed to thinking of reimbursement as beginning with diagnosis, but now need to look at the feasibility of reimbursement for care that begins when treatment ends. This will require grappling with issues related to potentially reimbursable clinic services and reimbursement for the services of staff, such as nurse practitioners.”

“When a patient completes treatment, we’ve historically helped them celebrate and then wished them farewell to enjoy life without treatment,” says Grant. “This can be a frightening proposition for patients who have been monitored so closely for so long. Survivorship care follows in the footsteps of cardiac care, which has a long history of comprehensive rehabilitation and follow-up. Such care is long overdue for those who have battled cancer.”

Laura Bruck is a freelance writer and editor based in Cleveland, Ohio. She has specialized in healthcare reporting since 1987.