Novel design stimulates a coordinated attack by T and natural killer cells that prevents metastasis in mice
By Lindsay Brownell
(BOSTON) — When normal cells experience DNA damage, they present proteins on their outer surfaces that serve as a “kill me” signal to both T cells and natural killer (NK) cells, members of the immune system that come and destroy the labeled cells. Some cancer cells, however, have figured out how to clip those proteins off of their surfaces, allowing them to evade detection by the immune system’s search-and-destroy team.
A team of scientists from the Wyss Institute and Dana-Farber Cancer Institute (DFCI) led by Kai Wucherpfennig, M.D., Ph.D. has developed a novel cancer vaccine that targets this process by inducing the body to manufacture antibodies against the “kill me” proteins. This approach effectively locks them in place on cancer cells’ surfaces, preventing the cells from destroying them. That, in turn, makes them available to trigger killing responses from both T and NK cells.
The team demonstrated the vaccine’s usefulness in mice with melanoma and triple-negative breast cancer, both of which frequently metastasize even after a patient has surgery to remove existing tumors. They surgically removed the animals’ tumors, then administered the vaccine, and saw that the rate of metastasis was greatly reduced. When they re-challenged some of the vaccinated animals with cancerous tumors four months later, none of them developed the disease.
The vast majority of other cancer vaccines must be personalized for each individual patient because they are designed to target specific molecules on the surface of a patient’s tumor. This vaccine, in contrast, can be used “off-the-shelf” without the need for a lengthy and expensive personalization process, because the “kill me” protein is present in most cell types. Also, because it recruits both T cells and NK cells, it can potentially treat cancers that are resistant to other types of cancer vaccines.
“This approach has great potential to treat patients suffering from a number of types of cancer, and really demonstrates the power of combining fundamental immunology insight with new technologies developed at the Wyss,” said co-author Dave Mooney, Ph.D., who is a Core Faculty member of the Wyss Institute and the Robert P. Pinkas Family Professor of Bioengineering at Harvard’s John A. Paulson School of Engineering and Applied Sciences (SEAS).
Additional authors of the paper include first author Soumya Badrinath from DFCI and Harvard Medical School (HMS), and co-second-authors Maxence Dellacherie and Aileen Li from the Wyss Institute and SEAS, and Shiwei Zheng from DFCI; Xixi Zhang and Sabrina Haag from DFCI and HMS; Miguel Sobral from the Wyss Institute and SEAS; Jason Pyrdol, Kathryn Smith, Yuheng Lu, and Guo-Cheng Yuan from DFCI; Hamza Ijaz from the Wyss Institute; Fawn Connor-Stroud from Emory University; Tsuneyasu Kaisho from Wakayama Medical University; and Glenn Dranoff from the Novartis Institutes for BioMedical Research.
This research was supported by James and Tania McCann, the Parker Institute for Cancer Immunotherapy, the Ludwig Center at HMS, NIH grants R01 CA238039, R01 CA251599, P01 CA163222, P01 CA236749, R01 CA234018, and R01 CA223255, a sponsored research agreement with Novartis, a U.S. Department of Defense fellowship (DOD CA150776), and a Baruj Benacerraf Fellowship in Immunology.