Researchers covering a variety of specialties—including biology, microbiology, immunology, genomics, epigenomics, computational biology, vaccines, and medical genetics—are investigating new immune-based techniques to prevent cancer. Several cancers are ripe for immediate prevention efforts. Lynch syndrome, for one, is an inherited condition that increases risk of many cancers, including of the digestive and gynecologic tracts. Another is clonal hematopoiesis, an age-related precursor to leukemia. Cervical intraepithelial neoplasia, a third example, is abnormal growth of cervix tissue that can become cancerous.
Their strategy appears in the Sept. 16 issue of Proceedings of the National Academy of Sciences (doi:10.1073/pnas.1608077113). Although the immune system’s success in intercepting premalignancy and preventing cancer has so far been “anecdotal and isolated,” according to the article, the researchers believe the promise of immunotherapy should be a main focus of new initiatives, including the Human Vaccines Project and Cancer Moonshot program.
Scott M. Lippman, M.D., director of the Moores Cancer Center at UC San Diego Health Sciences in La Jolla, Calif., and co–senior author of the report, said he believes a key to their success will be the expertise assembled to tackle complex issues. “By pulling together a team . . . with diverse areas of expertise—instead of the same groups that always work together—we see the potential to cure patients [who] were incurable before. We still have a ways to go, but [judging from] the success of the vaccine for preventing human papillomavirus [HPV], we believe that . . . the eradication of other cancers can happen by stopping them before they become cancer.” HPV infections can lead to anal cancer and cancer of the throat, as well as cervical, vaginal, and vulvar cancers in women, and penile cancer in men.
Lippman said vaccines and immune checkpoint inhibitors are two techniques researchers are exploring to prevent cancer. “The success of immune checkpoint inhibitors has been a game-changer for a number of patients, producing deep and durable clinical responses in a variety of malignancies, particularly high-mutational types.” Certain proteins stop immune cells, such as T cells, from killing cancer cells. Immune checkpoint inhibitors are drugs that counteract those proteins.
“Curing cancer that has already formed is much harder than preventing cancer in the first place. That’s why this is so important.”
Lippman said the initial focus will be on genetic high-risk groups: people with a familial propensity for developing a specific cancer because they often have an identifiable mutational signature. “We now know and can identify the risk groups that exist in all cancer types.”
Elizabeth M. Jaffee, M.D. is co–senior author, cochair of the Cancer Moonshot Blue Ribbon Panel, and deputy director of the Kimmel Center at Johns Hopkins University School of Medicine in Baltimore. She said the idea of developing cancer prevention strategies isn’t farfetched; the body’s immune system intercepts premalignancies and prevents cancer every day. “This natural ability is what we want to leverage.”
Jaffee said several studies suggest that developing immune-based approaches to intercept cancer development should be possible. “These findings address two critical questions required to develop immune approaches for prevention. The first is, what are the best antigens? The second is, when is the best time to vaccinate against a nonviral cancer? We know that once someone is exposed to causative agent (HPV), it is harder to vaccinate successfully.”
With the advent of genetically engineered mouse models, researchers have started to develop vaccines that target the products of the earliest mutations. “We have published the success of targeting mutated Kras as long as we also deplete or minimize the influx of inflammatory cells that are pro–cancer development,” Jaffee said. “These models also have been used to demonstrate that as soon as the normal cell undergoes its first genetic alteration, this creates a premalignant microenvironment that attracts inflammatory cells and other stromal cells.”
“This understanding has shown us that we need to deal with the early inflammation with immune approaches in order for a cancer-targeting vaccine to work,” Jaffee said. Still needed, she argued, are biomarkers that can be detected with noninvasive methods to determine when someone has had the first genetic changes; identification of the best antigens associated with that genetic change; safe methods to vaccinate with antigen delivery systems; and adjuvants that alter the inflammation so that it helps with an anticancer response.
Jaffee is encouraged because the science behind cancer development and the immune response to the disease is progressing rapidly. “We are now able in preclinical models to study ways to intercept cancer development. We hope to be able to conduct small studies in subjects at high risk, such as with families with inherited mutations in the BRCA1 and BRCA2 genes, in the next 3–5 years to determine the feasibility of accomplishing immune prevention.” Besides breast cancer, BRCA1/2 mutations increase the likelihood that someone will develop ovarian and pancreatic cancers.
Anirban Maitra, M.B.B.S., professor of pathology and translational molecular pathology at the University of Texas M. D. Anderson Cancer Center in Houston, applauds the initiative. “There are opportunities with patients in high-risk groups that are ripe for this approach and receive preventative measures before the cancer develops,” Maitra said. “It would be a huge advance if we can intervene and blunt the progression to cancer by trying some of these approaches.”
Besides the technological advances making cancer prevention possible, Maitra mentioned an even more important practical consideration. “We focus so much on therapy of established disease, but curing cancer that has already formed is much harder than preventing cancer in the first place. That’s why this is so important.”