Tipping the Scales
The human body is full of complex processes that are constantly being dialed up or down to keep us healthy.
“Our body’s immune system is a prime example of this complexity,” says Jeong Kim, scientist and group leader at Genentech. “Immune cells have developed a series of molecular checks and balances that can activate the immune system to heighten our defense against foreign invaders, or inhibit this response from becoming too strong and attacking our own healthy cells.”
Maintaining Balance in the Immune System
When a virus or bacterium strikes, the immune system usually kicks into high gear. But cancer is different; because cancer cells are actually very similar to healthy cells, the immune system typically fails to be sufficiently activated. As a result, cancer cells can multiply and spread throughout the body unchecked.
Cancer immunotherapy is designed to shift the balance toward activation, spurring the immune system to attack cancer cells and minimize the effect on healthy ones. But the immune system is complex, and there are many different ways to tip this scale in either direction. So how do we do this? Let’s take a look.
T Cell Boost
The goal of immunotherapy is to harness the power of T cells, immune cells that can recognize and attack cancer cells. To do this, T cells first need to be activated. Specialized immune cells— called antigen presenting cells—display cancer-specific proteins called antigens that allow T cells to recognize the target they need to attack. This also triggers a series of cellular events that leads to T cell activation.
One investigational approach we’re working on is to target this specific process. When T cells are presented with antigens, a protein called OX40 on the cell’s surface helps enhance T cell activation. By using an immunotherapy called anti-OX40—which counter to its name is an antibody that actually binds to and turns on OX40—we can increase immune system activation.
“In some ways, anti-OX40 appears to work like a T cell ‘‘power boost’ that may enhance different properties to make them more effective at fighting cancer,” says Lisa Damico-Beyer, project team leader at Genentech. “It’s thought that one effect of anti-OX40 is to actually increase the number of T cells that can be mobilized to seek and attack cancer cells.”
Anti-OX40 may also increase T cell survival, which means these cells might live longer and have more time to form a “cellular memory” against cancer antigens. Having a cellular memory can produce a faster and stronger immune response against cancer cells when they are encountered again.
An additional benefit of anti-OX40 may be increased production of immune system alarm signals called cytokines. As Damico-Beyer explains, “Anti-OX40 may help T cells produce a number of cytokines, like interferon-gamma, that are known to have anti-tumor properties.”
Increasing immune system activation with investigational tools like anti-OX40 is a promising strategy for fighting cancer. However, sometimes focusing on just activation may not be enough to tip the scale – we also need to reduce inhibition.
One of the challenges with immunotherapy is that cancer is smart, and has evolved ways of hiding from the immune system. As an example, PD-L1 is a protein found on cancer cells that tips the scale in favor of immune system inhibition. It does this by binding to proteins on the surface of T cells called PD-1 and B7.1, which inactivates them.
In another type of immunotherapy, we can use an antibody that blocks PD-L1 (called anti-PDL1) from binding to PD-1 and B7.1 on T cells. Anti-PDL1 may allow T cells to recognize and attack cancer cells, potentially reducing inhibition, and tipping the scale back towards immune system activation.
Working the Cycle
A way to conceptualize these two different approaches to immunotherapy is the Cancer Immunity Cycle, which outlines the seven steps required to mount an effective immune response and protect the body against cancer. Our scientists are targeting various steps in the cycle. In this particular instance we’re focusing on Step 3 (anti-OX40) and Step 7 (anti-PDL1) because of their complementary roles in T cell activation and cancer cell recognition.
By targeting multiple steps in the cycle, our scientists are taking a comprehensive approach to cancer immunotherapy, and are evaluating which combinations of approaches may best recruit the immune system to attack specific cancers. These types of immunotherapy approaches may also affect healthy cells, which is why our scientists are committed to studying them further in both the lab and the clinic.
Shifting the Balance through Combinations
“The Cancer Immunity Cycle has provided us with a roadmap for finding unique ways of helping the immune system, and it’s our job to discover which combinations may work best,” says Kim. “By increasing activation with anti-OX40 and reducing inhibition with anti-PDL1, we may have found a way to tip the scales in favor of the immune system, and its all-important job of fighting cancer.”