Column: Translating Cancer Research in Mice to Patients

by Ralph M. Steinman, M.D.

June 8, 2009

At first glance, two recent immunological studies on cancer in mice seem contradictory. In the New Scientist article “Boosted Immune System Could Devour Brain Tumors,” the immune system provides resistance against cancer, and in a recent paper in the Journal of Experimental Medicine it enhances the spread of cancer. Let’s consider this perplexing situation and how it sheds light on the challenges involved in moving cancer research from mice to human patients.

The first article briefly summarizes the research of Maria Castro, Pedro Lowenstein and colleagues in Los Angeles, which addresses a mouse model of glioma. This prevalent form of brain cancer almost always resists treatment. Therapies and outcomes have not changed appreciably for years.

Castro and her colleagues set out to mobilize the immune system to resist glioma. It’s no easy task to coax the system to recognize a tumor as if it were an infection and reject it. To do so, the investigators took advantage of recent advances in immune system communication.

Their paper describes how a growth factor called Flt3 ligand can be used to expand the cells—called dendritic cells—that initiate the body’s rejection response. However, once they arrive at the tumor site, these dendritic cells require further information to know that an enemy, typically an infection, is at hand.

One of the many ways dendritic cells are called into action involves toll-like receptors (TLRs), newly described sensor molecules that detect infection. In the study the tumors were not infected, but when the scientists killed some of the tumor with chemotherapy, they found that a protein released from dying tumor cells, HMGB1, provided the TLR signal to dendritic cells, leading to the healing of 50 percent of the mice harboring an otherwise lethal cancer.

The Journal of Experimental Medicine article looks at research by Michael Karin and his team at the University of California, San Diego, on the contrasting “pro-cancer” roles of the immune system. The group reports that the protein versican, made by mouse lung- and breast-cancer cells, teaches another cell type, the macrophage, to make tumor necrosis factor, which drives the spread of tumor cells.

But here’s the most perplexing thing. Dendritic cells and macrophages sense products from cancer cells through the same toll-like receptors, yet the outcomes are entirely different. When HMGB1 signals TLRs on dendritic cells, resistance to glioma is the outcome, but when versican signals TLRs on macrophages, lung cancer spreads.

I think future work will figure out the apparent conundrum. I doubt it is a matter of the different experimental tumors under study. Rather I suspect it relates to the cell type operating in each setting: dendritic cells vs. macrophages. Alternatively, different information may be transmitted via TLRs depending on whether HMGB1 or versican is the inciting agent.

A bigger conundrum is apparent when we try to extend the research to patients with cancer. Currently, even when appropriate reagents can be produced for use in humans (as with the Flt3 ligand growth factor), the research community lacks a means to energize and optimize the hundreds of studies that are ready to be done in patients with cancer.

There is much to do. A consensus group recently came up with a short list of 20 priority products that should be studied in cancer patients. The list is available here. We must evaluate the effects not only of each agent but also various combinations of agents on many cancers and stages of cancer.

Currently there is a severe lack of support for studying immunology in cancer patients, where the immune system has a distinct capacity to attack multiple alterations in cancer cells. This gap is perplexing when one considers that immunology already provides many promising new cancer treatments, such as trastuzumab (Herceptin) antibodies as a treatment for breast cancer.

More important, we must not overlook new approaches to cancer, which causes more than 500,000 deaths each year in the United States. See Gina Kolata’s article “Advances Elusive in the Long Drive to Cure Cancer,” from the front page of the New York Times.

Scientists have proposed how to change the unacceptable lack of a major effort to study immunology in cancer patients. They urge that a vigorous, national, cooperative network be formed to translate discoveries in immunology into optimized research in patients. However, support for this proposal has been slow to materialize.

President Obama has urged us to cure cancer in our lifetimes and win the war on cancer that President Nixon declared in 1971. Immunologists need to be enfranchised to help win this war because immune approaches are logical and promising. With much exciting knowledge in place, cancer immunology is ready to provide patients the kind of innovation and evidence they deserve.