Beyond The Cycle

The pace at which cancer immunotherapy is being investigated for many types of cancer is astounding. In fact, clinical insights are often outpacing our understanding of the underlying science. Fortunately, this provides us with a unique opportunity – the ability to combine emerging insights into a new conceptual framework that may help guide the future of personalized cancer immunotherapy.

Researchers build intellectual frameworks to take seemingly disparate concepts and organize them into a cohesive whole. These frameworks not only help us make sense of existing data but also provide a road map for future research. In fact, they’re critical to scientists’ ability to formulate and test new hypotheses – the backbone of all scientific progress.

In cancer immunotherapy, one framework that laid the foundation for a wide range of scientific advances is the Cancer-Immunity Cycle. Published in a seminal paper by Dan Chen, vice president, global head of cancer immunotherapy development at Genentech, and Ira Mellman, vice president of cancer immunology at Genentech, the Cancer-Immunity Cycle breaks down how the immune system mounts an attack against cancer into seven simple steps. Today, the cycle is a guiding principle for cancer immunotherapy research around the world.

However, while simplifying complex biology is essential towards generating and testing new ideas, it is the complexity that defines the basic science and clinical results. In clinical studies we treat people as a population – but as individuals we are all different.

In the years since the Cancer-Immunity Cycle was first published, we’ve learned that the cycle alone can’t explain why some people respond to treatment with current cancer immunotherapies but others don’t. Every person’s immune system is unique, and there are many factors beyond the cycle that determine its ability to mount an effective attack against cancer.

Now, a new framework from Drs. Chen and Mellman combines these diverse factors into a unified theory of the state of a person’s immune system – their “Cancer-Immune Set Point.” Rooted in the biology of the Cancer-Immunity Cycle, this framework bridges clinical and scientific insights and provides an explanation for how and why each set point varies from person to person. It is poised to shape personalized cancer immunotherapy research for years to come.

Cancer-immune phenotypes fall into three broad categories: immune-desert tumors, immune-excluded tumors, and inflamed tumors. These are grouped based on what step in the Cancer-Immunity Cycle is impacted: the early, middle, and late steps, respectively.

To understand these three phenotypes, it’s helpful to think of the immune system’s goal of killing cancer cells as a mission with multiple stages. Like a mission to the moon.

Immune-Desert Tumors: Failure to Launch

Like a rocket that can’t even get off the ground, the immune system in this phenotype isn’t able to launch an effective attack against cancer. For example, this could happen if the cancer cells don’t express any mutated and foreign proteins that can be recognized by immune cells. Problems with immune system signaling and activation early in the process can also be the culprit.

Immune-Excluded Tumor: Lost in Space

A mission to the moon can go awry if the rocket never actually reaches the moon, for example because of asteroids that block its path. Similarly, immune cells aren’t able to attack cancer cells if they can’t enter the tumor itself. They may be blocked by physical barriers like blood vessel walls or connective tissue.

Inflamed Tumor: Mission Not Quite Accomplished

Imagine our astronaut’s frustration if she completes her journey, arrives at the moon, but is unable to complete her mission at the very end. The same problem applies to this third phenotype. The immune cells have arrived in the tumor but are unable to complete their attack, perhaps because of molecular signals that shut down the immune cell’s activity.

The set point idea recognizes that these phenotypes do not occur by accident, but rather, likely reflect a variety of factors (microbiome, genetics, and environment) that determine each person’s likelihood of mounting an effective immune response to cancer. As a result, the cancer-immune set point framework establishes a way for researchers to keep pace by quickly contextualizing the massive amounts of new data emerging from immunotherapy studies.

Ideally this framework will continue to evolve as well, with new information contributed by scientists based on discoveries into which factors contributed to clinical responses, and which did not. To accelerate this evolution, we’re sponsoring a new interactive online platform from Nature, the journal that published Drs. Chen and Mellman’s framework in January 2017.

This platform will engage the global cancer immunotherapy research community around the set-point framework in an entirely new way – through crowdsourcing.

Through “A Community Map of Cancer Immunity”, scientists can add, edit or remove factors based on their own validated findings. Tapping into the knowledge of the entire community, in real-time, could help rapidly advance the field of personalized immunotherapy*.

Ultimately these collective insights may point to new therapeutic approaches, with synergistic combinations based on set points that might extend the benefits of immunotherapy in more people with cancer.

Immunotherapy has already revolutionized cancer research, and it appears this is just the beginning.

(*Originally published on March 31, 2017, this article was updated on June 2, 2017, to reflect the publication of “A Community Map of Cancer Immunity”)