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Immunotherapy in oncology

August 5, 2016 | cancer immunotherapies, immuno-oncology, immunotherapy

Consultant David Cooney explores the medical insights, unmet needs, and future of the vastly growing area of immunotherapy as the fourth pillar in oncology.

We’ve been killing cancer cells for years. We’ve poisoned them, starved them, targeted them, lysed them, and irradiated them – even cut off their blood supply. This has led to major progress in disease control and prolonging the survival of cancer patients, but there are still major areas of unmet need. We are certainly some distance away from the Obama administration’s moon-shot of curing cancer… or are we?Immunotherapy has progressed at a phenomenal rate over the last 5 years, and it is now seen as the fourth pillar of care in oncology. To date, Blue Latitude Health have worked with 4 of the 9 immunotherapies currently approved by the FDA, and this article will provide an overview of the area; sharing some of the scientific, medical and commercial insights we have picked up as well as the topics we anticipate will shape the future of this exciting and innovative pillar of cancer care.

What is Immunotherapy?

Immunotherapy, is a type of cancer treatment designed to boost the body’s natural defences to fight the cancer. It uses materials either made by the body or in a laboratory to improve, target, or restore immune system function.

To understand the value of immunotherapy, it is important to consider the dynamic relationship between a tumour and the immune system. This can include anti-tumour immunity and tumour-promoting inflammation; the process is known as immunoediting.

Three states of interaction exist in immunoediting;

Elimination, in which the immune response eradicates cancer cells
Equilibrium, in which the immune response controls tumour growth
Escape, in which the tumour outgrows the immune response.

These three states align with the clinical observations of response, stable disease and progression of disease. However, what is critical about this concept is an understanding that there is a survival benefit when a patient is in both a state of elimination and equilibrium.

This is very different to how we currently assess chemotherapies – by their response rates – where stable disease would be perceived as a poor response. With immunotherapies, even patients with stable disease have experienced significant survival benefit while responders have far exceeded the typical expectancy.

This was the case with the development of ipilimumab (Yervoy) where response-based endpoints (overall response rate [ORR] and progression free survival [PFS]) were the primary endpoints of the phase II trials. This yielded results of 5-15% ORR, which were relatively low at inspection. However, the group recognised that delayed responses and prolonged stable disease were having a significant survival benefit, underscoring the clinical benefit of the therapy. This led to a changing of the primary clinical endpoint for the phase III trials to survival, which proved pivotal in demonstrating the clinical value of ipilimumab and leading to its approval by the FDA in March 2011.

This was a crucial learning in how we interpret immunotherapeutic data, and led to the development of the immune-related response criteria (irRC). This criteria will be critical to the development of immunotherapies as well as the correct use of these therapies in the clinic. One of the phenomenon we have seen with products we have worked with is tumour flare, where tumours or lesions increase before they can shrink. This has also been called pseudo-progression, and poses a risk of patients being taken off treatment before the benefit of the therapy has taken effect.

Time is a critical factor in immunotherapy due to the nature of the immune system, and understanding the different systems for immunity help shine a light on why responses take time.

Download the full article from Blue Latitude Health

This content was provided by Blue Latitude Health