[UPDATED: Sept. 2013; see update note at bottom] A biomedical research team at Stanford University School of Medicine reported yesterday the results of mouse experiments using an antibody molecule to treat various types of tumorous cancer cells — with results showing significant tumor shrinkage and slowed tumor growth in all cancer cell types tested. In some cases, the tumorous cells were completely destroyed by host immune cells with no recurrences four months after the treatment was stopped.
This breakthrough results from the application of an earlier discovery by Irving Weissman some ten years ago showing that a certain cell marker protein — known as CD47 — normally found on the surfaces of blood cells, serves as a biological “flag” to immune cells, telling them “don’t eat me”. As it turns out, cancer cells have found away to exploit this innate host protection by secreting the same molecular flag as normal blood cells. Macrophages — large “killer cells” of the immune system — “see” the correct flag, and generally leave the cancer cells alone to replicate, and even metastasize (i.e., spread throughout the body).
In just the past few years, the research team, led by Dr. Weissman, developed an antibody that blocks production of the CD47 cell marker, and then more recently began trying out the antibody on blood cancers such as leukemia.
“What we’ve shown is that CD47 isn’t just important on leukemias and lymphomas. It’s on every single human primary tumor that we tested.”, said Weissman [source: Science Now].
The team also discovered that tumor cells tended to produce higher levels of CD47 on their surface membranes than did healthy cells. Thus, the amount of CD 47 produced by a given type of cancer cell could be used as a predictor of patient recovery.
In theory, blocking the production of this molecular flag on the surface of tumor cells should then make them detectable to the body’s protective immune cells.
To test this hypothesis, in vitro experiments were conducted first using tumor cells grown in petri dishes and exposing them to macrophages, with and without the additional antibody. Without the anti-CD47 drug, the macrophages did not recognize the cancer cells as alien, and left them alone. But when the antibody was present in the culture, the macrophages quickly engulfed and eventually destroyed the tumor cells. This anti-cancer activity, known as phagocytosis, was demonstrated with every type of tumor.
The team next tested out the drug on mice who were given transplants of various human tumors. When the mice were then treated with the anti-CD47 drug, the tumors decreased in size and failed to metastasize. The process was repeated with other human tumor transplants such as colon cancer tumors. The team found that these tumors shrank to less than one third of their original size on average. And in mice with breast cancer tumors, the drug eradicated all sign of the tumors, with the mice remaining cancer free for four months after cessation of the treatment.
Although this treatment also rendered blood cells susceptible to immune cell targeting, this ill effect was transient and red blood cells levels eventually recovered to normal levels.
“We showed that even after the tumor has taken hold, the antibody can either cure the tumor or slow its growth and prevent metastasis.” said Weissman [source: Science Now].
While quite promising, other researchers say that the transplanted tumors do not possess the same ‘micro environments’ as ‘real’ tumors (which have additional immune suppressing tricks) and question if the same results will be achieved in humans. Others also wonder about how this antibody will interact with other medications; an antagonistic effect could result, possibly causing cells stressed from chemotherapy to over-produce CD47.
That said, the results from these recent experiments are undeniably positive and compelling enough to justify moving ahead with more advanced testing: from mice to humans.
The Stanford team has already received a $20 million grant from the California Institute for Regenerative Medicine to initiate planning of human safety trials.
The results of these experiments were published yesterday (March 26, 2012, submitted in Dec. 2011) in the Proceedings of the National Academy of Sciences, under the title: The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors (Willingham et al, 2012)
Quote (from the paper’s Abstract):
“These results suggest all human solid tumor cells require CD47 expression to suppress phagocytic innate immune surveillance and elimination. These data, taken together with similar findings with other human neoplasms, show that CD47 is a commonly expressed molecule on all cancers, its function to block phagocytosis is known, and blockade of its function leads to tumor cell phagocytosis and elimination. CD47 is therefore a validated target for cancer therapies.”
UPDATE (Sept. 2013): Additional testing of the experimental antibody treatment has been conducted with promising results, showing that “anti-CD47 antibody–mediated phagocytosis of cancer by macrophages can initiate an antitumor T-cell immune response.” The researchers (Tseng et al) also found that macrophages recruited to tumor sites not only phagocytosed the cancer cells but “primed CD8+ T cells to exhibit cytotoxic function in vivo. This response protected animals from tumor challenge.” The abstract and full paper can be found on the PNAS website.
Top Image: National Cancer Institute
Additional Photos: (phagocyctosis) Supporting Information, PNAS