Once a Canadian, always a Canadian. By day, postdoctoral research fellow Leah Schmidt, PhD, works in the Fred Hutchinson Cancer Research Center lab of Philip Greenberg, MD, a pioneer of adoptive T-cell therapy. She meticulously explores the effectiveness of genetically modified T cells and modified T-cell receptors in tumor-bearing animal models in a grand plan to improve treatment for lung cancer patients.
By night, however, this transplanted Ontario native spends her downtime checking off as many maple leaf activities as time allows. "I play in a co-ed ice hockey league," she said with a chuckle. "In fact, I met my fiance playing ice hockey." The couple also likes to brew beer, and have become especially skilled at producing a good Belgium variety. Admitting that slamming a puck toward a goalie, then drinking a cold brew after the game, can help release the tension associated with complex medical research, she joked, "Hockey and beer are just more of those Canadian stereotypes."
Schmidt credits a high school biology teacher's infectious love of genetics with her decision to major in biochemistry with a specialization in genetic engineering at McMaster University in Ontario. It prepared her for graduate work at the Massachusetts Institute of Technology where she eventually earned her PhD in biology. While at MIT, Schmidt studied immunology in the context of tumors in the lab of Tyler Jacks, PhD, recognized in part for having developed extremely sophisticated mouse models of cancer.
"A traditional animal model of cancer is an animal into which a tumor has been transplanted. Dr. Jacks, however, uses genetically engineered mouse models," explained Schmidt. "This allows researchers to 'turn on' cancer mutations that are commonly found in human patients to transform what was previously a normal, healthy cell into a tumor. For instance, the KRAS gene is frequently mutated in human lung cancers. We can engineer that gene in the mouse model to activate an oncogenic form of KRAS."
These sophisticated models provided Schmidt with a great appreciation for preclinical models that faithfully mimic human disease. "Especially in the context of the immune system, it is really important to observe how the immune system experiences a certain stimulus," she told Oncology Times. "If you suddenly just put tumor cells into an animal, you'll get a very different kind of stimulation compared to what occurs in a healthy, normal cell slowly transforming into a tumor, alongside a fully competent immune system."
Current Research
Having segued into her work on lung cancer at Fred Hutchinson last year, following an interim stint at The University of Washington, Schmidt said, "Over the past decade, immunotherapy has revolutionized the way we treat cancer and is now the standard of care for many malignancies, including lung cancer, the No. 1 cancer killer in the world today."
She noted, however, that only about half of lung cancer adenocarcinoma patients benefit from checkpoint inhibitors, an immunotherapy that is now standard of care for this disease.
"We believe that checkpoint inhibitors work by reinvigorating preexisting anti-tumor immune responses in patients. Evidence shows that patients without signs of these preexisting responses, referred to as T-cell inflamed immune signatures, are less likely to benefit from these therapies. This population makes up about half of all lung cancer patients, highlighting a significant clinical need. Engineered T-cell therapy is a strategy for generating de-novo anti-tumor immune responses in patients who don't already have them."
While these therapies have already proven invaluable in blood cancers, there are more hurdles to jump in solid tumors. "There remain significant challenges," said Schmidt, "including the difficult selection of antigen targets sufficiently specific to the tumor to avoid toxicities, failure of therapeutic T cells to hone into or persist within a tumor, and suppression of T-cell function within the tumor microenvironment." In fact, the lung microenvironment differs from that of other solid tumors and appears more suppressive of some T-cell activities.
Studying the use of engineered T-cell therapy against lung cancer, including the identification of tissue-specific hurdles to these therapies and the development of strategies to overcome them, is the daily call to action that Schmidt has taken on.
"We use genetically engineered animal models of lung cancer that closely mimic human disease and that are also resistant to the currently available immunotherapy, checkpoint blockade. Similar to what's being done in the clinic, we genetically modify T cells using either viruses or CRISPR-Cas9 technology," she described. "We introduce T-cell receptors that can recognize tumor-associated antigens, allowing the T cells to recognize the tumor. Sometimes we do other modifications, change different metabolic pathways, or tweak other pathways to change the function of the cells. Then we administer those modified T cells into tumor-bearing animals, and track their localization and function in the tumors over time, as well as their ability to impact disease progression."
Early Findings
Schmidt and team have found in their model systems that T-cell therapy can be effective against lung cancer in that setting, but the benefits are short-lived.
"We can significantly extend the lifespan of the animals, but the T cells do rapidly lose function within the lung tumor microenvironment, and the animals eventually succumb to disease," Schmidt lamented. "T-cell function is lost even within 3-7 days. If we pull the T cells out of the lung tumors and we stimulate them in vitro or in culture, they already have diminished function compared to pulling them out of the spleen, a control tissue that the T cells are also present in. So there's something in the lung tumor microenvironment that's suppressing the functionality of the cells."
Asked why lung-related T cells lose their potency so much faster than spleen-related T cells, Schmidt said, "We've shown that this suppression of T-cell function to the degree that we see is dependent on the T cells actually seeing their antigen. So it's somehow a T-cell signaling problem.
"But we think it is more than that because we also have a pancreatic cancer animal model that's very similar, and it expresses the same antigen that we're targeting. And yet, in that context, while T cells do lose function, they do not lose it to the same extent as we see in the lung. So we think that there's something specific to the lung tumor microenvironment that could be suppressive."
Now the lab is investigating strategies to overcome this loss of function of the T cells by blocking suppressive molecules or cells in the tumor microenvironment, or by using other genetic engineering tricks to modify the functionality of the T cells.
"We have some preliminary results," Schmidt said optimistically, "showing that at least some of the strategies we've tried are able to help boost therapeutic T-cell function in the lung tumors. We've done some very cursory surface profiling of the tumors to see what kinds of usual suspects are there. We can see certain suppressive molecules or cell types-such as neutrophils-that already are known to suppress T-cell function in the context of lung cancer. Now we have experiments underway to test the roles of each of these different suppressive factors in the tumors using drugs or molecules to inhibit them. At this point, however, we're not 100 percent sure what the offender is. That's where we're at now."
Translating Research
Clearly, if the lab can surface greater understanding of this T-cell suppression, and a way to overcome it, it would represent a leap forward in the treatment of lung cancer.
"One of our long-term goals is to bring these therapies into the clinic for lung cancer patients," said Schmidt. She noted that the work of a former colleague from the Greenberg lab, Ingunn Stromnes, PhD, in a genetically engineered pancreatic cancer model, led to a clinical trial that is about to enroll pancreatic cancer patients to test these therapies against human disease. Pending the early outcomes of that trial, there is great interest among lung cancer researchers and clinicians at Fred Hutchinson to bringing the same therapies to lung cancer patients.
"That is one of the wonderful things about working at a place like Fred Hutch," said Schmidt, earnestly. "We have strong ties to the Seattle Cancer Care Alliance. The clinicians there allow us to translate these important findings into the clinic pretty quickly and have a more tangible effect on patient outcomes. We're really lucky at Fred Hutch to have resources and collaborators able to help push the research forward in new directions.
"For example, last year we became members of the Fred Hutch Lung SPORE, which stands for Specialized Programs of Research Excellence, a group of scientists and clinicians at Fred Hutch and the Seattle Cancer Care Alliance who are engaged in lung cancer research. We're leveraging those connections within the Lung SPORE to be able to test interesting potential adjuvant therapies in combination with our T-cell therapy in our lung cancer model."
Interaction and collaboration with clinicians has been the icing on the metaphorical cake of Schmidt's cancer research. "It is very rewarding to have those connections. Back at MIT, I learned more of the basic cancer biology side of things. Now at Fred Hutch, the connections to the clinic are much stronger and the work has become much more translational. It's really important to me that the work that I'm doing is actually benefiting patients, so that direct line of communication is really critical. It's very motivating," said Schmidt.
As they work toward the big-picture goals, Schmidt and others in the Greenberg lab remain busy with immediate goals as well. "For example, this week, we're performing deeper transcriptional profiling of the lung tumor microenvironment in our system, with and without T-cell therapy, to be able to identify these culprits, suppressive pathways that might become activated in the context of adoptive T-cell therapy," detailed Schmidt.
"And then we're planning to leverage our clinical connections within the Lung SPORE to be able to compare the findings that we see in our animal system with data from lung cancer patients in the clinic. We hope to better understand which patient subsets we're best modeling in our system. That's another angle of the work that we're doing."
While the overarching hope of these cancer researchers is to find a cure for lung cancer, there are myriad victories to be had along the way.
"Because we have sophisticated, genetically engineered animal models closely mimicking human disease, we have been able to show that engineered T-cell therapy does hold promise for lung cancer patients. That's a huge thing in itself. And we do have some encouraging early insights about the strategies that do lead to enhanced functionality of the therapeutic T cells within the lung tumor microenvironment. So the works grinds on. It's our hope that we can use these strategies to broaden the subset of lung cancer patients who can actually benefit from immunotherapy."
Valerie Neff Newitt is a contributing writer.
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