Clinical Trials Network Aims to Strengthen Cancer Immunotherapy Pipeline ► NCI Cancer Bulletin for February 21, 2012 - National Cancer Institute

Clinical Trials Network Aims to Strengthen Cancer Immunotherapy Pipeline

A T cell (green) killing a cancer cell (blue)

Later this year, the first clinical trials will be launched under a new NCI-funded initiative to spur the development of cancer treatments that work by revving up the immune system's response to tumors. The Cancer Immunotherapy Trials Network (CITN) includes the foremost researchers in cancer immunotherapy from 27 top U.S. cancer centers and universities who are working collectively to identify promising agents and to formulate and run the trials in which they will be tested.
The first immunotherapy agents to enter CITN trials have been selected, and several trials are moving closer to launch. The first two agents, interleukin-15 (IL-15) and CP-870,893, were selected "based on broad consensus and the field's collective experience and 'wisdom,'" explained Dr. Martin A. "Mac" Cheever, the CITN's principal investigator and director of the CITN Central Operating and Statistical Center (COSC), located at the Fred Hutchinson Cancer Research Center in Seattle.
All CITN trials will be phase I or phase II trials. The network's aim is to establish a pipeline of agents to test in the large phase III trials that ultimately determine whether a new treatment will make it to the clinic, said Dr. Cheever, who, along with co-investigator Dr. Kim Margolin, runs the network's day-to-day operations. Correlative science studies, such as those that look for biomarkers that indicate which patients are likely to respond to a treatment and that assess the extent to which treatments stimulate an immune response, will be built into the trials. These studies will be performed under the direction of Dr. Cheever's other co-investigator, Dr. Mary L. "Nora" Disis.
"The goal," Dr. Cheever explained, "is to design trials that can quickly demonstrate proof of concept and patient benefit, ultimately helping to define a path toward regulatory approval."
The Field Comes Together
The concept of using a patient's own immune system to destroy tumors has enticed researchers for decades. Until quite recently, however, regimens focused on boosting patient immune responses to their own cancers, although effective in some patients, have failed to produce many broadly effective treatments. (For years, blood and bone marrow transplants, which restore or replace patients' immune systems, have been highly effective treatments for leukemia and lymphoma, and some monoclonal antibodies, such as trastuzumab [Herceptin], are believed to work, in part, by stimulating an antitumor immune response.)
But a confluence of events has propelled the field forward, said Dr. William Merritt of NCI's Division of Cancer Treatment and Diagnosis (DCTD) and NCI program director for the CITN. Chief among them has been the "vastly improved understanding of tumor immunology and the number of agents known to modify the immune response to tumors," Dr. Merritt said.
A major tipping point was the first NCI-sponsored Immunotherapy Agents Workshop, held in 2007, which brought together leading cancer immunologists to identify the most promising immunotherapy agents for further study and development. From more than 120 candidates, 20 agents were chosen. NCI held additional workshops to help further prioritize agents for development, with an emphasis placed on agents with the greatest potential for broad usage by multiple investigators in different regimens, Dr. Cheever explained.
"Everything that's happened progressed from that first workshop," Dr. Cheever added.
Not long after the series of prioritization workshops, a group of immunotherapy researchers approached then-NCI Director Dr. John E. Niederhuber and urged him to increase the institute's support for efforts to facilitate the development of high-priority agents, Dr. Merritt recalled. Dr. Niederhuber and DCTD leaders agreed, and the CITN concept was born.
In addition, the Food and Drug Administration last year approved two cancer immunotherapies: ipilimumab (Yervoy) to treat advanced melanoma and sipuleucel-T (Provenge) for the treatment of advanced prostate cancer.
The impact of those approvals was enormous, said Dr. Jedd Wolchok, a CITN investigator at Memorial Sloan-Kettering Cancer Center. "For pharmaceutical companies and the industry to see a successful immunotherapy that can be administered in a doctor's office has really changed the field," Dr. Wolchok said.
Researchers have historically had difficulty gaining access to the diverse array of investigational immunotherapy agents that have shown significant promise in laboratory testing as well as early phase clinical trials. In some cases, the company that developed an agent prioritized its development for a disease other than cancer, or the agent needed to be developed in combination with other agents as part of a multi-component regimen.
Availability has "definitely been a major bottleneck," said Dr. Thomas Gajewski, a CITN investigator at the University of Chicago Medical Center.
That is now beginning to change. Numerous companies are more interested in making agents available for study and developing new investigational immunotherapy agents, Dr. Wolchok said. Several are even establishing immuno-oncology departments.
"And we, as a community of cancer immunotherapy investigators, need to be prepared to help them test [these agents] in a thoughtful way," he continued. "And that's where the CITN can play a major role."
Collaboration Pushing Science Forward
Having a network of investigators and centers "means that we can initiate trials in a timely way," Dr. Merritt explained. "We don't have to wait for individual grants to get funded, with  [researchers] doing their own trials at their own institutions." And having multiple centers involved in each trial, he added, will significantly improve how quickly trials can accrue patients and be completed.
But the potential benefits go well beyond speedier trials, Dr. Gajewski stressed.
"With a network, data are shared, and data management and statistical analysis are all uniform," he explained. "Before data are published, we'll all be exchanging this information, so the cross-fertilization potential will be huge. Ideas will move much more readily among investigators and among projects."
The CITN has benefitted greatly from the support of staff from another NIH-funded clinical trials initiative run out of Fred Hutchinson, the HIV Vaccine Trials Network supported by the National Institute of Allergy and Infectious Diseases, Dr. Cheever noted. And potential research collaborations are already being discussed between the CITN and a similar international cancer immunotherapy trials network led by Dr. Wolchok, the Cancer Vaccine Collaborative.
The CITN is funded for 5 years, Dr. Cheever said, and he has had encouraging discussions about obtaining additional funding from industry and philanthropy groups.
Getting the initial trials up and going is an important step, Dr. Merritt said. But it's just the beginning. "Several CITN working groups and its steering committee are now discussing the trial concepts for the next group of agents to move forward," he noted. "I'm very encouraged by the progress so far."
—Carmen Phillips

The First Agents
Numerous types of immunotherapeutic agents have been developed, including T-cell and NK-cell growth factors like IL-15, others that stimulate T cells or activate dendritic cells, so-called immune checkpoint inhibitors like ipilimumab, and others that inhibit or neutralize factors secreted by tumors that suppress the immune system.
The first two agents to be tested in CITN-led trials, selected from the 20 identified in the 2007 workshop, will be IL-15 and a dendritic cell-activating  monoclonal antibody called CP-870,893.
The first human trial of IL-15 was recently launched at NCI by Dr. Thomas Waldmann, who co-discovered IL-15 nearly 18 years ago, and Dr. Kevin Conlon. For these first trials, NCI is manufacturing IL-15 at its drug production facility on the NCI-Frederick campus. The CITN trial of IL-15 is separate from Dr. Waldmann and Dr. Conlon's trial, but CITN investigators are working closely with Dr. Waldmann on IL-15's development, Dr. Cheever noted.
The Pfizer-developed CP-870,893—which targets the CD40 antigen on certain immune cells—has already shown efficacy in a small phase I trial of patients with advanced pancreatic cancer. The CITN trial, to be led by Dr. Robert Vonderheide of the University of Pennsylvania, will test the CD40-targeted antibody as a presurgical treatment in patients with operable pancreatic cancer.
Planning and negotiations are underway to test several other treatment strategies, including the cytokine IL-7 and an agent in development that targets the immune checkpoint protein PD-1 on the surface of certain immune cells.

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