Future Horizons in Lung Cancer
Understanding the mechanisms of immunotherapy in lung cancer
Dr Rafael Rosell - Catalan Institute of Oncology, Barcelona, Spain
Today my duty was to pave the way for understanding the mechanisms of action of immunotherapy because immunotherapy has been a new therapeutic tool that was unexpectedly found and is not too far away now, it was three years ago that was the discovery and the first evidence that there were new classes of therapy for cancer patients different from chemotherapy. This is what integrated as immunotherapy and these are mainly called immune checkpoint inhibitors, antibodies, that when you are facing the patient and the family just to explain still it’s a little complex, just in a dynamic manner to make easy understanding for the patient and the family what it is. Then when I was talking today it was in the potential mechanisms of signalling pathways that can influence in a positive or negative manner and how we can predict in a relatively accurate manner that immunotherapy can be something that could be of substantial benefit to the patient in terms of changing the tumour in lung cancer. Not only this, the duration of response is the second pertinent question and then duration of response runs in parallel – what is the concept of interval free of disease that technically is progression free survival and ultimately overall survival.
There are many factors and currently we will be using immunotherapy as one of the ultimate therapies for the treatment of our patients in the case of lung cancer. But today I was focussing on preclinical research, understanding the signalling pathways that are giving some answers to the effect of immunotherapy and they are very promising. It was a good start today.
What success has there been in immunotherapy for lung cancer?
There are a plethora of studies that since their discovery, we can say they were discovered three years ago, it’s been amazingly growing, the number of studies, the number of patients that have been treated, the number of reports. There are many different pharmaceutical firms that have developed in very rapid, positive competition new inhibitors of this class that are generally well tolerated and they are not associated to the common side effects of chemotherapy. Therefore still nowadays there are some regulatory rules that are needed to be fully there, for instance the use of immuno-staining, detection of the predicted marker that is the expression of this ligand on the receptor of tumour cells that is called PD-L1 and how this eliminates the mechanism of defence of the host that are the immune T-cells and therefore how this problem can be solved. That is one of the things that today I was explaining.
There are many important central hubs in the tumour cells that are providing output, many signalling pathways that are involved. There are several layers of evidence that we can just target in an efficient manner just to increase the efficacy, the number of responses, the duration and therefore how we can, better still at the beginning when this is challenging, the practical aspect is very well known for specialists, that is the fact that different subclasses of lung cancer patients are responding better, for instance here are one little disease among the patients with lung cancer we have not to forget always that we are speaking and most of the patients at the time of diagnosis of lung cancer is metastatic disease. This means that their survival is limited and is a very short-lived survival, maybe one, two, three years because nowadays we have different manners to attenuate the progression of the disease. Then there are some subgroups of patients, for instance in smokers that are normally associated with the presence of a type of driver mutation that is still undruggable or untargetable, that is the KRAS mutation. Immunotherapy just has been showing that these patients respond very well and then because with chemotherapy, or other means of therapies that are not substantially available or not with efficacy, the survival of metastatic advanced non-small cell lung cancer patients with KRAS mutations unfortunately is short, dramatically short, less than one year. Now we have this new unexpected benefit of immunotherapy that in one third of these patients it is inducing responses in some of them, dramatic responses of very long duration. This is one of the things that I was dedicated just to explain more in depth as well as why another subgroup, an important subgroup of patients, that is cell carcinoma of the lung, these patients are responding rather well and therefore how we can still not only figure out in advance of the treatment which patients will respond well and which will be negligible or monotherapy, how we can therefore augment the response or avoid the initial lack of response.
Are these immunotherapies used in combination with other treatments?
Yes, this was one of the key aspects because during these two or three years, particularly in the field of lung cancer research, these drugs have been given in formal clinical trials as the less resource of therapy. Therefore are now switching from previously heavily pre-treated patients to first line and then in combination up front and in combination with chemotherapy. Until now has been the first already reported publication with nivolumab, that is one of these anti-PD1 antibodies, that was of significant benefit as a whole in the first study. Two year survival of 62%, this percentage is amazingly high, therefore this is a lot of hope. Today one of my concerns was just to explain why chemotherapy can enhance up-front the effect of immunotherapy and therefore there are several plausible hypotheses that have been previously explored in chronic viral infections like HIV or other types of hepatitis. Therefore there are, from the biological point of view, many links between different classes of diseases and this is a very positive challenge and reward for medical doctors or other types of researchers that are dedicated to improving the knowledge of lung cancer.
Does this mean potential new targets?
We have a lot of positive work and we have the tools to examine because nowadays we can explore more in these genetic alterations in the tumour biopsies of the patients. But not only this, we can do a lot of studies in human lung cancer cell lines and these cell lines can be treated in different manners and different conditions and we can explore the signalling pathways, we’re looking at the expression of the proteins and then also we can treat these cells with different types of combinations. This is also formulating a new class of work with immunotherapy because also a different type of implementing the techniques of the cell cultures of these cancer cells.
