For a scientist, one of the most exciting things to happen is when basic principles established in laboratory models lead to new therapeutic approaches for humans. Most recently, the understanding of several checkpoints in T cell self-tolerance, infection and transplantation led to the development of immune checkpoint blockade to treat cancer.
The use of drugs blocking specific checkpoints, such as Programmed Death 1 (PD-1) and its major ligand PD-L1 or Cytotoxic T Lymphocyte Antigen 4 (CTLA-4), have revolutionized the treatment options for patients with various types of cancer.
Apart from different aspects of immunotherapy like engineering specific effector T cells or regulatory T cells (so-called CAR T cells) to treat cancer or autoimmunity, one of the major topics at the International Conference of Immunology (ICI), which took place in Melbourne in August 2016, was the immune checkpoint blockade. The interest in this topic was enormous and several presentations focused on the aim to unravel the remaining mysteries and the full activity spectrum of checkpoint-blocking drugs. It transpired that for CTLA-4 and PD-1 the distinct expression patterns, signalling pathways, and mechanisms of action commence in different clinical implications.
In a very impressive talk James Allison summarized the differences of anti-CTLA-4 and anti-PD-1 treatment during his talk:
|Targets CD28 pathway||Targets TCR pathway|
|Works during priming||Works on exhausted T cells|
|Expands clonal diversity||Does not expand clonal diversity|
|T cells migrate into the tumour||T cells do not migrate into the tumour|
|Disease recurrence after response is rare||Disease recurrence after response is significant|
It was presented that the treatment with CTLA-4 (Ipilimumab) in advanced melanoma induced a partial or complete response in 11% of all patients. In addition, prolonged overall survival was 22% of all patients, as reported by Allison and others. As a consequence, the US Food and Drug Administration (FDA) approved CTLA-4 in 2011 as a monotherapy. The response to anti‐PD-1 therapy was even superior, i.e. 31–44% with advanced melanoma, 19–20% in non‐small‐cell lung cancer and 22–25% in renal cell carcinoma and the drug was better tolerated when compared to CTLA-4. However, neither drug is effective against all types of cancer. Nonetheless, the extended overall survival compared to conventional therapies resulted in an approval of two different anti‐PD1 drugs (Nivolumab and Pembrolizumab) by the FDA for these indications.
A very special talk was given by a cancer patient named Peter. He reported very emotionally how he got interested in immunotherapy because of his cancer diagnosis and that he got cured from cancer after immunotherapy. This was a striking example for the remarkable success of immunotherapy. On the other side of the coin it was also mentioned that apart from the broad spectrum of anti-PD1 therapy it can only cure 10-30% all the cancer patients within this spectrum. As a result, not every patient with a certain cancer type which was described to react to this therapy will respond.
Although we have a plethora of exciting routes to follow for patients and scientists, driven by the clinical data and using basic immunological science, we should also consider that there is still a lot to do. One such example is the need for specific biomarkers to guide patient selection for both, monotherapy and combination therapy, e.g. identifying patients who most likely respond to anti-PD-L1/PD-1 treatment or combination therapies that boost the response to PD-L1/PD-1. Based on our developing scientific understanding of the biological mechanisms underlying the different checkpoint blockades such biomarkers should function as early indicators for the response to the treatment. Furthermore, these biomarkers should help to unravel unusual response patterns, including delayed or mixed tumour regression and position further clinical challenges like the generation of new targets to overcome immunosuppression, thus enhancing T cell expansion. Next to the development of good and useful biomarkers we also need to expand our focus to find good targets for stromal cells, to understand host genetics, the microbiome, and the cancer environment.
Finally, I would like to end this article with a statement from Ira Mellman who mentioned on his last slide: “Although the journey is just beginning, we can see the destination, justifying courageous action to accelerate our arrival time“ which I think summarizes our current point of view nicely.
(featured image from colourbox.com)