If you have read about cancer or even just watched the news, you are probably aware that the advent of immunotherapy has revolutionized the treatment paradigm of several solid tumors including melanoma. But what does it mean? Where does it come from? And How does it work?
Cancer immunotherapies characterize any type of treatment that aims at stimulating the immune system in order to improve the recognition and elimination of cancer cells.
History of Immunotherapy
As early as 1893, a scientist discovered that some patients experienced spontaneous remission of tumors when they contracted an acute infection (Coley 1893, Am. J. Med. Sci.). Over the following century, numerous attempts at harnessing this concept were undertaken. However, due to limited understanding of the immune system function at the time, the correlation between immunological parameters and clinical outcomes was not elucidated. Later on, the emergence of new therapeutic options such as radio- or chemotherapy took the precedence and research on immunotherapy was neglected.
It is only in the 1990’s that the two first drugs (interleukin-2 and interferon-α) aiming at boosting the immune system were approved for cancer treatment. Despite some remarkable cases of total remission, the severe side effects associated with the therapies and the relatively small response rate resulted in an overall very limited survival benefit. As with chemotherapy treatments, first-generation immunotherapeutic drugs were not specifically targeting cancer cells and therefore, deleterious for the surrounding healthy tissues. As a result, important efforts were devoted to find more targeted treatment. A decade later, fostered by the fundamentally new insight gained into the immune system, a second-generation of immunotherapeutic drugs was designed. Ipilimumab (Yervoy®) shortly followed by Pembrolizumab (Keytruda®) and Nivolumab (Opdivo®) showed unprecedented results in the first clinical trials which lead to their rapid approval as first-line treatment in the clinics. Indeed, they significantly improved overall survival of metastatic melanoma patients, the side effects became manageable and most importantly, some of the patients achieved complete remission! However, this optimistic picture is not without its downside, unfortunately only less than 50% of the patients respond to these therapies and 25% of those eventually develop resistance. This is why, nowadays, efforts are focused on combining those drugs together and with different agents, in order to avoid resistance.
First of all, it is important to remember that the immune system is extremely good at recognizing cells that are different from our owns cells, as observed in the case of graft rejection. In melanoma, it was shown that cancer cells bear a lot of mutations and therefore is very different to a healthy cell. So why is the immune system not able to recognize it? Although the mechanisms are multiple and various, the answer is simple: The cancer cell hides itself!
As mentioned above, the immune system is very good at eradicating foreign cells, however, if not tightly regulated, this process can have disastrous effect on healthy tissues, as it is the case in auto-immune diseases. Some signals exist in order to prevent an over-reaction or to “flag” the tissues not to be attacked such as the placenta. It is precisely those control mechanisms that are hijacked by the cancer cells to avoid being detected by the immune system. The immunotherapies are aiming at overruling those effects and allow the immune system to recognize the cancerous cells. Two types of immunotherapies have been approved for the first line treatment of metastatic melanoma.
- Pembrolizumab (Keytruda®) and Nivolumab (Opdivo®) are two drugs targeting the same receptor (PD-1) present on melanoma cells. The blockade of this receptor will enable T-cells (white blood cells trained to recognize foreign molecules) to now detect melanoma cells and attack them. The main advantage of this drug is that its effect is very specific and therefore the side effects are minimal.
- Ipilimumab (Yervoy®) is an immunotherapy targeting a receptor (CTLA-4) present on T-cell. Blocking this receptors enable a better activation of the T-cells that will then be more efficient at recognizing melanoma cells. Yet, as opposed to the previous drug, a higher activation of T-cells is a less specific reaction and can in some cases lead to adverse event such as diarrhea, rashes or hepatitis.
Those two categories of drugs are also called “immune checkpoint inhibitors” thanks to their mode of action. Given the unprecedented results obtained by targeting those “immune checkpoints” (PD-1 and CTLA-4) which interfere with the immune response, research is now focusing on harnessing the same potential by targeting other similar receptors.
– Written by Sabrina Schindler [SWISS01]