Team awarded $4.4 million from the National Cancer Institute for pioneering immunogenic cancer research

Harnessing new technologies of high-throughput screening and large-scale public data mining to find new immunotherapy targets
Dr. Martin McIntosh
Dr. Martin McIntosh

SEATTLE – Scientists at Fred Hutchinson Cancer Research Center have received $4.4 million over four years from the National Cancer Institute to pioneer an ambitious new way to harness the power of the adaptive immune system to control cancer.

The team, led by Martin McIntosh, Ph.D., head of the Computational Biology Program at Fred Hutch, is using high-throughput technology and emerging public data resources to help identify hundreds of proteins as possible immune targets and verify which ones might be immunogenic, i.e., capable of provoking an immune response in the body and therefore potentially useful in immune-based therapies.

A variety of molecular alterations in cancer cells may result in the expression of proteins that are unique to tumors. These proteins make attractive targets for a variety of therapeutic approaches because of their potential to be targeted without adversely affecting normal cells. McIntosh’s effort, however, is focused on using these proteins for therapies that will harness patients’ immune systems to control cancer.

A major challenge in identifying these targets is distinguishing which proteins are truly altered in cancer cells and that are not present in healthy tissue. “What we’re doing is finding what could be hundreds of possible cancer-specific proteins, but we do not know whether they are likely to be useful for immune-based therapy until we find out whether the body recognizes them as foreign,” McIntosh said. “We do this by experimentally testing each predicted protein to see if we can observe an immune response in a cancer patient whose tumor harbors one of these proteins. Experimental verification is necessary because, although the Human Genome Project can guide us to what a healthy genome sequence looks like, there is no existing data resource yet telling us what proteins exist, or do not exist, in the body of a healthy individual.”

The team is taking a new approach by surveying potential therapeutic targets in a comprehensive manner, using new high-throughput genome-sequencing methodologies that can sequence those RNAs that are actively being translated into proteins. They then integrate these data with public data derived from large-scale studies of cancer, such as The Cancer Genome Atlas and other public data resources, to help predict which proteins are possibly unique to cancer cells. They intend to identify the immune repertoire for ovarian and lung cancers, among others.

One of the focal points of the research is to identify tumor antigens in lung cancer patients who are being treated with newly developed therapies that help the adaptive immune system fight the cancer.

Many cancers develop the ability to suppress, or inhibit, the adaptive immune system, and thus avoid destruction. Recent studies have shown that a sizable number of patients with advanced lung cancer undergo a dramatic improvement when they are treated with drugs that prevent T-cell inhibition and promote programmed cell death, or apoptosis.

Laura Chow, M.D., assistant professor of medicine at the University of Washington, is co-author of that study, and she is currently working on other clinical trials at Seattle Cancer Care Alliance to test this approach in patients with lung and other cancers.

“It is clear that a number of people have mounted an immune response to lung and other cancers and these new therapies allow the T cells to do their job better. It would help improve our ability to understand how cancer avoids immune-surveillance and also design better treatment and prevention strategies if we knew which proteins were being recognized by T cells,” she said.

The identification of an immunogenic protein is not on its own sufficient to develop a therapy. Cancer is complex, and solid tumors, like those of the ovary or lung, are in fact a mixture of cell types, not all of which are cancer cells. Non-malignant cells may also have altered proteins that are recognized as foreign. As such, the next research step is to confirm that the immune response is directed specifically against cancer cells and not some other non-malignant but cancer-associated cell types. Once these cancer-specific immunogenic proteins are identified, a number of therapeutic approaches may be possible, including adoptive T-cell therapy, tumor vaccines or antibody-based methods that target the protein and destroy the cancer.

The project includes a cross-disciplinary group of researchers at Fred Hutch and UW. Other members of the team include co-principal investigator Edus “Hootie” Warren, M.D., Ph.D., and co-investigator Stan Riddell, M.D., both immunologists in the Fred Hutch Clinical Research Division, who are world-leading experts in the development and use of immune-based therapies to treat cancer; David Koelle, M.D., a professor in the Division of Allergy and Infectious Diseases at UW, who has expertise in evaluating the immune response; and David Morris, Ph.D., professor of biochemistry at UW, who has expertise in capturing and measuring RNAs that are being translated into proteins.

The grant complements one recently awarded by the NCI to another team of Fred Hutch researchers led by Christopher Kemp. Ph.D., a member of the Human Biology Division, and Carla Grandori, M.D., Ph.D., a research associate member of the Human Biology Division, who are also using high-throughput technology along with RNA interference to rapidly test thousands of genes in patient-derived tumor cells to identify new gene targets that may be highly specific to that patient’s tumor.

Kristen Woodward