Cancer Immunotherapy
As previously discussed, many inhibitory checkpoints provide another major platform for cancer to evade detection and killing by the immune system. Blocking their action therefore, should release their hold on the immune system’s function (1). This might be particularly useful in combination with immunotherapy such as vaccines that aim to boost the immune system’s specific recognition of cancer cells. We could expect T cell responses to cancer to increase, immunosuppression to decrease and perhaps some unwanted immune activity such as autoreactivity. The name for this type of therapy is 'Immune Checkpoint Blockade'.
There are many targets for immune checkpoint blockade, however the two of interest to us are CTLA-4 and PD-1, blocked by the monoclonal antibodies Impilimumab and Nivolumab respectively. We've chosen to examine these because according to several studies, they have a rather intertwined relationship. Referring back to the "importance of context" when it comes to the immune system, we'll see shortly that CTLA-4 and PD-1 must sometimes be considered together. Due to their similar actions and mechanisms, it could be argued that they make one another somewhat redundant. Based on that, targeting one of them alone might allow the remaining checkpoint to continue to prevent the immune system from mounting a sufficient response against the tumour cells. Therefore, combinatorial blockade therapy may have further perhaps even synergistic beneficial effects (2).
The figure to the right by Chang et al, provides a basis to the synergism of combined CTLA-4 and PD-1 blockade. It shows that blockade of both CTLA-4 and PD-1 improves CD8+ T cell functional recovery, better than the cumulative individual benefit of both individually (3). Despite this being in the context of viral infection rather than cancer, the principle of a synergistic increase in cellular immune response due to combined therapy, still stands. In any case, this result is also apparent when considering immune response to tumours. In fact, tumour eradication in mice is synergistically improved by combination therapy (4).
Perhaps most exciting, are the results of a very recent study in July 2015. 945 untreated melanoma patients were divided equally and received either Ipilimumab, Nivolumab or Ipilmumab and Nivolumab. The respective median progression-free survival rates were 2.9 months, 6.9 months and 11.5 months (5).
References
1. Egen J, Kuhns M, Allison J. CTLA-4: new insights into its biological function and use in tumor immunotherapy. Nature Immunology. 2002;3(7):611-618.
2. Sharma P, Allison J. Immune Checkpoint Targeting in Cancer Therapy: Toward Combination Strategies with Curative Potential. Cell. 2015;161(2):205-214.
3. Nakamoto N, Cho H, Shaked A, Olthoff K, Valiga M, Kaminski M et al. Synergistic Reversal of Intrahepatic HCV-Specific CD8 T Cell Exhaustion by Combined PD-1/CTLA-4 Blockade. PLoS Pathog. 2009;5(2):e1000313.
4. Mangsbo S, Sandin L, Anger K, Korman A, Loskog A, Tötterman T. Enhanced Tumor Eradication by Combining CTLA-4 or PD-1 Blockade With CpG Therapy. Journal of Immunotherapy. 2010;33(3):225-235.
5. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. New England Journal of Medicine. 2015;373(13):1270-1271.
6. Kandalaft L, Powell D, Singh N, Coukos G. Immunotherapy for Ovarian Cancer: What's Next?. Journal of Clinical Oncology. 2010;29(7):925-933.
7. Hanahan D, Weinberg R. Hallmarks of Cancer: The Next Generation. Cell. 2011;144(5):646-674.