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Wash U Team Aims to Develop Sequencing-Based Individualized Vaccines for Breast Cancers


By Monica Heger

Taking personalized medicine to the extreme, researchers at Washington University are set to test a hypothesis that sequencing patient tumors can guide the development of individualized cancer vaccines.

Under a five-year, $6.5 million grant from the Susan G. Komen for the Cure foundation (CSN 4/19/2011), the researchers will test the approach in animal models, with the hope of beginning human trials for the vaccine within the next two years.

Led by William Gillanders, a professor of surgery, and Ted Hansen, a professor of pathology and immunology, the team will perform either whole-genome sequencing or whole-exome sequencing of the patients' tumors and matched normal samples. They will then analyze the data, choosing only non-synonymous mutations from which to select tumor-specific antigens that can form the basis for a vaccine.

Gillanders said that cancer tumors typically contain between 30 and 50 tumor-specific antigens, so he and his colleagues will create a polyepitope DNA vaccine — a vaccine with all the different tumor-specific antigens — that will contain "fragments from each individual mutated protein" for individual patients.

He added that they will either incorporate all the patient's tumor-specific antigens, or will use an algorithm to choose the top 30.

Incorporating that many tumor-specific antigens into one vaccine will increase the chances for success, said Gillanders. For example, if an individual has "50 candidate, unique tumor antigens, the immune system may not be able to target all of them," Gillanders said. "But, if we integrate all of them [into one vaccine], the immune system can pick and choose which ones it wants to attack."

Currently, the team is still completing its preclinical work, testing the approach in animal models. Gillanders said he is collaborating with Timothy Ley, associate director of Wash U's Genome Institute, who has sequenced a mouse model of acute promyelocytic leukemia. Additionally, under the Komen grant, the team is sequencing mice with an over-expressed HER2 gene that develop spontaneous breast cancer. In both cases, the researchers will create vaccines based on the mutations in the mouse model, and test their efficacy in mice.

Gillanders said he expects to start human trials within the next two years, after the animal studies are completed.

The researchers hope to eventually recruit 15 and 30 women for a phase I clinical trial, which will not be limited to any specific subtype of breast cancer. In the trial, each patient will be given the vaccine after standard treatment in the hope that it will help prevent recurrence of the disease.

Of particular concern is whether the sequencing and vaccine production can be done in a time frame that is reasonable to treat a cancer patient. Gillanders said that he is hopeful that it will be possible, citing Ley's recent JAMA publication that found that whole-genome sequencing could be done in real time to guide patient treatment (see story, this issue).

While the current plan calls for the use of whole-genome sequencing, said Gillanders, since the team is choosing only mutations that result in an amino acid change, they are also considering using whole-exome sequencing, since it is the less expensive option.

For the clinical trial, the vaccine will be given to patients after they have undergone standard care — including surgery, chemotherapy, and radiation — and are declared disease-free.

Following initial diagnosis, a biopsy of each patient's tumor will be taken, and the team will then do the sequencing, analysis, and vaccine development while they undergo treatment.

"When the patient becomes disease free after the treatments, there is a window of opportunity to treat the patients with the vaccine that may be protective," Gillanders said.

In the future, it is possible that the vaccine could be given in conjunction with chemotherapy and radiation, or even in place of those treatments, but the team is first testing it for its ability to prevent recurrence.

Gillanders said that aside from the preclinical work, the team is figuring out the different regulatory requirements it will have to meet before doing the trial. Not only is using next-gen sequencing in clinical trials still very new, but so is testing DNA vaccines in humans, he noted.

One open question is whether the trial should be done in a CLIA-certified laboratory.

Gillanders said that for the development of a commercial vaccine, sequencing would have to be done in a CLIA lab, but it is unclear whether that would be the case for the clinical trial. The team is currently reviewing this issue with regulators, he said.

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