The I-O Quest

From biologic discovery to translational science, Bristol Myers Squibb’s I-O experts are engaged in a relentless pursuit to discover, develop, and design the next generation of immunotherapies. 

Hunting Promising Targets

The hunt starts by learning as much as possible about the biology of cancer and the human immune system. Nils Lonberg, senior vice president of Oncology Biology Discovery, says three biological mechanisms affect cancer’s ability to evade detection and grow out of control:

1. Cancer cells have mutations that may or may not be expressed. Cancer cells are fickle. They might make neoantigens, proteins on their cell surfaces, that enable immune cells to detect their presence and target them for destruction, or they might not. Not to mention, the total number of mutations varies among cancer types. Childhood leukemias, for example, are driven by a limited set of mutations that can be well controlled with targeted therapies. Most cancers, though, have many mutations that make them hard to target, thus allowing them to grow out of control.  
2. The balance of the body’s inflammatory response is disrupted. In a healthy inflammatory response, immune cells respond to signals by rushing in to deal with a problem, causing inflammation and swelling—like when you cut your finger and it becomes red and swollen. When the threat is over, other signals tell the inflammatory response to end so that the wound can heal. A healthy body maintains a proper balance in both directions of the inflammatory pathways. Tumors, however, are stuck at a particular point in this cycle where inflammatory attenuation signals have shut down a productive T-cell response before the cancer cells have been cleared. 
3. Cancer cells are always mutating. Like bacteria, cancer cells are under tremendous molecular pressure, rapidly dividing and mutating all the time. New mutations can equip cancer cells with other ways to escape attack from immune cells, such as blocking infiltration, masking themselves from detection, or developing resistance to earlier therapies by expressing different surface proteins.

As a means of identifying the most promising targets to pursue, scientists look for the specific protein receptors on the surfaces of immune cells that are involved with those biological mechanisms. Bristol Myers Squibb is researching dozens of targets at various stages of investigation.

That input-gathering process includes reviewing published literature, scouring The Cancer Genome Atlas—a large public database that has multidimensional diagrams of genomic mutations in 33 types of cancer—and analyzing genomic datasets from patients in clinical trials. “We look for targets that are highly expressed in tumor types that have a higher incidence and a higher medical need,” says Bruce Car, vice president and head of Translational Sciences.

"We are actively engaging commercial partners  who have diagnostic expertise and a global market reach to ensure that we are delivering the best customer experience and bringing the right drugs to the right patients," says Anil Kapur, vice president, I-O Early Assets & Biomarkers Commercialization. Biomarkers can be used to characterize a tumor and the tumor microenvironment, which may inform how a patient might respond to immunotherapy. Companion diagnostics are used to identify patients who will benefit from an available treatment.

Pursuing Next Generation I-O Research

The next generation of I-O research is already underway across the sector. With it has come an exciting shift in approach to investigate combination treatments that may be able to address more than one cancer target at the same time.

“If cancer is like a room that has multiple lights turned on, standard chemotherapy is like breaking all the lights at once to turn them off,” says Steven Averbuch. “Targeted therapy, using a targeted drug to treat a cancer largely driven by a single mutation, is akin to turning off a switch that controls most of the lights in the room. In our current era of immuno-oncology, we are researching a whole bank of light switches that we hope to one day be able to turn off in different sequences and combinations along the patient journey.”

Furthermore, a growing number of industry collaborations with biotech firms and academic research centers will allow Bristol Myers Squibb to leverage new understandings about the nature of cancer, and find new ways to use informatics and other tools to apply data in a way that wasn’t possible in the past.

“We’re getting closer to knowing why some people respond to I-O and others don’t,” Averbuch says. “Our goal is to keep going in hopes that we can potentially turn out the lights on cancer for good.”