Engineering Macrophages to Ignore "Don't Eat Me" Signals from Cancer Cells

Macrophages are one of the types of immune cell responsible for destroying potentially dangerous cells, such as those that have become cancerous. Unfortunately cancerous cells tend to circumvent the immune system by displaying molecules on their outer surface that cause macrophages to leave them alone. This is an abuse of recognition mechanisms that exist to protect other cell types. Researchers here show that producing engineered macrophages that ignore this signal can be a viable approach to cancer therapy, even though past attempts have proven too harmful to normal cells to proceed towards the clinic. Their new methodology manages to avoid the destruction of non-cancerous cells to any significant degree, which is a promising step forward for the use of macrophages in cancer immunotherapy.

One reason cancer is so difficult to treat is that it avoids detection by the body. Agents of the immune system are constantly checking the surfaces of cells for chemical signals that say they belong, but cancer cells express the same chemical signals as healthy ones. Without a way for the immune system to tell the difference, little stands in the way of cancer taking over. Now, researchers have learned how to re-engineer macrophages, the "first responders" of the immune system, so that they can distinguish between healthy and cancerous cells. Armed with this ability, the engineered cells were able to circulate through the body of a mouse, invade solid tumors and specifically engulf human cancer cells therein.

​​​​​​​"Our new approach takes young and aggressive macrophages from the bone marrow of a human donor and removes a key safeguard that cancer cells have co-opted to prevent them from being engulfed. Combined with cancer-specific targeting antibodies, these engineered macrophages swarm into solid tumors and rapidly drive regression of human tumors without any measurable toxicity." Immune cell therapies using engineered T-cells have recently emerged as successful treatments for some blood cancers, which are referred to as "liquid" tumors. Tumors in other tissues are generally more solid, which can physically impede the ability of T-cells to penetrate into the mass of the tumor. Macrophages readily infiltrate diseased and damaged tissues, including tumors. As such, macrophage-based cancer therapies were investigated decades ago. While they were found to be safe in patients, they were not effective in destroying cancerous cells. It is now understood that such macrophages received the same "don't eat me" signal from both healthy and cancerous cells.

It was since shown that a protein on human cells called CD47 functions as a "marker of self" by interacting with a protein on the surface of macrophages called SIRPA. When SIRPA contacts CD47 on any other cell, it serves as a safeguard that prevents the macrophage from engulfing the other cell, even if it's cancerous. With that in mind, the researchers thought that controlling this protein might revitalize macrophage-based cell therapies. Injections of antibody molecules that block CD47 from interacting with SIRPA are already being tried in the clinic based on observations of some reduction in the sizes of tumors in mouse models. However, such molecular treatments reproducibly cause rapid loss of many circulating blood cells, as macrophages now attack some healthy cells as well. In addition to causing anemia, some mice with depleted CD47 die from autoimmune disease.

To get around these safety concerns and to potentially maximize therapeutic effects on tumors, researchers took fresh, young macrophages from human donors as well as mouse donors and directly blocked their SIRPA. They also injected various antibodies that bind to cancer cells, which help to activate macrophages that might enter the tumor. "The big surprise is that injected macrophages circulate all around the body but accumulate only within the tumors where they engorge on cancer cells." After two injections, cancer cells were depleted 100-fold from tumors the size of a dime, and tumors regressed 80 percent in size. Importantly, blood cells were unaffected by the treatments, which suggests that this approach is safe.

Link: https://news.upenn.edu/news/penn-researchers-engineer-macrophages-engulf-cancer-cells-solid-tumors

Comments

Good stuff, Discher lab at leading the way in this and many other areas, particularly in muscle, heart etc.
Regarding the TDP-43 and potential for amyloid clearance etc alluded to the other day, Lee and husband Trojanowski tag team have been leading the way at Penn as well, they just came out with this one too:
http://www.cell.com/neuron/fulltext/S0896-6273(17)30475-0

Posted by: john hewitt at July 20th, 2017 9:19 AM

"New biological mechanisms were uncovered by the study, including the observation that the injected macrophages which accumulate in the tumor stop engorging on cancer cells after about a week. Further injections, however, safely drive tumor regression.

"The first phase of clinical trials are tests of human safety, so this is a promising start," Alvey said. "The potency of these engineered macrophages is relatively clear, but the crucial issue is how to maximize the anti-cancer effects while minimizing side effects, namely the engulfment of normal cells."

Ongoing studies from the Discher lab are focused on finding that sweet spot with additional tumor models, as well as on how to engineer macrophages for longer-lasting effect."

Trying to find a sweet spot sounds like a waste of time. Maybe it is easier said than done, but why not genetically engineer the macrophages so that the CD47 receptor signal is always switched to "on" until a co-signal from a engineering in CAR to one of the antigens the antibodies are currently targeting switches it to off?

Or use Unum Therapeutic's antibody coupled T cell receptor technology in a marcophage to switch the CD47 receptor signal off.

Posted by: Jim at July 20th, 2017 10:42 AM

Post a comment; thoughtful, considered opinions are valued. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.