In the December 2013 issue of Science, Cancer Immunotherapy was named as the Breakthrough of the Year.   My initial reaction to this was a little shocking and wondering what finally swayed the sceptics to realize this?  Internally, we have been calling it a breakthrough for sometime, what did we mean by calling it a breakthrough in the first place?

If is not clear, immunotherapy may very well be the end for Cancer even if the future remains a question mark.  In the previous few ASCO meetings immune checkpoint blockers has brought forth encouragement for people suffering with Cancer and undoubtedly become the highest-profile area of drug development.  It has been driven by remarkable data seen in early clinical studies of the anti-PD-1/PDL-1 agents that has marked out this drug class as the potential future cornerstone of therapy for many solid tumours.   This is a radically different way of treating cancer – by targeting the immune system, not the tumour itself.

At the foundation of the immune response we need T cells that play a central role in cell-mediated immunity. T cells are immune cells that are ordinarily activated in response to cancer cells in order to seek and destroy them.   T cells also have a regulator switch in the form of PD-1 on there surface to stop them from continuous destruction once the target cells are gone, this acts as a failsafe to stop them from destroying healthy tissue – hence, the origin of the term immune checkpoint.  However, cancer continues to evolve and become intelligent and tumour cells have evolved by producing the ligand PD-L1 and PD-L2 on the surface.  This naturally produced ligand binds PD-1 and trips the shutdown switch stopping the T Cells from doing there job.  The objective of the checkpoint blockers is come between the receptor and the ligand, turning the switch back on and freeing the T cells to attack cancer.  This is commonly referred to as removing the veil or cutting the “brakes,” which stops immune cells to see tumour cells as “self” and an immune response to continue.

What is cancer Immunotherapy?

Immunotherapeutic approaches leverage the patient’s immune system to eliminate or slow the growth and spread of cancerous cells. Older biologic agents such as interferon alpha2b and Proleukin (IL-2) were used with some success in the 1990’s but had limited impact given high toxicity and limited patient responsiveness in only select tumour types. New advances in tumour biology are enabling the development of newer potent T-cell mediated therapies that prevent the tumour from evading immune detection with manageable safety profile.  Experimental T-cell immunotherapy comprises multiple modalities. These include checkpoint blockers (such as, anti-CTLA-4, anti-PD1/ PDL-1, CD137 etc.), therapeutic vaccines, oncolytic viruses, bispecific antibody-based approaches, small molecules  and more recently cell-based therapies.  A report published by Citi Research on Immunotherapy in May 2013 estimated the market for immunotherapeutic approaches in cancer treatment will likely exceed $35bn by 2023, driven by novel agents, combination therapy, longer treatment times and the emergence of predictive biomarkers.

Citi Research further went on to conclude that, “in 10 years, immunotherapy will likely form the backbone of 60% of all cancer management regimes in the developed world given likely paradigm shifting changes in OS improvements in responsive patients.”

Immunotherapy will likely form the backbone of c.60% of all cancer treatment in 10 years compared with <3% today

Who are the players dominating the immune checkpoint blockers space?

Bristol-Myers Squibb’s anti-PD-1 agent, nivolumab, has shown remarkable activity and duration of response in melanoma and several other indications this year, which has propelled it up the industry rankings to become the most valuable oncology project and its two close competitors, Merck & Co’s anti-PD-1 antibody MK-3475/ lambrolizumab and Roche’s anti-PDL-1 antibody, RG7446 (MPDL3280A), follow closely behind.  Merck has significant basic science research experience backing its anti-PD-1.  While Roche has no other late-stage checkpoint inhibitors, it has an immune-conjugate platform and leading monoclonal antibody design expertise, which facilitates the development of many anti-PDL-1 based combination therapies.

The anti-PD-1/PDL-1 agents appear to be on a path towards becoming a cornerstone of therapy for many, perhaps even most, solid tumours.  Most of the studies to date have been of monotherapy.  Yet the real potential of these drugs may lie in there use in combination, either with other immunotherapy agents, cancer vaccines or types of cancer drugs.  Although it is still too early to tell whether they will be used in combination or sequence with existing therapies.  2014 should see key study readouts for the three anti-PD-1/PDL-1 agents that could inform this debate, as well as the start of new studies that look set to define the emerging competitive landscape.