By Gesa Junge, PhD
Our immune system’s job is to recognize foreign, unfamiliar and potentially dangerous cells and molecules. On the one hand, it helps us fight infections by bacteria and viruses, while on the other hand it can leave us with annoying and potentially dangerous allergic reactions to harmless things like peanuts, pollen or pets. Tumor cells are arguably very harmful to our health, and yet the immune system does not always eliminate them. This is partially because cancer cells are our own cells, and not a foreign, unfamiliar intruder.
The immune system can recognize cancer cells; this was first postulated in 1909 by Paul Ehrlich and subsequently found by several others. However, detecting cancer cells may not be enough to prevent tumor growth. Recent research has shown that while detection can lead to elimination of cancer cells, some cells are not killed but enter an equilibrium stage, where they can exist undisturbed and undergo changes, and finally the cells can escape, if they have changed in a way that allows them to grow undetected by the immune system. This process of elimination, equilibrium and escape is referred to as “cancer immunoediting” and is one of the most active research areas in cancer, particularly in regard to cancer therapy.
Immunotherapy is a form of cancer therapy that harnesses our immune system to kill cancer cells, and there are various approaches to this. Probably the most established forms of immunotherapy are antibodies, which have been used for almost two decades. They generally target surface markers of cancer cells; for example, rituximab is an antibody to CD20, or trastuzumab, which targets HER2. CD20 and HER2 are cell surface proteins highly expressed by leukaemia and breast cancer cells, respectively, while normal, healthy cells have lower expression, making the cancer cells more susceptible. Rituximab was approved for Non-Hodgkins Lymphoma in 1997, the first of now nearly 20 antibodies to be routinely used in cancer therapy. In addition to this, there are several new antibodies undergoing clinical trials for most cancers. These are mainly antibodies to tumour-specific antigens (proteins that may only be expressed by e.g. prostate or lung cancer), and checkpoint inhibitors such as PD1 (more on that in part 2).
Initially, antibodies were usually generated in mice; however, giving murine antibodies to humans can lead to an immune response and resistance to the mouse antibodies when they are administered again later. Therefore, antibodies had to be “humanised”, i.e. made more like human antibodies, without losing the target affinity, and this was only made possible by advances in biotechnology. The first clinically used antibodies, such as rituximab, were chimeric antibodies, in which the variable region (which binds the target) is murine and the constant region is human, making them much better tolerated. Trastuzumab is an example of a humanised antibody, where only the very end of the variable region (the complementarity-determining region, CDR) is murine, and the rest of the molecule is human). And then there are fully human antibodies, such as panitumumab, an anti-EGFR antibody used to treat colorectal cancer. There is actually a system to labeling therapeutic antibodies: -ximab is chimeric, -zumab is humanised and –umab is human.
Antibodies can also be conjugated to drugs, which should make the drug more selective to its target and the antibody more effective in cell-killing. So far there are only very few antibody-drug conjugates in clinical use, but one example is Kadcyla, which consists of trastuzumab conjugated to emtansine, a cytotoxic agent.
Other examples of immunotherapy are cytokines such as interferons and interleukins. These are mediators of the immune response secreted by immune cells which can be given intravenously to help attack cancer cells, and they are used for example in the treatment of skin cancer. Interleukin 2 (IL-2) was the first interleukin to be approved, for the treatment of advanced melanoma and renal cancer, and research into new interleukins and their therapeutic potential is still going strong. Especially IL-2 and IL-12, but also several others are currently in clinical studies for both and various other indications, such as viral infections and autoimmune diseases.
In addition to passive immunotherapies like antibodies and cytokines, there are also active immunotherapies which re-target our immune system towards cancer cells, for example cancer vaccines. More on this, and on new drugs and their issues in part 2.