In medicine, five years can bring a world of change. That difference has been especially profound for people facing a diagnosis of cancer. The promise shown by a new class of medicines known as “checkpoint inhibitors” has sparked a renaissance of research and development, and provided new hope and treatment options desperately needed by patients, many of whom had no other options left.
Checkpoint inhibitors work through an entirely different mechanism than all preceding cancer treatments, by activating a person’s immune system to target and destroy cancer cells. They are among the first examples of a therapeutic approach known collectively as cancer immunotherapy.
During their first years in the clinic, checkpoint inhibitors have provided an exciting glimpse at the power and potential of cancer immunotherapy. Today, they drive responses some cancer patients, including those with historically difficult-to-treat forms of the disease, but not all.
We’ve come a long way in a short time. But can we do better? Can we build on the current successes of cancer immunotherapy to widen the circle of responders and include others who don’t yet benefit?
It won’t be simple, says Ira Mellman, Vice President of Cancer Immunology at Genentech. But with the right approach, he’s confident it is possible.
“Realizing the larger potential of cancer immunotherapy requires an approach built on a better understanding of why some patient populations do not respond to checkpoint inhibitors, and more generally, how cancer evades the immune system,” Mellman says. “If we use a mechanistic approach to understand how cancer-immune interactions work, I believe we will continue to grow the group of responders to 50 percent, 75 percent and beyond – and get as many people as possible to respond to immunotherapy.”
The question now is, how exactly do we get there?
To envision that path, it’s useful to first take a look back.
A Mechanistic Approach
In 1928, even the most minor cut or scratch had the potential to spiral into a deadly infection, and physicians had almost nothing they could do about it—until Alexander Fleming accidentally discovered penicillin, setting in motion a medical revolution.
But the full realization of that revolution didn’t happen overnight, or with that single discovery. It would be well over a decade before anyone figured out how to purify and scale up production of penicillin. Researchers then spent several more decades discovering additional and better ways to kill various strains of deadly bacteria. Ultimately, this mechanistic approach to antibiotic research and development led to an entire class of medicines far more effective than penicillin alone—one that has fundamentally changed humanity’s relationship to bacterial disease.
In other words, they learned how bacteria work, then leveraged that understanding to help more patients with more diseases. The story of how penicillin launched the antibiotics industry provides a powerful example of how we can learn from the successes already achieved by checkpoint inhibitors, and take a mechanistic approach to building on those successes in order to reach even more patients with cancer immunotherapy.
This next generation of immunotherapies will be built on a deeper understanding of why checkpoint inhibitors work for some patient populations and why they don’t in others. To gain that understanding, researchers are developing better biomarkers, which indicate a person’s potential to respond to checkpoint inhibitors, and a more complete map of the nuances of how different types of immune systems interact with the diverse biology of different types of tumors.
The hope is that such an approach will allow us to take better advantage of the checkpoint inhibitors we already have, and expand the number of patients who benefit. It may also inform strategies for developing new types of immunotherapies, and reaching even more patients with more types of cancer.
“It is critical that we take a systematic, mechanistic approach to the development of cancer immunotherapies,” Mellman explains. “If you don’t, you stand the chance of being wrong about things that you thought you understood, and you can’t make meaningful progress.”
In fact, he believes that may have already happened.
A Revised Understanding
Six years ago, Mellman and his colleague Daniel Chen set out to clarify the emerging biological framework of how the immune system interacts with and eliminates cancer, creating a seven-step visualization now known as the cancer-immunity cycle. More recently they proposed another conceptual layer to that framework, called the immune set point, which characterizes the unique cancer-fighting state of a person’s individual immune system. These models help researchers create and test hypotheses about how cancer immunotherapies influence the interplay between cancer and the immune system.
As data on checkpoint inhibitors accumulates, Mellman and his team continuously reevaluate where in the cancer-immunity cycle they act. Based on the most recent data, they now believe that action may be in a different phase of the cancer-immunity feedback loop than researchers initially assumed. This is how science progresses; by constantly re-evaluating old hypotheses based on new data.
A more accurate understanding of how and where in the cycle the currently successful checkpoint inhibitors work could provide researchers with a better compass to chart a course to the next generation of cancer immunotherapies that further widens the circle of cancer patients who respond.
“The immune system is complex, of course,” says Mellman. “But identifying the various barriers to successful immune response and coming up with therapeutic strategies to overcome them is our responsibility as industry leaders. We can’t stop until we widen the circle of responders all the way and include everybody, 100 percent.”
Piecing Together the Puzzle
The majority of treatment strategies today aim at helping T cells do their job of killing cancer cells. Checkpoint inhibitors represent one way of doing this, but they’re only the beginning.
Another strategy helps a patient’s T cells activate against cancer by identifying that tumor’s unique protein signature, or “neoantigens”. Those tumor neoantigens are then encoded into a therapy and delivered to the patient’s immune system, providing their T cells with the “scent” of the cancer they need to attack. This approach is called individualized neoantigen specific therapy, or individualized cancer vaccine.
This approach may be an effective T cell strategy for some subset of patients. Others might need help overcoming an immune barrier at the next stage of the cancer-immunity cycle, which requires activated T cells to replicate in numbers sufficient to effectively attack the tumor.
“For such immunosuppressed patients, it may not be enough to simply alert their T cells to a neoantigen signature,” Mellman explains. “What can we do if we can't convince that patient’s immune system to make more T cells on its own?”
One potential strategy is cell therapy. Rather than rely on a patient’s inhibited capacity to grow T cells in the body, our teams are working on approaches to grow T cells up in a lab instead, then infusing them back into the patient to attack the cancer. Mellman likes to refer to such engineered approaches to scaling up an immune response as “synthetic immunity”. Another approach creates bispecific antibodies engineered to synthetically help guide T cells to their tumor targets. These immune matchmakers attach to the T cells with one hand and cancer cells with the other, increasing their chances to meet and interact.
And finally, there is the issue of getting the T cells to the tumor. Up to 50 percent of tumors employ a physical barrier, called stroma, which acts as a protective immunosuppressive shell around the cancerous tissue, foiling the T cells’ targeting mechanism. One strategy being developed to help patients with these encased tumors will be based on molecules capable of physically disrupting the tough stroma wall, making it easier for T cells to get across the barrier and do their cancer-killing job.
The Unknown Unknowns
Together with checkpoint inhibitors, these other T cell-based strategies could address many of the barriers that prevent a durable immune response to cancer for the majority of patients. But as we follow the science, the data may reveal the existence of a subgroup of cancer patients who will not respond to T cell based immunotherapies.
Who will these patients be? What will their tumors look like? Such questions are interesting, but still several steps of biological mastery away from even being properly formulated. What’s clear is that in order to widen the circle of responders enough to include everyone with cancer, researchers will probably need to reach beyond T cells. They will need to use the same mechanistic approach to create new therapies using other types of immune cells that have also been discovered to kill cancer, such as natural killer cells and macrophages.
Exactly what this future generation of cancer therapies will look like, we don’t yet know. But what the last several years have made clear is that to help 100 percent of cancer patients, those therapies will have to harness the power of a complex, creative and adaptable immune system. It contains within its design the capacity to recognize and eliminate any cell that deviates from normal growth and development, without risking grievous harm to the individual. To realize the potential of this remarkable living machine against cancer, immunologists like Ira Mellman will need to take a page from nature and be complex, creative and adaptable too.