10 platforms of expertise and technology support the program’s progress
Since discovering that leukemia cells contain a target that can attract an immune attack leading to remission, Jeff Molldrem, M.D., and his colleagues have doggedly sought ways to help the immune system home in on the cancer.
In 2011 the team developed an antibody that recognizes and binds to that target, a peptide called PR1/HLA-A2. This attack triggers destruction of acute myeloid leukemia (AML) cells by the complement system, a component of our overall immune system.
The antibody, named h8F4, became a prime candidate for a clinical trial — one that could potentially result in a new drug to treat AML. However, that step from successful preclinical research to first clinical trial is where many ideas falter and die.
“Unfortunately, advancing novel discoveries from the laboratory to drug development has been historically challenging,” says Molldrem, a professor of Stem Cell Transplantation and Cellular Therapy. “Antibodies pose their own difficulties, including a more complex and expensive manufacturing process than other types of drugs.”
“Platforms are a unique aspect of the program. We’ve embedded these industry-quality capabilities in an academic organization to allow scholars who are really good at discovery to translate their findings more systematically, rapidly and deliberately to save as many lives as possible in the next five to 10 years.”
Antibodies in orbit
Molldrem connected with , a scientist with a long record of research achievements in the pharmaceutical industry and executive director of a platform for 体育app’s called Oncology Research for Biologics and Immunotherapy Translation, or ORBIT. The platform is designed to help accelerate and execute the translation of 体育app immune system discoveries into therapeutic treatments.
ORBIT accelerated development of H8F4 by funding the start of the manufacturing process for the antibody, developing a detailed, three-year plan to bring the drug to clinic, and reaching out to potential pharmaceutical company partners.
As a result, in April, 体育app signed an agreement with the international drug company Astellas Pharma Inc., to develop h8F4, with clinical trials set for 2017.
“Jeff Molldrem’s connection with ORBIT is a good example of how the Moon Shots Program meets its promise of applying existing scientific knowledge to bring new therapies to patients at an accelerated pace,” says , co-leader of the Moon Shots Program and director of the (IACS).
ORBIT is one of 10 platforms, or research engines, built by the moon shots, which are designed to harness established knowledge and new, disruptive technologies to dramatically reduce cancer deaths through prevention, early detection and treatment. The platforms provide an empowering infrastructure of expertise and technology to support the program’s efforts.
The initial moon shots are targeting chronic lymphocytic leukemia, breast and ovarian cancer, melanoma, myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) and lung and prostate cancers. A number of additional moon shots pilot programs have been initiated.
With their expertise and capabilities in drug development, prevention, cancer genetics and proteomics, immunology, preclinical cancer modeling, and the storage, processing and use of massive amounts of medical and scientific information, the platforms are primed to deliver on the cutting edge of science and medicine.
New drugs and cellular therapies
ORBIT, IACS and the Center for Co-Clinical Trials (CCCT) and Applied Cell Therapy (ACT) are platforms devoted to novel drug development. They discover potential medicines to offer the moon shots and 体育app clinical departments and also collaborate with the institution’s investigators who have ideas for new drug targets.
The institute specializes in small-molecule drug development and functions much like a biotech company, if one was embedded in an academic institution.
Many IACS scientists honed their craft in the biotech/pharmaceutical sector and apply that insight in their collaboration with 体育app’s clinical experts.
As an example, IACS, collaborating with the CCCT platform and the , is in the final stages of mandated safety testing of IACS-10759, a novel inhibitor of a key cellular component required for energy production to which some tumors appear addicted.
Working together, the team rapidly advanced IACS-10759 through preclinical development and plans to start clinical trials in early 2016, beginning with AML.
“The drug discovery team designed, synthesized and evaluated multiple rounds of compounds, steadily improving their overall profiles over 18 months to identify a single compound to move into clinical development. IACS-10759 is in the final stages of preclinical testing leading to an Investigational New Drug submission,” says , head of Drug Discovery at IACS. “IACS-10759 starves certain vulnerable cancer cells of energy in a new way.”
In addition to AML, preclinical work on the drug indicates it might also work for some patients with lymphomas, colon, pancreatic and skin cancers, and glioblastoma.
ACT is a new platform that develops customized cellular therapies, including immune system T cells, to attack cancer, and will guide the moon shots in this promising area of research. Clinical trials of T cells genetically engineered to more efficiently find and kill cancer are in the works.
Another trial cultivates different types of immune cells, called natural killer cells, from donated umbilical cord blood and gives them to patients as immunotherapy in the Chronic Lymphocytic Leukemia Moon Shot, along with chemotherapy.
Improving an innovative combination
The CCCT focuses on how genomic alterations drive tumor growth and progression, and seeks to identify vulnerabilities that will enhance treatment. It conducts comprehensive preclinical research using patient-derived tumor models, cancer cell lines and unique engineered mouse models to position novel drugs with distinct patient populations.
In collaboration with the Melanoma Moon Shot, 体育app scientists developed a promising new two-drug targeted therapy for a specific group of melanoma patients. The dosing schedule used in a first-in-human phase I clinical trial showed promise but also significant toxicity, says , CCCT co-director.
“We’ve taken what we learned from the clinical trial back into the mouse model to develop an effective but less toxic treatment schedule,” he says.
This repeat process, from preclinical insight to clinical trial, then back to the lab to improve treatment before returning the therapy to the clinic, is a hallmark of the CCCT. The same drug combination is being tested in colorectal and pancreatic cancers.
“Based on initial clinical experience, the CCCT’s approach will likely be critical to maximizing the clinical impact of these very promising approaches by identifying safe and effective treatment regimens,” says , associate professor of and co-leader of the moon shot.
Swift, deep genomic analysis
The (CGL) is a platform that provides genomic tumor sequencing on an accelerated schedule. Samples are sequenced and analyzed within 10 to 12 weeks after submission. In addition to supplying information for an investigator’s specific project, everything is deposited into 体育app’s big data platform, where it’s available to all researchers.
“CGL provides rapid, high-quality sequencing with open access to data,” says Maggi Morgan, the platform’s scientific manager.
Earlier this summer, eight projects were in the CGL platform’s pipeline, and that number is expected to increase. Investigators in the pilot moon shot for human papillomavirus (HPV)-related cancers are using CGL sequencing results to better understand how the virus inserts its DNA into a person’s DNA, and the role that genomic integration plays in the development of cervical and head and neck cancers.
A follow-up study of nine HPV-positive and 50 HPV-negative cell lines and patient samples will further examine the role of HPV in tumor origination, patient outcomes and as a biomarker for personalized treatment.
Tumor and matched blood samples also are sent to the immunotherapy platform led by , the scientist who opened up a new way to treat cancer by unleashing the immune system to attack it.
Allison’s platform conducts preclinical and clinical research to identify and evaluate new single-agent and combination therapies, including immune monitoring of tumors before, during and after treatment. More than 60 体育app immunotherapy clinical trials for a variety of cancers rely on the platform for immune analysis.
Long-term research shows that 22% of patients with untreatable, late-stage melanoma survive 10 years or longer when treated with Allison’s drug, Yervoy.
Drugs such as Yervoy, which amp up the immune system, have shown similar improvements in clinical trials for lung, bladder, kidney, liver, head and neck and other cancers.
Allison believes combination therapies will yield even better results. The key is to identify the most promising combinations out of a multitude of potential choices.
“I think with immunotherapy drugs we’re going to succeed very quickly in improving survival in patients with a number of cancers,” Allison says. “Patients will survive decades — not just months or weeks as they did with conventional therapies.”
Homing in on protein targets
The proteomics platform identifies and analyzes the thousands of proteins in cancer cells to find the few that can be used as drug targets or biomarkers for screening or diagnosis.
“The platform is helping the MDS/AML Moon Shot understand drug resistance and identify new targets for these diseases,” says moon shot leader , professor of Leukemia.
One outcome: An agreement with drug company Amgen to provide and test proteins for a new type of therapy the company is developing to connect immune T cells to cancer cells.
Putting information to work for patients
Two other platforms are focused on efficiently gathering and managing information and combining it with medical data to improve patient care and research.
Adaptive Patient-Oriented Longitudinal Learning and Optimization (APOLLO) provides a framework to comprehensively and systematically gather relevant clinical information, tumor genomics and samples over time for each patient and to integrate it with research information. This improved system is designed to benefit individual patients and inform research for better treatment for future patients.
All these data are aggregated in the big data platform to improve physicians’ and scientists’ access to relevant information. APOLLO and big data are being piloted in the MDS/AML and Lung Cancer Moon Shots.
“The idea is to have each patient contributing to and benefiting from research,” says , co-leader of the Moon Shots Program and the APOLLO and big data platforms.
“Thanks to these platforms and our world-leading clinical trials engine, we now are positioned to precisely match any one of hundreds of novel drugs for our patients in so-called smart clinical trials,” DePinho says. “Nowhere else is there such a powerful confluence of in-depth molecular profiling, clinical data integration and myriad clinical trials.”
Prevention research and outreach
Through its Moon Shots Program, 体育app offers ways to help people stay healthy and avoid cancer altogether.
The includes smoking cessation and research programs such as ASPIRE (A Smoking Prevention Interactive Experience) — a multimedia, Web-based smoking cessation and prevention program for adolescents.
The supports legislation that bans minors from using tanning beds. And the moon shot developed a sun safety program for preschoolers called Ray and the Sunbeatables. The program is a project of the CATCH Foundation, a national organization that promotes healthy lifestyles for children. The cancer prevention and control platform supports these efforts and launches them in the community.
体育app has always been strong in developing evidence-based prevention programs, says , vice president of prevention, and it now devotes greater effort to translating those findings into public policy, patient care and education.
“Our platforms and the moon shots are central to our efforts to translate evidence-based cancer prevention to the clinic and community,” he says.
10 PLATFORMS PROPEL THE MOON SHOTS FORWARD:
Cancer genomics laboratory
|Provides rapid, high-quality genomic sequencing services and institution-wide access to genomic data|
|Proteomics||Sifts through thousands of cancer-related proteins to find those useful for diagnosis, imaging or as targets for treatment|
|Immunotherapy||Enables design of preclinical studies and clinical trials to evaluate novel immunotherapies as single treatments or in combination with other drugs|
Prevention research and outreach
|Cancer prevention and control||Develops and implements evidence-based programs involving public policy and public/ professional education, and service delivery to advance prevention, screening, early detection and survivorship|
Improving patient care and research
|Big data||Integrates 体育app’s information systems to improve patient outcomes with efficient, secure use of research and clinical data|
|APOLLO – Adaptive Patient-Oriented Longitudinal Learning and Optimization||Provides an operational framework to accelerate research-driven patient care by standardizing clinical workflows and sample collection. The goal is to ensure that high-quality clinical/research data are captured systematically over time for each patient to enhance learning and improve outcomes|
|Center for Co-Clinical Trials||Functions as an industrialized pharmacology unit to test the impact and tolerability of single drugs or combinations in appropriate preclinical models|
|Institute for Applied Cancer Science||Applies scientific knowledge of factors that drive tumor formation and progression to develop small-molecule cancer therapies for specific cancer patients, targeting areas of unmet medical need|
|Applied Cell Therapy||Innovates, develops and implements novel cell-based immunotherapies, including customized T cells to attack cancer|
|ORBIT – Oncology Research for Biologics and Immunotherapy Translation||Focuses on the rapid discovery and development of innovative monoclonal antibodies — targeted biologic drugs to treat cancer|