We could be near some real breakthroughs in cancer research. For too long, most new treatments being explored, especially for common cancers such as breast and prostate, have been just yet another chemotherapy drug that will work for maybe 15% of the lucky people who have to suffer through treatment with it. But fortunately (for the time being) governments are still publicly funding important research that could lead to many fewer people needlessly taking large doses of poison that sometimes kill people faster than the cancer they are supposed to take out, because if the pharmaceutical companies had their way forever, as they mostly have up to now, they would just keep poisoning as many of us as possible so as to maintain their bottom line.
But as it turns out, indiscriminate use of ineffective chemotherapy may also be undermining other treatment options, in more than one way. A big new area of research is on how to convince our immune system to attack and destroy cancer cells without them attacking healthy cells. From one perspective, invasive cancer can be considered an immune system failure, because somehow immune cells are diverted from doing what should be their job and clearing out these defective cells. Of course, it’s asking a lot of our immune system to recognize cells originating from our own body as foreign, especially given that cancer cells are very good at manipulating our natural immune response (Whiteside 2006). Immune function is also very complicated. But recently, more studies are helping scientists to manipulate the immune system in a way that shows very promising preliminary results that could significantly impact the way we treat cancer.
One trick is to train our immune system in a very similar way that we do with any regular vaccine against a disease. Of course it’s a lot more difficult to train our immune cells to selectively attack our own cancer cells while leaving healthy cells intact, because our immune cells work by targeting specific proteins on cell surfaces. One you have been exposed to an invader such as a virus or bacterial pathogen, your immune system “learns” what those cells look like based on their surface proteins, and produces a whole line of special cells designed to attack and kill any cells in the body with that specific protein signature. We never get sick from the same cold virus twice, because each time we develop immune cells ready to attack a previously experienced viral strain, before it multiplies enough to cause symptoms (unfortunately, in the case of cold viruses, there are hundreds of strains, and so there is always a new one we can catch). In the case of serious foreign pathogens such as those causing flu, measles, polio, hepatitis, and other life-threatening diseases, we can often pre-train our immune system by introducing a small amount of the pathogen into our bodies — usually it’s a killed version of the pathogen that cannot harm us but which still retains the identifying surface proteins.
The hard part of enlisting our immune systems to attack cancer cells is identifying surface proteins that are unique to the cancer cells. Fortunately a lot of progress has been made on this front. Adding to previous extensive work in this area (Cheever et al. 2009), Willingham et al. (2012) have found that some cancer cells overexpress a protein (called CD47) that sends a “don’t eat me!” message to white blood cells (immune cells) that are phagocytic, or cell-eating. In fact, the higher the level of expression, the lower the survival rate for someone with that cancer. The researchers exposed tumors in mice to a CD47 antibody, which enabled the mouse’s immune system to destroy the tumor cells. They also transplanted human tumor cells into mice and got the same effect — in several cases the tumors completely disappeared, making the mice cancer-free. They tried it with several types of cancer. When they gave mice tumor cells known to aggressively metastasize, the CD47 antibodies also prevented metastasis compared with controls.
Another step in this problem was alluded to earlier: researchers had to establish that the antibody attacking this protein, which is also expressed in some normal cells (to a lesser degree than in tumor cells) would not work as a toxin by causing the destruction of healthy cells (as most chemotherapeutic compounds do). They found that the primary side effect was anemia and neutropenia — a temporary killing off of red and white blood cells. And, they have reason to believe that the doses of antibody that they used in the mice were much higher than might be necessary, which reduces the probability that toxicity would be a problem in a therapeutic setting. (And let’s not forget that the neutropenia associated with commonly used chemotherapy regimens at this time has been deemed acceptable despite its danger, partly because we have drugs such as neulasta which mitigate the problem by stimulating overproduction of white blood cells.) A cancer treatment that could be applicable across a wide range of different cancers has truly been the holy grail of the “war on cancer.” Now it seems possible that the grail could exist.
Also interesting are the studies going on looking the anti-cancer effects of recombinant pox virus vaccines (Mohebtash et al., 2011). These work by the addition of genes into a pox virus that stimulate the immune system to attack other proteins associated with cancer cells, such as MUC1. This treatment also has essentially no side effects because it targets cancer cells. Their preliminary data from a human trial shows promise, with the interesting effect so far that the treatment worked better in patients who had not undergone previous chemotherapy. Given the damage that chemotherapy causes to immune systems, these therapies certainly wouldn’t work in conjunction with chemotherapy, but results raise questions about whether or not chemotherapy is causing longer term immune damage that we may be ignoring. At the same time, to make happy those wedded to continuing the use of chemotherapy are results showing that chemotherapy can actually be synergistic with immunotherapy, if treatment is manipulated with precision (Lake and Robinson, 2005; Ramakrishnan and Gabrilovich, 2011).
What few people realize is ideas relating the immune system to anti-cancer effects are hardly new, having existed for well over a hundred years. Infections themselves have been demonstrated to halt cancer progression, perhaps partly due to the fever response (Hobohm, 2009) but over the last several decades, this avenue of research has been essentially ignored (except by a few curious academics) in favor of a focus on chemotherapy. It’s hard not to think that the profit motive that has a huge influence on biomedical research has a lot to do with this.
Researchers are much further than most people realize at converting immunologcial research into clinical treatments, some of which are already being used outside the U.S, and others of which are currently being tested in a lot of trials around the world. These are hopeful signs that medical scientists are finally seeing the routine and usually useless poisoning of millions of people every year for the therapeutic dead end that it clearly is, and that this will be enough eventually to fight back against the inertia and competing interests contributing to the stagnation of progress in cancer treatment.
Cheever MA, Allison JP, Ferris AS, Finn OJ, Hastings BM, Hecht TT, Mellman I, Prindiville SA, Viner JL, Weiner LM, Matrisian LM, 2009. The prioritization of cancer antigens: a National Cancer Institute pilot project for the acceleration of translational research. Clin Cancer Res. 15(17):5323-37.
Hobohm, U., 2009. Healing Heat: Harnessing Infection to Fight Cancer. American Scientist, 97(1):34-40.
Lake RA and Robinson BW, 2005. Immunotherapy and chemotherapy–a practical partnership. Nat Rev Cancer 5(5):397-405.
Mohebtash M, Tsang KY, Madan RA, Huen NY, Poole DJ, Jochems C, Jones J, Ferrara T, Heery CR, Arlen PM, Steinberg SM, Pazdur M, Rauckhorst M, Jones EC, Dahut WL, Schlom J, Gulley JL., 2011. A pilot study of MUC-1/CEA/TRICOM poxviral-based vaccine in patients with metastatic breast and ovarian cancer. Clinical Cancer Research 17(22):7164-73.
Ramakrishnan R, Gabrilovich DI., 2011. Mechanism of synergistic effect of chemotherapy and immunotherapy of cancer. Cancer Immunol Immunother. 60(3):419-23.
Whiteside T.L., 2006. Immune suppression in cancer: effects on immune cells, mechanisms and future therapeutic intervention. Seminars in Cancer Biology 16(1):3-15.
Willingham SB, Volkmer JP, Gentles AJ, Sahoo D, Dalerba P, Mitra SS, Wang J, Contreras-Trujillo H, Martin R, Cohen JD, Lovelace P, Scheeren FA, Chao MP, Weiskopf K, Tang C, Volkmer AK, Naik TJ, Storm TA, Mosley AR, Edris B, Schmid SM, Sun CK, Chua MS, Murillo O, Rajendran P, Cha AC, Chin RK, Kim D, Adorno M, Raveh T, Tseng D, Jaiswal S, Enger PO, Steinberg GK, Li G, So SK, Majeti R, Harsh GR, van de Rijn M, Teng NN, Sunwoo JB, Alizadeh AA, Clarke MF, Weissman IL, 2012. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proceedings of the National Academy of Science USA. Mar 26. [Epub ahead of print]