Developing the next generation of cancer immunotherapies

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As a leader in the field of cancer immunotherapy – which taps into the body’s own ability to fight cancer – Roche is leveraging its growing insight into this complex process and its decades of expertise in delivering personalised medicines to develop novel immune-based treatment approaches for numerous types of cancer.

There has been massive interest in cancer immunotherapy in the last few years, with primetime TV shows and numerous articles showcasing patients whose tumours were all but eradicated by investigational products that harness the power of the immune system. This is all obviously very exciting, but what information is usually left out of these stories? The fact that this connection between the immune system and cancer was actually suggested more than a century ago. Yet, until recently, most researchers considered it a dead end. But not Pablo Umaña, Head of Cancer Immunotherapy at the Roche Innovation Centre in Zurich, Switzerland.

“We have believed for a long time that cancer immunotherapy could be a powerful, transformative approach to controlling tumours,” Pablo explains, “if we can properly engage the immune system.”

That “if” has been driving Pablo’s work for more than a decade. As a first step into this field, he and his team focused on creating a new technology called glycoengineering, which upgrades the ability of monoclonal antibodies to recruit the innate immune system of patients to attack cancer.

Since then, Pablo’s group has deepened its understanding of the biology of the immune system, how it interacts with a tumour, and the ways it might be manipulated to attack cancer cells more effectively. What they learned has become the roadmap for their current research strategy.

Generate, engage and modulate

“The new class of headline-worthy cancer immunotherapy drugs, known as checkpoint inhibitors, are showing very promising responses in hard-to-treat cancers. However, as single agents they only work in 20-30 percent of patients,” explains Pablo. These patients have tumours that are ‘inflamed,’ meaning they already are infiltrated with immune cells, but the immune response has been halted by a block in the process. The checkpoint inhibitor drugs counteract this block, allowing the immune cells to do their job.

Unfortunately, some inflamed tumours do not respond completely to checkpoint inhibitors because of complex interactions between the tumour microenvironment and the immune system. The remaining patients (70-80 percent) have ‘non-inflamed’ tumours, meaning that they lack immune cells altogether.

The Roche Pharma Research and Early Development Oncology team is investigating ways to improve immune responses against inflamed tumours and also convert non-inflamed tumours into responsive ones. To do so, it has adopted an approach centred on the role that T cells play in tumour immunity. Teams are focused on generating more T cells to attack tumours, engaging T cells directly to attack tumours, and modulating the tumour environment so that T cells can attack tumours more effectively.

As the name implies, ‘immune effector generators’ aim to generate a large new army of immune cells that can recognise the tumour. These could include anti-tumour vaccines or other approaches that could effectively prime the rest of the immune system to generate a response.

‘Immune effector engagers’ are designed to redirect existing immune cells to attack tumour cells that have a specific targeted cell surface marker. This class of agents could include T cell bispecific antibodies that bind simultaneously to tumour targets and T cells.

Finally, ‘immune effector modulators’ are designed to modulate factors that may suppress the immune response. Such treatments could include not only checkpoint inhibitors, but also agents that would aim to eliminate tumour-associated macrophages, or molecules that could revitalise “exhausted” T cells, such as tumour-targeted immunocytokines.

Critical combinations

“At the most basic level, an effective immune response to a tumour requires immune effector cells that recognise cancer cells, are present in the tumour in sufficient numbers, and stay active for long enough to complete the attack,” explains Pablo. “Because different approaches may well be needed to ensure each of these critical steps, synergistic combinations will probably be key to successful treatment.”

In addition, from the earliest stages of discovery, Roche Pharma Research and Early Development Oncology scientists look for biomarkers that may predict which patients will respond to which therapies. This lays the groundwork for Roche Diagnostics to ultimately develop effective tests – a pivotal process that has made Roche the leader in personalised healthcare.

“It is an exciting time to be part of the revolution in cancer immunotherapy,” says Pablo. “We are gaining sophisticated biological insights into why patients respond differently to treatment, and we are aiming to develop fit-for-purpose therapies to unleash the right immune response for the right patient at the right time. We strongly believe that combination therapy will play a critical role in achieving this.”

A personal view on cancer immunotherapy: an interview with Pablo Umaña

Pablo Umaña shares his insights on how the field of cancer immunotherapy will evolve, why scientists in early research remain mindful of people affected by cancer, and what inspires him to come to work every day.

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Pablo Umaña, Head Cancer Immunotherapy Discovery, Roche Pharma Research and Early Development

Where do you think the field of cancer immunotherapy will be in the next five to ten years?

The immune checkpoint inhibitor monotherapies will hopefully be well established and we also hope to have a much better understanding of which patients will respond well. We look forward to seeing the next generation of approaches, using investigational combinations such as T cell bispecific antibodies and immuno-modulators to treat those patients who do not respond well to checkpoint inhibitors. We will learn much from the data coming from advanced clinical trials and hopefully be able to use that to design new molecules and combinations. The challenge is how to prioritise these combinations and the resources needed to validate them in the clinic.

With your focus on molecules and research, is it hard to remain mindful of the people affected by cancer?

Cancer is so common that I don’t think there are any of us today without family or friends who have not been touched by it, which makes our work even more significant. Even though we mainly work in the discovery phase of drug development, we collaborate closely with oncologists conducting clinical trials. They bring a valuable patient perspective back to us that is important when we consider the development of novel therapeutic approaches. On a more personal note, when one of Roche’s drugs was approved and launched, I met many patients who had been in clinical trials to study this drug. These people were tremendously brave, and by going into the clinical trials they not only helped us but they also helped the rest of the world and future patients. Hearing their stories was touching and an experience that I will never forget.

What makes you want to come to work every day?

What drives me is the exciting challenge and opportunity to make a significant contribution to the next generation of cancer immunotherapy molecules. Roche is one of the leading healthcare companies in the world and has the talent, expertise, tools and resources to make this a reality. The great thing about working here is that Roche only invests in differentiated therapies, which means focusing on generating truly novel options for patients. Roche already has a strong and diverse foundation in cancer immunotherapy; to be able to bring molecules to the clinic and test them, particularly in combination, holds tremendous promise to impact many different types of cancer.