A first of its kind scaffold vaccine
For cancer immunologists who have long envisioned a vaccine that would train the immune system to rid itself of cancer, Provenge, the first therapeutic cancer vaccine to receive FDA approval in 2011, is a milestone worth celebrating. Now, David Mooney, PhD, a materials scientist and engineer at the Wyss Institute for Biologically Inspired Engineering and Harvard School of Engineering and Applied Sciences, is pushing the envelop even further with an innovative scaffold vaccine that he and DF/HCC colleagues are working to bring to clinical trials this year.
The scaffold vaccine builds on the foundation of Provenge, which contains dendritic cells that recognize abnormal or infectious cells. The vaccine is tailored to recognize a patient’s own cancer in a technological tour de force. The patient’s dendritic cells are removed and shipped to a facility where they are expanded. This large dendritic cell population is exposed to antigens from the patient’s tumor, along with adjuvant factors that stimulate dendritic cells by mimicking the inflammatory properties of bacterial and viral DNA. The dendritic cells do what they normally do in the body when they encounter a tumor cell, explains Mooney. They lyse the tumor cell and display its telltale antigens like flags over their heads. These antigen-presenting dendritic cells are then returned to the clinic and infused into the patient. Once back inside the body, the dendritic cells perform their usual duties after an encounter with suspicious cells. They travel to lymph nodes to “educate” immature T cells about the tumor cell. These activated T cells then stream through the body on search and destroy missions, and they retain long-term memories of this lesson for future encounters with similar cells. In this way, the dendritic cell vaccine activates a potent cytotoxic T cell response that can slow tumor growth or destroy the tumor.
“That’s a lot of back and forth, and some of the key biology happens outside the body,” says Mooney. “Our idea was to move all that biology back inside the patient.” Instead of removing dendritic cells to an external environment, he implants a porous disc the size of an aspirin tablet under the skin that will attract the endogenous dendritic cells inside. Made of biodegradable material similar to dissolvable sutures, the sponge-like scaffold has large enough pores for immune cells to enter.
The scaffold vaccine is designed to take advantage of the body’s natural immune system. The device is infused with tumor antigens, which entice dendritic cells inside, and with adjuvant factors, which stimulate the dendritic cells to become more active. The dendritic cells process the antigens and leave for the lymph nodes to activate T cells. This interaction occurs over a period of weeks while the device dissolves. Compared to the mere hours of interaction following a typical vaccine’s injection, this longer-term exposure produces a powerful vaccine. “We had hoped to see responses in the mice that were similar to those we saw in laboratory cultures,” says Glenn Dranoff, MD (DFCI), who is testing this scaffold vaccine in mouse models of melanoma. “But the response was much more potent, not just a slowdown of the tumor but complete regression.” In the mouse, the researchers put implanted two discs at different sites about a week apart – like booster shots. They may implant four in human trials, a month apart.
There will be more examples of materials science and engineering experts working closely with immunologists in coming years. “It’s important to know how to use specific cells and signals to regulate the immune response in the way you’d like,” says Dranoff, “but we’re also learning that the way you administer a vaccine matters. Coupling how the immune system works with knowledge of how to control it in time and space when delivering biologically relevant factors? Now that’s the beginning of a wonderful relationship.”