The immune system is the body’s first line of defense when it comes to fighting cancerous cells. It can identify and attack the smallest of threats before they become a danger, and distinguish tumor cells from the body’s normal cells, protecting our essential systems. But the immune system isn’t always successful. Tumor cells have mechanisms to evade or suppress immune response, allowing them to masquerade as normal cells and grow without restraint.
“Cancer cells can mutate in ways that make them undetectable to the immune cells. In other cases, a dysregulation in the body can lead to key signals being shut down so the immune system doesn’t respond as it should,” says David Feltquate, head of oncology early clinical development at Bristol-Myers Squibb.
Every tumor is unique: some respond well to chemotherapy, targeted or immunotherapy treatments, while others become resistant after an initial response or don’t respond at all. Researchers are looking at the tumor microenvironment to better understand how the tumor and immune system coexist, which could ultimately help inform the future of cancer treatment.
SETTING THE STAGE
The tumor microenvironment refers to the network of cells and structures that surround a tumor, including stroma, the connective cells and tissue, and immune regulatory cells, such as Tregs (regulatory T cells) and antigen presenting cells. In a healthy person, the immune system detects a cancerous or mutated cell and activates cytotoxic T cells, which recognize the tumor cell and target it for elimination. This process happens naturally in the body multiple times per day. But some cancer cells manipulate their environment and suppress the immune response, which prevents the T cells from detecting and eliminating threats.
“Think of it as a garden. When you see weeds start to bud, you pull them out before they cause any trouble,” says Feltquate. “But if you don’t see the weeds, they’ll start to multiply and overtake the garden, making them significantly more challenging to remove. In this case, the tumor cells escape the immune system and grow unchallenged.”
Researchers investigating the tumor microenvironment have uncovered a number of pathways that up- or downregulate T cell activity. Research into those pathways has already led to a new class of immuno-oncology treatments known as checkpoint inhibitors, which disrupt immunosuppression and restore T cell activity.
The immune system has a type of immune checkpoint receptor known as PD-1 (programmed death-1). PD-1 has two ligands, PD-L1 (programmed death ligand-1) and PD-L2 (programmed death ligand-2), that work to inhibit cytotoxic T cell activation and prevent an overactive immune response. But some tumors upregulate the PD-1 receptor, which restricts the ability of T cells to respond and disables essential functions, including the ability to fight tumor cells. PD-1 immune checkpoint inhibitors are designed to bind to PD-1 expressed on activated T cells, and enable the immune system to recognize, attack and destroy cancer cells.
While checkpoint inhibitors have demonstrated remarkable potential, not all tumors have a sustained response to them. Scientists are working to rapidly expand their knowledge of the tumor microenvironment and learn how to target even more pathways, some in combination with PD-1, to get the strongest anti-tumor response for as many patients as possible.
MAKING THEIR MARK
As researchers learn more about immune response, they are also looking at new ways to characterize tumors to predict how they might respond to treatment. Researchers now believe that the presence of certain biomarkers could indicate the specific pathway, or pathways, a given tumor uses to suppress the immune response. If researchers can understand a tumor’s method of immune suppression, they can begin to formulate a personalized approach to treatment.
For example, scientists at Bristol-Myers Squibb are studying an immune checkpoint receptor known as LAG-3 (lymphocyte-activation gene 3), a checkpoint pathway that acts in concert with PD-1. Typically, LAG-3 plays an essential role in regulating immune function by halting T cells before they can attack healthy cells.
“LAG-3 in the tumor microenvironment causes T cells to become desensitized and lose their ability to activate and target tumor cells. In some cases, tumors express increased levels of LAG-3 as an ‘escape door’ to evade anti-PD-1 therapy and continue to grow,” says Tim Reilly, head of oncology early assets development at Bristol-Myers Squibb. “Our research suggests that the higher the levels of LAG-3 in the tumor microenvironment, the more susceptible certain tumors may be to targeted investigational inhibitors.”
Another type of biomarker known as tumor mutation burden (TMB) is also being studied to help identify patients who may be more responsive to immuno-oncology treatments.
“TMB is the number of mutations carried by tumor cells,” says Jean-Marie Bruey, head of oncology biomarkers at Bristol-Myers Squibb. “As tumors acquire mutations, they begin to express proteins that result in the formation of neoantigens, which are more easily identified by the immune system. This has led us to believe that tumors with more mutations may have a higher likelihood of responding to immuno-oncology treatment.”
Scientists hope that by mapping key biomarkers, they’ll develop a more precise understanding of each individual’s disease biology and the therapies that could fight it.
“Ideally, when a patient is first diagnosed with cancer, we’ll be able to do a genetic analysis on their tumor, identify these biomarkers in the tumor microenvironment and determine a personalized course of treatment,” says Saurabh Saha, head of translational medicine at Bristol-Myers Squibb. “We’ve already started doing this to some extent for checkpoint inhibitors, but to see the field expanding with more biomarkers and treatment options is an exciting step towards precision medicine for more patients.”
THE FUTURE OF CANCER CARE
Researchers have made remarkable progress since discovering the intricacies of the tumor microenvironment, but there’s still a lot to discover. Companies like Bristol-Myers Squibb are investing in translational medicine to further the understanding of cancer biology and to identify the patient populations most likely to benefit from immuno-oncology therapy. Through advanced technologies, such as bioinformatics and digital pathology, as well as sophisticated pharmacology and pharmacometrics, scientists can see more, analyze more and glean better insights that could help inform clinical trial design and, ultimately, treatment choices.
“We’re starting to see the future possibility of finding the right treatment combinations for the right patients at the right time,” says Feltquate. “We still have a long road ahead, but every day, and every new learning, brings us one step closer to our goal of changing the outcomes for patients with cancer.”