What is I-O? What are checkpoint inhibitors?
What is immuno-oncology?
The field of immuno-oncology, also known as cancer immunotherapy, is centered on mobilizing the immune system to attack cancer cells and eradicate tumors. With this approach, therapeutics target molecules on lymphocytes that will either activate them or keep them from being inactivated, in order to sustain the immune response. With a sustained response, the immune system can search for and eliminate cancerous cells and tumors. Many years of research and development went into targeting these types of molecules on lymphocytes and, finally, with the approval of Yervoy® (ipilimumab, www.yervoy.com/) by Bristol-Myers Squibb in 2011 for late stage melanoma, the age of immuno-oncology began.
What is Yervoy®?
Yervoy® is a therapeutic antibody that targets the CTLA-4 molecule on T cells to prevent inactivation of T cell function. It was the first therapeutic molecule in immuno-oncology to be approved by the FDA and now belongs to a class of therapeutics called immune checkpoint inhibitors, which function to sustain the immune response.
Yervoy® works by binding CTLA-4 to prevent interaction with B7, its natural ligand. When bound to B7, CTLA-4 downregulates signaling pathways in T cells to inactivate them. However, in the presence of Yervoy®, the T cells remain functional because CTLA-4 cannot engage B7 to downregulate activation signals.
Are there other immune-oncology checkpoint inhibitors in the market?
With the approval of Yervoy® and its demonstration that the immune response could be used to fight cancer, the stage was set to identify more checkpoint molecules and develop checkpoint inhibitors. Today, there are 3 checkpoint inhibitors (including Yervoy®) on the US market with many more in development: Opdivo® (nivolumab, www.opdivo.com/) by Bristol-Myers Squibb and Keytruda® (pembrolizumab, www.keytruda.com/) by Merck both target the PD-1 molecule, which, like CTLA-4, downregulates T cell function. All three checkpoint inhibitors are approved for melanoma, while Opdivo® is also approved for squamous non-small cell lung carcinoma.
There are currently a number of checkpoint inhibitors in development by various biotech/pharma companies. Genentech/Roche and AstraZeneca/MedImmune are independently developing therapeutics that target the ligand for PD-1 called PD-L1. Genentech’s molecule has received “Breakthrough Therapy” designation from the FDA for bladder cancer, while AstraZeneca/MedImmune is working with the Cancer Research Institute (CRI) to bring the drug to patients with CRI’s Clinical Accelerator Program.
What’s the impact of immuno-oncology?
The impact of immuno-oncology has been tremendous on cancer treatment. Cancer treatment has evolved from using chemotherapies that are effective, yet harmful; to targeted therapies that home to specific cancer cells; to therapeutics that mobilize the immune system. With this latest class of therapeutics, doctors are armed with another set of treatment options, whether as stand-alone treatments or in combination with other therapeutics. Indeed, a survey of current clinical trials shows a number of combinatorial therapy trials in progress. In particular, checkpoint inhibitors have been paired with traditional chemotherapies, targeted therapies, or other checkpoint inhibitors.
In our next blog, we’ll visit several proteins known to be modulators of the immune response that are being developed as therapeutics. Stay tuned for Part 2!