New Discoveries in the Fight Against Cancer
Yaron Carmi (left) and Edgar Engleman (right)
By Kristin Stankus, digital community and social media specialist
Since its founding in 1978, Stanford Blood Center (SBC) has strived to not only save lives by providing transfusable blood products to patients in need, but also to provide tailored blood products and samples researchers utilize to contribute to the development of potentially lifesaving treatments and therapies. Thanks to the generosity of our donors, SBC had access to blood products that were used to make a significant discovery in cancer research recently. In April, the study’s findings appeared in Nature, a journal that publishes important new findings in science. SBC founder, Edgar Engleman, MD, a professor of pathology and of medicine, was the senior author on the study and postdoctoral scholar, Yaron Carmi, PhD, was lead author. Drs. Engleman and Carmi shared some insight into the years of hard work they have dedicated to the study and explained why the findings are meaningful.
Identifying the problem
Four years ago, Engleman and Carmi identified a problem to solve: how to encourage the immune system to reject cancer. To approach this complex issue, they needed an experimental model to study how to prompt the immune system to destroy a cancerous tumor, something that rarely happens in patients with cancer. They started by looking at a situation where a tumor gets permanently rejected since Carmi suspected that by studying an example of a situation where the immune system did work, maybe he could identify what factor is missing when it does not and then use that knowledge to treat cancerous tumors.
Carmi and his collaborators in the lab worked with two strains of mice, referred to as Mouse A and Mouse B. The strains were not blood relatives but genetically similar. Both species of mice were injected with tumors that would eventually kill them. Carmi took the tumor from Mouse A and transferred it to Mouse B, whose immune system rejected it, similar to what happens with an organ transplant. This occurred because the immune system of Mouse B identified the tumor of Mouse A as foreign.
“The ability of Mouse B to reject Mouse A’s tumor stems from the fact that Mouse B already had antibodies that recognized Mouse A. Conversely, Mouse A had antibodies that recognized Mouse B. In both instances, the mice did not have antibodies that recognized their own tumors. We found the same phenomenon in healthy people, all of whom have antibodies that recognize other people’s tumors” says Engleman. “In other words, the antibodies from one individual recognize tumors from other members of the same species but not that individual’s own tumors. This is because our immune systems are trained to recognize and attack foreign invaders, but not our own tissues.”
That finding wasn’t surprising to the team. What surprised them was the mechanism by which the tumor was rejected. They’d always known which of the white blood cells within the immune system were responsible for killing the tumor, the T-cells. What they didn’t know was how the process got started. What set off the alarm that alerted the T-cells to attack?
An Important Discovery
Once the antibodies recognize the tumor cells, they initiate a process that results in the killing of those tumor cells, but the antibodies do not directly kill them. Instead, they bind to the tumor’s surface, which enables nearby dendritic cells to “eat” the tumor cells. Dendritic cells are another kind of white blood cell that specializes in sampling cells and molecules in the environment and determining which ones are dangerous. When cells or molecules are identified as dangerous by dendritic cells, they then alert the T-cells to destroy them. Carmi discovered that all three steps are required for the immune system to successfully reject a tumor.
To recap, the tumor rejection process must include the following three steps:
- Antibodies binding the tumor tumor sound the alarm by making the tumors appear foreign to dendritic cells
- Dendritic cells, having determined that the tumors are dangerous, consume a small portion of the tumor cells, and display the tumor proteins on their surface, thereby signaling T cells to destroy cells containing those proteins
- The T-cells kill the tumor
The Next Step
All 3 of these steps occur naturally when mouse B is inoculated with a tumor from mouse A. So now that the 3 steps were identified, the next task was to determine if transfer of the tumor-recognizing antibodies from Mouse B into Mouse A, where the natural tumor was growing, would initiate the same kill process.
It didn’t work at first. The team knew exactly how all these steps took place in the allogeneic setting (using cells taken from different individuals of the same species) but realized that in the natural tumor setting the dendritic cells have been ‘hypnotized’ by the tumor. The tumor produces substances that render the dendritic cells weak and unable to function. But the Engleman lab had proven over the last 15-20 years that this phenomenon is reversible. So Carmi realized the antibodies were present and binding to the tumor, but the dendritic cells weren’t reacting. What he did was to inject into the mice, along with the tumor-binding antibodies, some molecules that are known to wake dendritic cells up.
Much to the team’s satisfaction, this combination of antibodies and dendritic cell stimulating molecules worked and resulted in the eradication of tumors in mouse A. In addition, Carmi was able to show that this approach works in many different types of tumors, proving that it is broadly applicable. The experiment was successfully conducted on models of melanoma, as well as pancreatic, lung, and breast cancer, and not only were the primary tumors destroyed, but so were distant lesions including metastases.
The importance of blood donors in this research
Once the experimental approach was deemed a success in mice, the lab was able to access human tumor cells from patients with cancer and, using their dendritic cells, T-cells and antibodies, was able to re-create the remarkable activation process in-vitro. That doesn’t guarantee that the approach will work on human beings but improves the likelihood. The plan is to eventually start human trials but that is a ways down the road.
“Most of the work done on the human side was done with white blood cells from SBC. We were also able to study the antibodies from blood donors. SBC played an absolutely critical role in this work, I’m proud to say. The synergies between SBC and the research lab have been critical to the success of this project.” Engleman said.
Potential Risks of the method
As far as potential risks of this method, Carmi and Engleman explained that over-activation of the immune system can be dangerous, but in these studies they saw little collateral damage. “Fortunately, T cells can attack their targets in a highly specific way, and we were able to show that normal tissues weren’t damaged along with the tumor. This is very encouraging, but a lot more research is still needed before the approach can be tested in clinical trials”.
How you can contribute
Many of SBC’s donors request that the non-transfusable blood byproducts from their donation be used for research to advance science in medicine. If you are interested in donating for research or obtaining products for research, please call our Customer Relations team at 650-724-2997.
