‘Accelerators and brakes’ to restore immune balance

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Our immune system is the most complex and sophisticated of the body’s defence mechanisms. Its key ability is to tell the difference between “self” and foreign, in order to defend against infections and diseases.

For reasons not fully understood, this ability is sometimes corrupted, such that the immune system goes into overdrive and begins to attack the body’s normal, healthy organs and tissues, causing deterioration and destruction.

Such immune-mediated diseases are relatively frequent (e.g. more frequent than cancer), and disproportionately affect women. To date, there are more than 80 known immune-mediated diseases, which can vary greatly in the severity of symptoms and their frequency of occurrence. However, all of these diseases have an enormous negative impact on peoples’ quality of life, and often affecting their work and social activities.

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For the most commonly occurring immune-mediated diseases, such as rheumatoid arthritis and inflammatory bowel disease, there are number of treatment options available. Nevertheless high medical need remains as none of these options achieves complete and long-lasting improvement of symptoms (remission) in the majority of patients.

Moreover, for many immune-mediated diseases, such as Sjögren’s syndrome, lupus nephritis and type 1 diabetes, there is simply no effective disease-modifying treatment available at all. We are actively pursuing research and development of potential new treatments for these diseases.

Current treatments usually suppress the whole immune system

In the attempt to combat the overdrive of the immune system, current treatments usually drastically suppress the whole immune system. These treatments include traditional immunosuppressants (e.g. methotrexate or corticosteroids) or biologic medicines that block broadly acting cytokines (chemical messenger molecules, e.g. Tumour Necrosis Factor or TNF) or reduce the levels of immune cells (e.g. B cells).

However, the suppressed immune system is no longer able to react efficiently against foreign bodies (e.g. pathogens). Patients can thus suffer from serious infections or other diseases due to the lack of proper defence mechanisms. The choice is, so to speak, between immune-mediated diseases or risk of life-threatening infections. In addition, long-term use of corticosteroids causes many serious side effects that contribute to organ damage and loss of their function.

Our approach aims to restore immune balance

Our research and discovery efforts at Roche are driven by scientific understanding of innate and adaptive immunity as well as tissue-driven inflammation, and are applied to the understanding and treatment of various immune-mediated diseases, such as autoimmune, inflammatory and fibrotic disorders.

Our approach is to develop treatments that can hopefully fine-tune (modulate) the immune system, instead of suppressing it. The aim is to restore the original balance (homeostasis) of the immune system, with no overdrive and no complete suppression. This should translate into more durable remissions and improved safety of treated patients.

To achieve immune balance, we need to understand the immune pathways, the drives of the immune system responsiveness. Today we know that immune-mediated diseases are complex and driven by the malfunctioning of multiple distinct immune pathways. In addition, we know that multiple immune-mediated diseases can share the same immune pathway dysfunction despite affecting different parts of the body. Our strategy is to make use of our growing scientific understanding of these immune pathways to selectively manipulate only those pathways implicated in the immune overdrive of a certain disease.

“If we focus on immune pathways, and develop treatments with this concept in mind, what’s very clear is that once we identify the right treatment to modulate a certain immune pathway, this often gives us an opportunity to treat multiple different immune-mediated diseases with a single drug,” said David M. Lee, Head of Immunology and Infectious Diseases at Roche Pharma Research and Early Development.

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Immune pathways regulate the immune system like accelerators or brakes, and can either activate or block our immune reactions. Therefore, if we could manipulate them with our novel treatments in a very refined way, block the accelerators or engage the brakes, we could restore the natural healthy balance of the immune system.

One example of our targeted immune pathway modulating approach is our initiative in Sjögren’s syndrome, a common rheumatologic disease with currently no available treatments. Instead of suppressing all mechanisms of T-cell activation, we hope to block only the harmful autoreactive antigen presentation driven by a limited subset of antigen presenting cells. This approach promises to leave protective T cell responses intact.

Precision combination therapy may achieve efficacy boost

Recognising the limited efficacy often seen in monotherapy approaches to immune-mediated diseases, another core principle of our strategy is exploration of precision combination therapies to achieve durable remission in these diseases.

This means combining novel immunomodulating therapies with existing ones that have demonstrated safety and efficacy, but perhaps for less than half of all patients. We have seen in infectious diseases and oncology that if you find a safe combination, you may get a synergistic efficacy boost. We hope to achieve that by combining new therapies for tissue-driven inflammation with established immune therapies.

“There has never been a better time for discovery and early development in immune diseases,” says David M. Lee. “A number of recent substantial advances in our understanding of human immune pathways give us new ways of getting more selective treatments for patients, and enable us to enter these very heterogeneous populations with a much higher degree of confidence.” 

Tags: Science, Innovation