I-O Quest

The I-O Quest

Exploring the research behind why some people respond to immunotherapy and others do not.

June 02, 2017

I

mmuno-Oncology (I-O), and the research behind it, aspires to beat cancer at its own game. But despite the progress to date, fewer than 50 percent of patients respond to I-O, depending on the patient population and the specific types of cancers involved. A stat like that begs the question: Why do some people respond to immunotherapies while others don’t?

Nils Lonberg

Nils Lonberg

Building on knowledge gleaned from more than 20 years of researching immunotherapies, Bristol-Myers Squibb scientists are hunting for answers to that question at an accelerated pace. Powered by translational medicine, researchers are using cutting-edge technologies to define the complex and unique interactions between the tumor, tumor microenvironment, immune system and individual patient and uncover new insights that will inform the next generation of oncology therapies.

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 express neoantigens --proteins on 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. Some cancers, such as melanoma, are more likely to express high volumes of mutations, making them more visible to the immune system, but others, like pancreatic cancer, have lower volumes of mutations which can make them hard to target. 
  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 allow cancer cells to leverage different immune evasion mechanisms, and in some cases, cause patients to become resistant to available therapies.

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.

Tim Reilly

Tim Reilly

"We follow the science, taking all the input around a potential target by studying the disease, conducting animal studies, looking at translational data, and then forming hypotheses to test and see what happens,” says Tim Reilly, vice president and head of Oncology Early Asset Development. “We also include the ability to learn why something worked or didn’t work, no matter the outcome. Understanding why something doesn’t work is often just as important as understanding why it did."

Bruce Car

Bruce Car

That input-gathering process includes reviewing published literature, scouring The Cancer Genome Atlas—a large public database that has multi-dimensional 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.

David Feltquate

David Feltquate

 

Evaluating Clinical Research Data

Bristol-Myers Squibb is currently studying many molecules specifically engineered to target different immune system pathways in a variety of cancer types.

“We adapt our drug development program based on what we learn, and it’s an iterative process,” says David Feltquate, head of Oncology Early Clinical Development. “With the tools at our disposal today, we aim to identify patients who are more likely to respond, by specific characteristics, much earlier in the research process. Those characteristics inform and enrich our whole program. And we don’t give up on the patients who are less likely to respond; we try to offer something else that may work instead.”

In addition to collecting standard clinical trial data such as safety information and response rates, the company’s scientists are also using advanced imaging technologies to examine the biology of immune response processes at the millimolecular level (one-thousandth of a molecule), which allows them to see more precisely how cancer responds.

"One example is the development of imaging agents that help us use PET imaging (positron emission tomography) to visualize interesting biology in patients," Feltquate says.

Learn More: The role of immune biomarkers in the tumor microenvironment

 

In addition to collecting standard clinical trial data such as safety information and response rates, the company’s scientists are also using advanced imaging technologies to examine the biology of immune response processes at the millimolecular level (one-thousandth of a molecule), which allows them to see more precisely how cancer responds.

"One example is the development of imaging agents that help us use PET imaging (positron emission tomography) to visualize interesting biology in patients," Feltquate says.

Pursuing Next Generation I-O Research

The next generation of oncology research is already underway, and researchers are working with urgency to advance research into treatment options that will make precision oncology a reality for more patients. Furthermore, a growing number of industry collaborations with biotech firms and academic research centers will enable 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. But no matter what direction oncology research takes, our goal remains the same – to increase quality, long-term survival for patients with cancer and make cure a possibility. 


Related Content

Thomas Lynch

Advancing Translational Cancer Research—Together

Collaboration could be the key to researching and discovering the next generation of I-O compounds

Applying Lessons from the Past

Head of Oncology Development Fouad Namouni discusses shifts in cancer research and what lessons can be learned from the past.