Without a functional immune system we would all have cancer early on and develop tumors on a very frequent basis. Effector cells of the adaptive immune system such as helper and cytotoxic T cells are able to distinguish between normal and tumor cells. But tumor cells can develop ways to bypass immune-surveillance. That’s why it makes so much sense to find new therapeutic strategies supporting the immune system so that it can be active against cancer (again).
Dr. Olivia Finn from the University of Pittsburgh wrote a comprehensive symposium article in 2012 in the Annals of Oncology how it can happen that balance is shifted from the immune system being the stronger party at first to cancer getting the upper hand and how immunotherapy can reestablish the balance (1).
Dr. Finn described three levels of immuno-surveillance: elimination, equilibrium and escape. During elimination, an immunogenic tumor is eliminated efficiently in an immuno-competent environment. When the immune system is compromised e.g. the tumor cells express less or no immunogenic surface proteins or due to biologic distraction for the immune system (ex. viral infection), equilibrium establishes meaning tumor cell destruction and regrowth are equal and the tumor size seems stable. The last level, escape, means that tumor growth outweighs the efficiency of the immune system.
Since 2012 so much happened in this area of research. Several therapeutics have been approved or significantly advanced in clinical development in different indications including not only melanoma where the first CTLA4 antibody has been approved by the FDA in 2011 but also in lung cancer, lymphoma, bladder, head & neck, renal cell carcinoma and others. CTLA4 was followed by PD1/PDL1 antibodies. These three target proteins belong to so-called checkpoint inhibitors of the immune system. Their role is to keep T cell activity under control so that inflammation does not get out of hand. Cancer cells use this as one mechanism to stop T cells from killing them.
The reason why this therapy has great potential to work in many different types of cancers and stages is that it does not target one specific driver like HER2 in HER2-positive breast cancer or EGFR mutants in NSCLC or BRCA mutants in ovarian and breast cancer. With immunotherapy the opportunity is broader and for several types of cancers but at the same time, it is also more complex and not all patients respond. The list of targets on the surface of cells of the tumor itself or the immune system and the microenvironment is much longer. In addition, not only inhibitors that inhibit the inhibition of the immune system but also activators of the immune system are in development. Wait – inhibitors of the inhibition? Yes …. immunotherapy is not straight forward at all and requires a different mind set than cancer treatment as we know it. The same is true for IO biomarkers. With biomarkers like CTLA4, PD1, PDL1, the research community has just seen the tip of the iceberg. It is likely that these biomarkers may potentially be helpful but not sufficient to predict therapeutic outcome or to select the right subgroup of patients with the best clinical benefit since PD-L1 negative patients with good clinical response have been reported.
According to the ASCO 2016 education session “Where does the truth lie in immune biomarker development” by Prof. Suzanne Topalian from Johns Hopkins, the percentage of responders can vary a lot between studies (2). She listed durable objective tumor regression for melanoma between 17 and 50% and 65-87% for Hodgkin lymphoma but for lung, kidney, bladder, ovarian and head & neck cancer “only” 10-30%, 12-29%, 15-30%, 6-23% and 20-25%, respectively. However, responding patients can have excellent clinical benefit for a long time. That’s why it is so important to identify biomarkers that allow reliable patient selection. This is meaningful from a health-economic point of view since immunotherapy can be very expensive.
A lot more clinical and preclinical research, data analysis, discussions and trouble shooting lies ahead of the medical oncology community before we can speak of understanding all the pros and cons of immunotherapy but it is already very clear that this is a major step into a much more promising future for cancer patients.
- ASCO 2016 Educational Session “Where does the truth lie in immune biomarker development” by Suzanne Louise Topalian from Johns Hopkins.