Perfecting the process
As it evolves from a concept to a usable tool, a cancer vaccine follows much the same course as any invention: after initial tests give a glimmer of promise, it is adapted and refined until its full potential is realized.
John Gribben, MD, PhD (center), pursues vaccine research with the help of (clockwise from bottom left) Jason Zauls; Blossom Marshall; Richard Boyajian, MN, MS, ANP; Margaret Koval; Katherine Stephans, RN, MS, NP; Lee Nadler, MD; and Zhinan Xia, PhD.
So it is with the melanoma skin cancer vaccine developed by DFCI's Glenn Dranoff, MD. Created in the laboratory and first tested in animals, this vaccine works as a kind of "truth serum" for melanoma cells, forcing them to reveal their presence to the immune system. To make it, doctors removed a portion of a patient's tumor and mixed it with retroviruses engineered to carry a gene called GM-CSF. (Retroviruses are viruses that carry their genetic material as RNA.) The viruses slipped inside the tumor cells and deposited their gene cargo, causing the cells to produce the GM-CSF protein. The tumor cells were then re-injected into the patient.
GM-CSF, researchers well knew, attracts a powerful immune attack. When investigators took tumor samples from patients and examined them under a microscope, they found that the melanoma cells were engulfed by immune-system cells — evidence of a vigorous immune response.
The results of the first human trial of the vaccine, in 1998, were so impressive that researchers have pressed ahead with efforts to make the vaccine more potent and simpler to produce, and they have extended its use to other types of cancer.
To streamline the process, researchers switched from using retroviruses to adenoviruses (weakened cold viruses) to deliver GM-CSF. The advantage is that, unlike retroviruses, adenoviruses can infect tumor cells that are not actively dividing. They also release their gene payload into cells quicker than retroviruses do and tend to be safer for patients.
"With the old method, it took three months, on average, to prepare and produce a vaccine for a patient," Dranoff notes. "Now, it takes just 10 days to two weeks."
Dranoff and his colleagues have also tested the approach in Phase I clinical trials for patients with lung cancer, ovarian cancer, and acute leukemia. Two of the trials have been completed, and they demonstrated not only that the vaccines are safe (the main aim of Phase I studies), but that they elicit an immune response in the vast majority of patients, Dranoff states.
The results of the lung cancer vaccine trial prompted a pharmaceutical firm to undertake a more advanced, Phase II trial, which confirmed the earlier findings. It's likely, Dranoff says, that the vaccine will soon be tested in a Phase III trial, which will show definitively whether it can prolong the survival of lung cancer patients.
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