How a clinical trial for a cancer-fighting vaccine came to include chordoma patients
Last month, the National Cancer Institute (NCI), for the first time ever, opened a therapeutic vaccine trial to chordoma patients, expanding an ongoing phase 1 clinical trial of a vaccine that targets the brachyury protein in a variety of cancers. How we got to this milestone is a story years in the making, combining hard work, extraordinary collaboration and fortuitous connections, and made possible in large measure by the work of the Chordoma Foundation and its many supporters.
At the NCI’s Laboratory of Tumor Immunology and Biology and its Clinical Center in Bethesda, Maryland, a cadre of dedicated investigators have pioneered efforts to use a type of immune therapy called therapeutic vaccines to battle cancer. One particularly promising focus has been on vaccines targeting brachyury, a protein that has been found to be over-expressed in a variety of tumor types, including breast, colon, lung and prostate cancers and chordoma, but not generally found in normal tissues. Brachyury is highly expressed in nearly 100% of chordoma tumors, making it a defining marker for this rare and often-fatal disease.
The brachyury protein plays an important role in normal embryonic development. In human embryos, it helps form the notochord, a cartilage-like structure that runs from head to tail that is eventually replaced by the spine. Once the notochord regresses, brachyury has done its job and stops being expressed. But somehow, in certain cancers, cells find a way to switch the brachyury protein back on, reversing the normal embryonic process and contributing to abnormal growth.
NCI investigator Claudia Palena, PhD has studied brachyury and its potential use as a target for immunotherapy in various cancers for many years. In 2007, she and her colleagues discovered that brachyury is switched on in a variety of cancers. Later, in laboratory experiments she was able to coax immune cells to destroy those brachyury-expressing cancer cells. Because brachyury is not expressed in normal cells, Dr. Palena reasoned that training the immune system to hunt for cells that express brachyury could result in the immune system destroying a tumor while sparing normal tissue.
Knowing the importance of the brachyury-chordoma link, in 2007 Chordoma Foundation Executive Director Josh Sommer got in touch with Dr. Palena to explore whether her work could be applied to chordoma. In the years since, the Foundation has provided chordoma cell lines for Dr. Palena’s research and included her as a speaker at the Foundation’s Research Workshops, where she has made valuable connections both with experts in chordoma and brachyury biology.
A Vaccine Goes to Trial
To translate findings from the lab into treatments for patients, the NCI tumor immunology researchers are collaborating with GlobeImmune, Inc., a biopharmaceutical company based in Louisville, Colorado that develops and tests promising immunotherapies for cancer and other diseases. NCI and GlobeImmune have worked together under a Cooperative Research And Development Agreement (CRADA) to create several human vaccines that stimulate the immune system to fight cancer cells, including one called GI-6301, based on Dr. Palena’s research, that trains the immune system to target cells that express brachyury.
In 2012, the team began a phase 1 clinical trial to test the safety of the heat-killed recombinant yeast-brachyury GI-6301 vaccine in human subjects – the only therapeutic trial targeting brachyury ever conducted. Led by the NCI’s Dr. James Gulley, the trial started with patients with more common cancers so they could enroll a sufficient number to get meaningful results. The enrolled patients – about 14 to date – receive doses every few weeks until the disease progresses. Initial clinical findings suggest that patients are tolerating the vaccine well, with limited, minor adverse reactions such as tenderness at injection sites and brief, flu-like symptoms.
“So far we’ve shown that you really can target brachyury immunologically in the laboratory,” said Dr. Gulley. “Our goal now is to see if we can replicate what we saw in laboratory experiments, where we found that we could generate immune responses against brachyury, and that those immune responses are capable of killing tumor cells. If successful, this could have a potential application for a broad range of tumors, including chordoma.”
Opening the Trial to Chordoma Patients
As the NCI and GlobeImmune continued this trial to assess the safety and efficacy of the GI-6301 vaccine, several key connections were falling into place. Coincidentally, at an NCI conference on another cancer topic, Sommer met Dr. Christopher Heery, another member of the Laboratory of Tumor Immunology and Biology clinical trials group and colleague of Drs. Gulley and Palena, who was involved on the clinical side of the GI-6301 studies.
Dr. Heery agreed that including chordoma patients in the trial would be beneficial, and Sommer felt certain that the Chordoma Foundation could help find patients to participate.
Dr. Heery introduced Sommer to Dr. Timothy Rodell, president and CEO of GlobeImmune, to discuss opportunities for the Chordoma Foundation and GlobeImmune to work together on this trial and perhaps others. Dr. Rodell attended this year’s Chordoma Research Workshop, where he participated on a panel about drug development. Drs. Palena and Heery also presented at this meeting.
From these interactions, Dr. Rodell learned a lot about chordoma. “There really is no good treatment other than surgery and radiation, and often by the time these tumors are discovered, these are no longer capable of curing the patient,” he said. “We realized that we might be able to help these patients, because if we can generate a protective immune response to brachyury, we may be able to slow down or stop the progression of chordoma.”
Collectively, the NCI, GlobeImmune and the Foundation agreed that now was the time to open up this phase 1 study to chordoma patients.
“We hadn’t been seeing or treating a lot of patients with chordoma at the NCI, but with the interest in brachyury in our lab and the development of this vaccine – and given that this patient population really has very few treatment options – we thought this made a lot of sense,” Dr. Gulley explained. “And everything really fell into place.”
This winter, the trial was officially expanded to include slots for up to ten chordoma patients. The Chordoma Foundation quickly posted information on the study on its website, and within just a few weeks, Dr. Heery received inquiries from more than 30 patients.
“With the Foundation’s help, we were able to fill those ten spots much more quickly than we had for patients with other tumors,” noted Dr. Heery. “This was terrific, because the faster we can enroll patients onto a trial, the more quickly we can gather data and observations. It’s good to know that if, in the future, there is a larger phase 2 trial, the Chordoma Foundation could help mobilize patients quickly enough to fill it.”
A Notable Milestone
The enrolled patients will visit the National Institutes of Health Clinical Center in Bethesda, Maryland to receive the vaccine every two weeks for the first three months, then once a month after that as long as their disease remains stable. (The NCI contributes toward travel and lodging.) Over the coming months and years, the investigators will collect data on the safety and impact of the vaccine in these patients.
Because of the limited number of chordoma patients and the relatively slow growth of the disease, gathering sufficient data to determine how best to proceed will take time as well as the input of other experts in the field. Realistically, an FDA-approved treatment is still many steps – and years – away. But as the first therapeutic vaccine clinical trial to include chordoma patients, it’s an important start – and a milestone for the chordoma community.
“We’re very excited about the future prospects of targeting brachyury,” said Dr. Jeffrey Schlom, who heads the Laboratory of Tumor Immunology and Biology. “Our lab is also studying how to enhance this vaccine’s efficacy by combining it with other types of therapy such as radiation, chemotherapy and targeted therapies. In the future, patients with chordoma and other tumors could really benefit from these synergies.”
Dr. Rodell and GlobeImmune are also enthusiastic about the possibilities. “This is a terrific partnership between a patient advocacy group, a government agency, and a company with a product that can potentially help. The Chordoma Foundation has done such a great job bringing attention to this little-known disease and to this trial, and they’ve really helped bring together all of the experts and stakeholders in this field. It’s an exciting thing to be involved in, and we just hope that it plays out in a way that we’ll be able to help people.”