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Read more about Fred Hutch achievements and accolades.
Fred Hutch Cancer Center researchers developing immunotherapies using engineered adaptive immune system cells have received over $4 million in research grants from the Washington Research Foundation (WRF). The foundation’s 2023 strategic plan included increased support for “large-scale emergent opportunities in life sciences research” within Washington state, according to the foundation’s October 22 announcement of the funding grants. Fred Hutch scientists will use the awards to advance a range of immunotherapies for diseases including Merkel cell carcinoma, osteosarcoma and solid tumor cancers.
Fred Hutch researchers receiving awards of $2 million each include Aude Chapuis, MD, to develop and test a novel T-cell therapy for Merkel cell carcinoma, and Soheil Meshinchi, MD, PhD, to continue the development of a chimeric antigen receptor T (CAR T) cell that can bind to a molecule found on the surface of osteosarcoma cells. An additional award of $250,000 has been granted to Joshua Veatch, MD, PhD, for the development of a novel engineered CD4 T cell that can be used to attack solid tumors by seeking out antigen-presenting cells in the immune system that locate foreign cells within the body and communicate with other immune system cells that can then target malignancies for destruction.
All three projects take advantage of Fred Hutch’s expertise in understanding the role of T cells, a key player in the adaptive immune system. (“T” stands for the thymus, the organ in which these cells mature.) The newly funded research studies will advance potential immunotherapies for a range of cancers using T cells engineered in specific ways to target diseased cells without harming healthy cells.
Engineering immune cells to fight a rare form of skin cancer
The Chapuis Lab focuses on T-cell receptor (TCR) gene-engineered immunotherapy. The WRF award will help fund Chapuis’ research on developing enhanced novel immunotherapeutics for Merkel cell carcinoma, or MCC, a rare form of skin cancer that afflicts about 3,000 people annually, according to the American Cancer Society. Chapuis is the holder of the John C. and Karyl Kay Hughes Foundation Endowed Chair.
Chapuis’ team identified a TCR that binds with great specificity to viral protein fragments from the Merkel cell polyomavirus, the most common cause of MCC, which is found in the cancer cells. Chapuis noted that an early clinical trial demonstrated that this TCR identified by her lab was safe and showed some efficacy against MCC, but that a classic escape mechanism of MCC by which the cells can hide from the immune system meant that this TCR had limitations in its effectiveness.
“Immune checkpoint inhibitors (CPIs) have demonstrated effectiveness in MCC patients, but about half of patients progess, constituting a need for new strategies,” Chapuis explained. “We identified a TCR that, when added to a patient’s own T cells, went to the tumors resistant to CPIs, but was just not potent enough to overcome MCC escape mechanisms. We went back to the lab and devised a new robust immunotherapy strategy, using the same TCR as an initial trigger, but this time potent enough to reverse the MCC escape mechanism, at least in mice. This award allows us to begin a clinical trial to treat five patients with this new TCR construct that improves on what we learned in earlier clinical trials using engineered TCRs to target the viral particles found in infected cancer cells.”
The project funded by the WRF gives Chapuis’ team the resources to generate and test the viral vector that is used to transduce (that is, to add) the enhanced construct including the TCR gene to patients’ own T cells, as well as to prepare the first human clinical trial using this therapy. Her team hopes to advance the understanding of how targeted TCR T-cell treatments can be engineered for improved efficacy, an approach that could have long-lasting impact for the treatment of other cancers as well.
Designing chimeric T-cell receptors to treat osteosarcoma
The Meshinchi Lab focuses on developing immunotherapy treatments for acute myeloid leukemia (AML) and other diseases that have been found to have similar cellular structures. For the WRF award, Meshinchi and his team will focus on treating osteosarcoma, a bone disease that is found most often in children and young adults, with CAR T cells that target a surface molecule found on malignant cells.
Meshinchi’s previous research on infant AML, a particularly aggressive disease, led to the discovery of a specific cell-surface protein that was overexpressed on leukemic cells. The research, funded by Project Stella, identified folate receptor alpha (FOLR1) as the surface protein that could be attacked with a targeted therapy. The lab engineered a CAR T-cell receptor, a synthetic molecule that could be placed on a patient’s own T cells that would attack cells overexpressing FOLR1 with extreme specificity, without harming neighboring healthy cells. Lab results were so successful that an infant AML clinical trial will be enrolling in the coming weeks.
Meshinchi expanded his research into FOLR1 overexpression, asking whether there could be other cancers that overexpressed the same protein and could therefore potentially be treated with the same CAR T-cell construct.
“We simply asked the question: Are there other malignancies that express the same target?” Meshinchi said. “[CAR T] is a therapy that can be directed against a very specific target, so there’s no reason we couldn’t use it for other diseases with the same target. We researched our genetic database and found that osteosarcoma, a very high-risk disease, hadn’t had any real development in treatments for over 40 years and expressed FOLR1.”
Meshinchi’s lab demonstrated using mouse models that the CAR T was highly effective, completely eradicating osteosarcoma tumors. The lab will use the WRF award to continue development of the CAR T and to fund a first-in-human clinical trial. Meshinchi has identified FOLR1 on several other types of cancer, including ovarian, uterine, lung and pancreatic cancer, and plans to build on his lab’s research by moving into developing immunotherapies for these cancers in the future.
Turning T-cell immunotherapy towards solid tumors
The Veatch Lab is developing novel T-cell therapies for solid tumors that aim to short-circuit the ways in which solid tumors successfully hide from a person’s immune system and grow unchecked. Veatch’s grant will support preclinical modeling of potential T-cell therapies in a humanized mouse model known as MISTRG (“Mister-G”) for a range of solid tumor cancers. Veatch’s Fred Hutch collaborators on this project include McGarry Houghton, MD, and Anthony Rongvaux, PhD, along with Paul Nghiem, MD, PhD, of the University of Washington’s Department of Dermatology.
Solid tumors present specific challenges that make them less treatable with engineered T-cell therapies. These tumors can alter the microenvironment around them in such a way that it suppresses immune system cells from finding them in the first place. They can also express fewer specific cell-surface proteins that could be used as targets for engineered T-cell immunotherapies. For these reasons, engineered T-cell therapies have traditionally been far more successful in treating blood cancers such as leukemia than in solid tumors.
“Every solid tumor has to evade the immune system in order to survive,” Veatch said. “This can include such things as making molecules that prevent T cells from ever finding the tumor, or inhibiting the T cells by reprogramming immune system cells around the tumor microenvironment that keep T cells from being stimulated. It’s a combination of hiding directly and having no visible cell targets, and changing the environment around them.”
Veatch’s research will test the efficacy of a new type of T-cell treatment focused on CD4 “helper” T cells, which bind not to cancer cells directly. Instead they bind to antigen-presenting cells, or APCs, in the patient’s own immune system that find foreign proteins in the body, digest them, and present a string of peptides from the invading protein to other immune system cells, which respond by stimulating both the innate and adaptive immune systems to fight the tumor. The MISTRG mouse model, developed by Rongvaux and others, will be used in preclinical research for its ability to express a humanized immune system.
Veatch and his collaborators hope to demonstrate in these mouse models that human immune system cells can be stimulated to fight solid tumors using this engineered CD4 T-cell approach, and to lay the groundwork for eventual clinical trials.
