Pictured: Professor Andreas Radbruch, President of the European Federation of Immunological Societies (EFIS)
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Cancer checkpoint blockade – this year’s Day of Immunology theme – has revolutionised cancer treatment for many patients.
Every year on April 29th, the European Federation of Immunological Societies – EFIS – celebrates the Day of Immunology; a day designed for European and international scientists to bring immunology into the public domain – a key mission of EFIS.
This year’s topic is cancer: checkpoint blockade. It is a perfect opportunity for immunologists to show the public the importance of immunological research and how it can revolutionise treatment of diseases that have exhausted all other treatment options.
Furthermore, by translating our basic research into clinical success, such as with the introduction of cancer checkpoint blockade therapy in treating late-stage metastatic cancer, we can bring much needed new hope for many patients suffering from cancer and other diseases.
Immune checkpoints
The immune system is like many things in life, it works best when it is perfectly balanced – too little a response leaves us susceptible to infection, while too much can result in the development of autoimmunity. This balancing control comes from the inbuilt ‘fine-tuners’ of the immune response: checkpoint inhibitory receptors.
These receptors inhibit the activation of immune cells such as T cells, following antigen/MHC presentation by terminating downstream signalling cascades. The best described, and clinically targeted, inhibitory receptors are cytotoxic T lymphocyte associated antigen-4 (CTLA-4, CD152) and programmed cell death-1 (PD-1, CD279).
CTLA-4, expressed on naive and memory T cells, competes with the stimulatory receptor CD28, but has far higher affinity for the shared ligands CD80 and CD86, resulting in its ability to outcompete CD28 for ligand binding. PD-1 is also expressed on T cells, among others, and binds to its ligands PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273).
Switching off the immune brakes is beneficial for the destruction of cancer cells, but it is not without consequences.
Cancer and inhibitory checkpoint blockade
One mechanism by which cancer deactivates the immune system involves subversion of immune checkpoints. Cancer cells have been found to express ligands that bind to the inhibitory receptors on tumour-infiltrating immune cells, effectively “switching-off” the immune response. In order to “switch-on” these cells, anti-CTLA-4 and anti-PD-1 antibodies have been generated to block these inhibitory receptors and unleash the immune response.
The first anti-CTLA-4 antibody (ipilimumab) was given FDA approval in 2011 for patients with metastatic melanoma and was found to enhance survival in a significant number of patients [1]. Anti-PD-1 antibodies (pembrolizumab and nivolumab) were licenced in 2014 and have proven successful in the treatment of numerous types of cancer [1]. Given the advanced stage of many of these cancers, such antibodies have completely revolutionised cancer treatment for many patients.
Autoimmune responses following checkpoint blockade
Switching off the immune brakes is beneficial for the destruction of cancer cells, but it is not without consequences.
Immune responses are fined-tuned for a reason, with one of the pitfalls of checkpoint blockade therapy being the development of immune-related adverse events (irAEs), essentially autoimmune-like reactions resulting from the lack of inhibition of checkpoint inhibitors.
Such irAEs are not rare, with severe irAEs (grade 3 and 4) occurring in 55% of metastatic melanoma patients undergoing combined CTLA-4 and PD-1 antibody therapy [1]. irAEs can be lethal, although thankfully, rarely, and in most cases, discontinuation of treatment or addition of immunosuppressive therapy is enough to control the irAEs. While most patients no longer experience symptoms following the end of therapy, unfortunately, there are instances when autoimmune diseases develop from irAEs.
Checkpoint blockade treatment for autoimmunity
Not surprisingly, given the already activated state of the immune system in autoimmune patients, use of anti-CTLA-4 blocking antibodies in cancer patients with pre-existing autoimmune conditions, exacerbated the autoimmune response in a quarter of patients [2].
While the development of autoimmune diseases is clearly multifaceted, much can be learned from checkpoint blockade therapy in cancer patients for the treatment of autoimmune conditions. Indeed, a CTLA-4-Fc fusion protein (abatacept) was the first checkpoint targeting drug used for the treatment of rheumatoid arthritis and has been found to have clinical success [3].
Balancing the immune system is key
Clearly, the maintenance of a balanced immune system is the optimal situation in most instances. However, as scientists and clinicians, we are now able to manipulate this balance as evidenced by targeting inhibitory receptors, providing us with an invaluable immunological tool for the treatment of diseases such as cancer and autoimmunity.
1. Larkin, J., et al., Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med, 2015. 373(1): p. 23-34.
2. van der Vlist, M., et al., Immune checkpoints and rheumatic diseases: what can cancer immunotherapy teach us? Nat Rev Rheumatol, 2016. 12(10): p. 593-604.
3. Blair, H.A. and E.D. Deeks, Abatacept: A Review in Rheumatoid Arthritis. Drugs, 2017. 77(11): p. 1221-1233.
Dr Mairi McGrath
EFIS President’s Office
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