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The immune system has the potential to eradicate cancer. But cancers are expert escape artists, with numerous tools for shutting down or hiding from immune attack. Three research teams at Fred Hutchinson Cancer Research Center have launched new projects aimed at revealing some of these secrets and laying the groundwork for developing better immune-harnessing cancer therapies, or immunotherapies.
The one- to two-year, early-stage research projects cover a range of malignancies: colorectal cancer, blood cancers and certain sarcomas. They were funded by Fred Hutch immunotherapy spinoff Juno Therapeutics, a Celgene company, through a competitive process overseen by the Hutch’s Immunotherapy Integrated Research Center.
How inherited genes influence cancer immunity
You got your nose from mom and your laugh from dad. How about your immune system? In a first-of-its-kind study, Fred Hutch statistical geneticist Dr. Jeroen Huyghe and epidemiologist Dr. Ulrike “Riki” Peters aim to find out how the genetic variations we inherited from our parents affect the way our immune systems respond to a variety of cancers.
This study incorporates genomic and clinical data from thousands of research participants. It’s the first to take such a deep look at the influence of genetic variants within a patient’s normal cells.
“We are excited about the project, because so far all work to identify genetic predictors of the tumor immune response has focused on the cancer genome, with very little — if any — attention being given to the host, or patient, genome,” Peters said. “As we have seen that the host genome is important for many immune-related diseases, it is very likely that it also impacts the immune response to a tumor.”
The study will have two main parts. First, the team will delve into the data of more than 8,500 cancer patients who participated in The Cancer Genome Atlas, a publicly funded cancer-genetics initiative. The researchers will look across this valuable data set to identify inherited genetic sequences linked to better penetration by certain immune cells, called T cells, into that person’s tumor. (Having more T cells naturally in a tumor has been linked to better outcomes in many cancer types.)
Then, the research team will zoom in on colorectal cancer and study how the key genetic variants they identified in the first part of their study affect a person’s risk of developing a colorectal tumor and of dying from their cancer. Their analysis will leverage a huge data set — including data from more than 125,000 people — from large research consortia co-led by Peters that focus on colorectal cancer genetics.
The researchers anticipate that the insights they gain through this study will provide a foundation that could, for example, reveal targets for new immune-stimulating drugs or lead to better methods to predict which patients are most likely to benefit from cancer immunotherapies.
Predicting T-cell behavior, outcomes
Genetically engineered T-cell therapies have made some patients’ advanced blood cancer disappear without a trace. But other patients with the same cancers have not had the same result.
Why? In this new study, computational biologist and biostatistician Dr. Raphael Gottardo is harnessing cutting-edge computational methods to look for telltale biological signatures that can predict how different subsets of the engineered cells will behave after being infused back into the patient and how each patient fares after receiving the engineered cells.
Finding the answers could one day help scientists improve this type of engineered T-cell therapy, called CAR T-cell therapy, so it would work for more patients more safely, the investigators said.
“We now have access to new technologies and computational tools that can be used to interrogate immune responses, including CAR T cells, at a scale we couldn’t even envision five years ago,” Gottardo said. “We hope to use these new technologies and tools to better characterize CAR T cells before and after treatment and, hopefully, identify characteristics of these that correlate with clinical responses.”
Gottardo will work with samples collected from people with acute lymphoblastic leukemia enrolled on two Fred Hutch trials of experimental CAR T-cell therapies, one now closing and another that is still ongoing. Gottardo’s main collaborator on this study will be Fred Hutch immunotherapy expert Dr. Cameron Turtle, one of the trials’ leaders.
Samples of the genetically engineered cells, collected before and after infusion back into the patients, will be analyzed using several different methods that can reveal aspects of cell biology, such as patterns of gene activation. Gottardo will integrate all the large, complex data sets produced by these different methods to uncover the hidden signatures that might predict the cells’ behavior and effects in patients.
Why do T cells refuse to attack sarcoma tumors?
Hutch sarcoma immunotherapy expert Dr. Seth Pollack and his collaborators are facing down a mystery: Why do some patients’ cancers keep growing, even if they’ve been breached by superpowered T cells that should be detecting them and killing them off?
Pollack hypothesizes that other cells in the tumor environment must be interfering with the cancer-killing power of the T cells. In this new study, he is taking a close look at how immunotherapies affect the diverse cells within certain sarcomas. This work is being conducted in collaboration with Fred Hutch cancer immunology expert Dr. Robert Pierce and surgical oncologist Dr. Venu Pillarisetty of the University of Washington.
The team will take super-thin slices of sarcoma tumors removed from patients undergoing surgery and grow them in a special lab system that does not disrupt the tumors’ complex structure or mixtures of cells. Then, the scientists will treat the tumor slices with an immunotherapy, either a genetically engineered T-cell therapy or an immune-boosting drug. They’ll analyze how the therapies affect the activities of the cancer cells and the complex community of immune cells within the tumor tissue.
If the team can learn how cancer-killing immune responses are getting shut down, perhaps researchers can develop new methods to overcome those shutdown mechanisms, Pollack said.
"We are incredibly excited about the potential of targeted immunotherapies in certain sarcomas, but it can be so frustrating when patients don't respond, even though they have strong expression of the [T cells’] target” on their cancer cells, Pollack said. “This project really has the potential to explain why this happens and give us ideas for how to overcome this barrier to effective immunotherapy."
