New ‘immunoprofiler’ initiative will advance drug discovery
UC San Francisco scientists have formed an innovative research alliance with three global pharmaceutical companies to improve patients' responses to cancer immunotherapy and to increase the effectiveness of immunotherapy across a wider range of cancer types. In 20 to 40 percent of patients with certain cancers, immunotherapy can trigger dramatic remissions, but despite recent advances most patients do not experience these profound responses, and many do not respond at all. In some cases, autoimmune side effects may also result. The sources of these variations are, as yet, unknown.
Known as the UCSF Immunoprofiler, the two-year project is backed by investments from UCSF, AbbVie, Amgen, and Bristol-Myers Squibb, totaling over $10 million in the aggregate and supporting the collection and analysis of at least 500 tumor samples from more than 10 different forms of cancer. Over the course of the project, extensive information on immunologically relevant characteristics of these tumors will be gathered, and these data will then be made easily accessible to all parties via a purpose-built, UCSF-designed data browser.
The new initiative is unusual, said principal investigator Matthew "Max" Krummel, PhD, professor of pathology at UCSF, because of an explicit agreement among the parties to "share and share alike." UCSF technically "owns" the project, and each of the three companies is contributing only a portion of the cost to perform the necessary biopsies and subsequent analyses, but all parties will have access to the complete dataset.
"It's rare to see three large, competing companies contribute substantial funds toward something that they'll all be able to use equally," said Krummel. "We at UCSF and all three corporate project participants are absolutely on a level playing field in our ability to see and make use of all the data, because we all acknowledge that's what it will take to find cures for more people."
The remarkable successes of immunotherapy, as well as its limitations, have underscored the need to view cancer through a "new lens" that takes immunology into account, said Krummel, a member of the UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) as well as of UCSF's branch of the Parker Institute for Cancer Immunotherapy.
"At one time, physicians and scientists alike viewed cancer mostly in terms of its tissue-of-origin — as breast, lung, or kidney cancer, for example. And we've also used an 'oncogene lens,' focusing on the genetic mutations that drive malignancy and metastasis," Krummel said. "But with the advent of immunotherapy we've learned that there are also crucial differences among tumors and among patients in the strength and durability of the immune response, and we need a deeper understanding of this dimension."
In addition to Krummel, UCSF leaders of the Immunoprofiler project include Lawrence Fong, MD, the Efim Guzik Distinguished Professor in Cancer Biology, co-leader of the HDFCCC's Cancer Immunotherapy Program, and co-director of UCSF's Parker Institute; Adil Daud, MD, professor of medicine and director of Melanoma Clinical Research at HDFCCC; and Chloe Atreya, MD, PhD, assistant clinical professor of medicine and HDFCCC member.
Roughly 20 additional UCSF investigators from clinical and basic science departments are also participating, and the entire project is being coordinated by Vincent Chan, PhD, a senior scientist and project manager in the Department of Pathology.
The UCSF researchers will collect samples, each containing several million cells, of several types of melanoma and breast, kidney, and colorectal cancers; head and neck cancers; pancreatic cancer; liver cancer; lung cancer; bladder cancer; and prostate cancer. They will then use several advanced technologies to arrive at a comprehensive immune profile of the cancer tissue, including:
- A composition analysis step based on flow cytometry, a technology that measures the quantities and relative abundance of various cell types within a given tissue and their gene-expression, will establish how many immune cells of various types are within a tumor and how they compare to cancer cells and support cells. With this approach, UCSF scientists hope to gauge the robustness of the immune response in various patients and tumor types.
- The quantitative information offered by composition analysis will be complemented by spatial mapping, an imaging technique that will show where immune cells are and how deeply they have infiltrated tumors.
- Whole-exome sequencing will reveal the genetic mutations within tumors, with the aim of discovering genetic factors that may enhance or inhibit the immune response.
All measures will be done with fresh samples, sometimes within hours of collection, and will be performed following strict and consistent quality control. The program's emphasis on the way it processes tumors is consistent and standardized across all cancer types, in both treated and untreated tumors, which allows clinicians the ability to cross-compare and find common properties.
Participants in the Immunoprofiler project will be able to easily search and analyze the assembled data using "Timur," a new browser developed at UCSF. By discovering new relationships among these various sets of data, the companies aim to create new immunotherapy drugs, but also to advance precision immunotherapy by selecting patients with characteristics that predict response for both existing therapies and clinical trials of novel drugs.
The alliance of UCSF and the three industry participants was developed and launched with the assistance of UCSF's Office of Innovation, Technology and Alliances, which is responsible for coordinating the University's efforts in building collaborations that focus on translating the university's cutting-edge science into therapies and products that directly benefit patients worldwide.
"The way this partnership blossomed is that everybody wants this sort of data," Krummel said. "If we can learn what kinds of immune cells are present in tumors, and how those correlate with gene expression genes express proteins, which are targets of the immune system — we'll have a better idea what might be lacking in patients who don't respond. For those who do respond, we now have a chance to learn what they are expressing that's special."
UC San Francisco (UCSF) is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with nationally renowned programs in basic, biomedical, translational and population sciences; and a preeminent biomedical research enterprise. It also includes UCSF Health, which comprises top-ranked hospitals, UCSF Medical Center and UCSF Benioff Children's Hospitals in San Francisco and Oakland – and other partner and affiliated hospitals and healthcare providers throughout the Bay Area.