Posted on Jul 25, 2017, 8 a.m.
Researchers have successfully engineered macrophages, the "first responders" of the immune system, to enable them to distinguish between healthy and cancerous cells.
Cancer is difficult to treat and one reason is its ability to avoid detection by the immune systems first responder cells (called macrophages). Macrophages are constantly checking for chemical signals on the surfaces of cells to determine if they belong or not. The problem is that cancer cells mimic the same chemicals that healthy cells have and with this deception, cancer cells are free to take over.
In a new study published in the journal Current Biology, researchers from the University of Pennsylvania have re-engineered macrophages to distinguish between cancerous and healthy cells. In experiments on mice with embedded human cancer tumors, the new macrophages were allowed to circulate the bloodstream invading tumors and engulfing the cancer cells. The new technique could be a major advance in solid cancer immunotherapy.
Tricking Macrophages To Detect Friend From Foe
The job for macrophages is to devour foreign or diseased cells from the body. However, macrophages should also destroy cancer cells but because cancerous cells are derived from healthy ones, they mimic healthy cells and are protected by the immune system. The new approach targets the proteins of young aggressive macrophages obtained from the bone marrow of donors. This method allows for the newly improved macrophages to tell which cells are cancerous. The treatment, when combined with anti-cancer antibodies, allows the engineered macrophages to easily penetrate solid tumors bringing a rapid regression of tumors without any toxic side effects.
Engineered T-cells have been used successfully in the past for soft tumors and cancer of the blood. T-cells have trouble penetrating solid tumors, but macrophages have fewer problems infiltrating diseased tissue or tumors. Cancer therapies based on macrophage treatments were considered decades ago but the technology had not yet matured. Now scientists understand macrophages and have shown that proteins on tumors prevent macrophage cells from engulfing any cancer cells. Since cancer cells have the same surface proteins as healthy cells, researchers came up with the idea of controlling the proteins to revitalize the macrophages for therapeutic treatments.
Tumors in Mice Reduced by 80 Percent
Antibody molecules injected into the bloodstream was the answer to blocking proteins from interacting with macrophage cells. Clinical trials have shown a reduction in the size of tumors in mice but such treatments cause a rapid loss of blood cells and some macrophages still attack healthy cells. Some mice suffered anemia or died from auto-immune diseases.
To overcome these concerns while maximizing the effects on the tumors, researchers used young macrophages from human and mouse donors. These cells are mixed together with antibodies which help the macrophages penetrate the tumor and then devour cancer cells. The big surprise was that as the macrophages circulated through the body, they only concentrated inside tumors killing the cancer cells. After only two rounds of injections, the tumors in the mice shrank by 80% in size and there was no loss of blood cells suggesting the treatment is safe.
An observation uncovered during the study showed that macrophages stop engulfing cancer cells after just one week. However, further injections did continue tumor regression. According to graduate student Cory Alvey, the first phase of the trials are safety tests before human trials begin but it is a promising start. They have demonstrated the potency of the engineered macrophages, but the next hurdle is to minimize side effects while still maximizing the effectiveness of the treatments. Ongoing trials will focus on experimental tumor models and extending the macrophages ability to engulf human cancer cells.
Cory M. Alvey, Kyle R. Spinler, Jerome Irianto, Charlotte R. Pfeifer, Brandon Hayes, Yuntao Xia, Sangkyun Cho, P.C.P. Dave Dingal, Jake Hsu, Lucas Smith, Manu Tewari, Dennis E. Discher. SIRPA-Inhibited, Marrow-Derived Macrophages Engorge, Accumulate, and Differentiate in Antibody-Targeted Regression of Solid Tumors. Current Biology, 2017; DOI: 10.1016/j.cub.2017.06.005