Sometimes it pays to think differently about a problem. Who would think that treating a cancer without actually targeting the cancer could be a viable strategy? But this is exactly what the latest major breakthrough in cancer therapy has shown.
The breakthrough is in a group of drugs called “Immune checkpoint blockers”. They have already provided remarkable results in the treatment of two of the most common and dangerous cancer types (melanoma skin cancer and lung cancer), and they are being tested in other tumour types with promising results so far. Interestingly, these efficient and powerful chemotherapies do not kill tumour cells directly. Instead, they are cleverly designed to boost the body’s own defences against the tumours.
In order to understand how they operate, it is important to note that the immune system protects our body by recognizing, attacking and remembering potential harmful elements like tumours, viruses, or other invaders. These elements are generally called antigens.
The key players in an efficient immune response are a subtype of white blood cells called T-cells, which are normally in a resting state. T-cells need to get activated in order to start attacking the bad guys. To do so, they need to interact with another type of blood cells, the presenting cells. These search the body for antigens. If they encounter one, they present it to the T-cells, which get activated and start proliferating, moving to the site of the antigen and mobilizing other immune cells to the same site in order to orchestrate an efficient attack.
This outright response is necessary to confront most threats. However, an excessive T-cell activity results in damage to the own tissues or autoimmunity (have a look at this article about autoimmunity in our blog). Hence, the activation of T-cells needs to be counteracted and tightly regulated.
This control is mediated by immune checkpoints, a group of mechanisms which modulate the interaction between T-cells and presenting cells or between T-cells and the target tissue and attenuate the activation of the T-cells and the immune response.
However, these crucial immune checkpoints are often co-opted by tumours in order to escape from the immune system. This leads to the hypothesis that by blocking the immune checkpoint we could reactivate the immune system against the tumour.
This hypothesis was tested in 1996 by injecting tumour cells into mice treated with an immune checkpoint blocker or with a control treatment. All of the blocker treated-mice rejected the tumour. These promising results on animal models prompted the scientific community to explore this hypothesis in human patients. After years of exploratory studies to ensure the safety of the drugs, finally in 2011 the drug was ready to be tested in advanced melanoma patients.
The clinical trial showed a discrete increase in survival of the patients. It is important to keep in mind that even a small increase of survival is a great success when dealing with advanced cancers. Moreover, the toxicity was as expected related with autoimmune problems (mainly in skin and gastrointestinal system) but it was mostly tolerable and controllable. The most striking result was that 20% of the blocker-treated patients seemed to respond to the treatment long term, entering into complete remission. These results open the door to the exciting possibility that these drugs could actually cure the tumours of a subset of patients.
The second generation of immune checkpoint blockers, called PD-1 inhibitors, were described as “Drugs of the year 2013” by some scientific journals. They proved to increase survival not only in metastatic melanoma, but also in a subtype of advanced lung cancer, and in 2014 two molecules were approved for the treatment of those patients. Their toxicity is lower and the percentage of responders is higher. They are also being tested with promising results in other tumours such as renal cell carcinoma and bladder cancer.
The field is now working against the clock to understand which patients are more likely to benefit from the remarkable effects of these compounds and to develop tests to identify them. In the meanwhile, the investment in these molecules is increasing exponentially, trying to quickly develop them and get them into the clinic. And while it is still early days to fully comprehend the long- term benefits of these drugs, it is undeniable that new strategy is a powerful tool to fight cancer.