Cancer immunotherapy

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Engineered antibodies may be designed to help the body's own defense mechanisms fight diseases. For example, antibodies used in cancer immunotherapy — an emerging therapy option for cancer patients — aim to activate or support the body's immune system in identifying and destroying cancer cells.

At Roche Pharma Research and Early Development, we are working on a novel form of engineered antibodies for cancer immunotherapy that we call T-cell bispecifics.

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The immune system is a very large army of cells, organized in different specialized units and regulated by a complex network of messengers. Normally, this defense mechanism protects against foreign organisms such as viruses and bacteria, as well as cancer cells. Sometimes, these mechanisms can fail, and diseases — including cancers — develop. When the immune system fails, cancer immunotherapy helps it get back into action.

Among the many types of cells in the immune system, T-cells are the most powerful ones that specifically attack cancer cells.

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Normally, T-cells engage in this fight only when they receive a specific message from the cancer cells, presented by an ambassador — the so-called major histocompatibility complex, or MHC. The message is triggered when the ambassador raises specific flags on the cell surface. These flags are called antigens. Only when the ambassador's flags are recognized as foreign do T-cells spring into action. This ensures that no healthy cell is attacked by mistake.

T-cell bispecific antibodies are basically matchmakers between T-cells and cancer cells.

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These antibodies have two handles that recognize specific markers on the surface of cancer cells, and one handle that is designed to hook to T-cells, bringing them into close proximity to the cancer cells. The T-cells are then activated to attack the cancer cells. The ambassador role of MHC is not needed anymore, while the need to recognize tumor markers keeps the intervention specific to cancer cells.

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T-cell bispecific antibodies are designed to be very similar to natural antibodies and to have a long half-life. They can do their job on their own, without requiring further technology or modification of the T-cells. This is what makes T-cell bispecific antibodies a potential new therapeutic option for cancer patients.

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[Music] Our task at Roche is to find ways to help our immune system fight not only infections, but to enhance it so it can also fight cancer — and our research has given us the understanding and opportunity to do exactly that. Recent research into cancer immunotherapy and human immune biology has led to two innovative approaches to treating cancer from the Roche Research and Development teams.

One of these exciting approaches is the ability to understand how best to separate all human cancers — of which there are over 200 known types — into just three primary immune profiles.

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We refer to these profiles as:

Inflamed tumors

Immune-excluded tumors

Immune deserts

When thinking about these profiles, we like to think of an army of immune cells, also known as T-cells. When the tumor is inflamed, it has an army of T-cells armed and ready to attack the cancer from inside the castle grounds of the tumor. We call the castle grounds the tumor microenvironment.

When the tumor is described as immune-excluded, you can imagine the T-cell army is ready to attack but is unable to scale the walls or cross the moat of the castle to attack effectively.

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Finally, the immune desert is exactly as it sounds — there is a tumor, but no T-cell army is present to mount an attack.

Now, the importance of understanding this biology is that we can start to be very specific about what we are trying to do in any person that presents with one of these immune profiles. This allows us to apply different treatment strategies to target the individual immune biology, ensuring that the individual has the best chance of a response to a specific treatment.

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We now understand that by using this vital information — together with another approach to personalizing treatments — we can target specific immune biologies even further.

The cancer immunity cycle is a framework that my friend and colleague Dan Chen and I devised, which helps to describe how a tumor interacts with the immune system. We've broken that down into seven major steps. Here's Dan to explain the seven steps:

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The cancer immunity cycle is a framework that helps to describe how a tumor interacts with the human immune system.

Step 1: This is where cancer cells die and release antigens — protein bits of themselves.

Step 2: Those protein bits can get picked up by antigen-presenting cells, such as dendritic cells, which migrate to local draining lymph nodes.

Step 3: In the lymph nodes, those antigen-presenting cells can present the cancer protein bits to T-cells. When functioning correctly, these T-cells become activated against those proteins.

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Step 4: Activated T-cells enter the bloodstream and circulate throughout the body, searching for tumor deposits.

Step 5: T-cells arrive at the tumor site and must now infiltrate the tumor by exiting the blood vessels and entering the tumor microenvironment.

Step 6: Within the microenvironment, T-cells must recognize cancer cells. T-cells are highly specific and will look for their target protein bits on the surface of cancer cells.

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Step 7: Once the T-cell recognizes a cancer cell, it must kill it. This step is critical. However, many inhibitory factors can block a T-cell from effectively killing cancer cells.

Blocking PD-L1 or other inhibitory signals may help those activated T-cells do their job. And once they succeed in killing a cancer cell, the cycle restarts.

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So now that we understand the cancer immunity cycle, we can ask:

Whom do you give a cancer immunotherapy to?

Which therapy is most likely to achieve the best results for an individual patient?

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Armed with this level of knowledge — and a detailed map of potential treatments and pathways — we are now able to target specific steps of the cancer immunity cycle. This helps our own bodies fight cancer, and takes us a step closer to personalizing cancer immunotherapy for individual tumors and people.

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