Fine-Tuning T-Cell Therapies for Leukemia, Lung and Skin Cancers
Aude Chapuis, Cancer Physician and Immunology Researcher
There’s something about America that Dr. Aude Chapuis picked up on very early in her career. “You can be very spontaneous and take risks,” she said. “A lot more risks than in Europe. And people will also give you a chance.”
Fresh out of medical school in Lausanne, Switzerland, not far from where she grew up, Chapuis signed up to work in an immunology lab where researchers were studying HIV. Her soon-to-be mentor, Dr. Giuseppe Pantaleo, had just come to Lausanne after 10 years at the U.S. National Institute for Allergy and Infectious Diseases, working with the legendary AIDS researcher Dr. Anthony Fauci. Chapuis was then 23 years old and unsure where her career was going. “I had no experience whatsoever,” she recalled, “And he said, ‘Yeah, I’ll give you a chance.’ It was a fantastic two years.”
Having fallen in love with immunology, Chapuis then came to the U.S. for a fellowship at Fred Hutch and soon was making a name for herself working with Dr. Philip Greenberg on adoptive T-cell therapy for leukemia. The technique exploits the powerful disease-fighting capacity of certain white blood cells called T cells. Taken from the blood, the T cells can be genetically modified with receptors to recognize cancer cells, multiplied, and returned to the patient’s bloodstream. The key is to find the right target on the cancer, ideally a protein found on few if any healthy cells, and find the right T-cell receptors to latch onto it.
The work soon focused on a mutated protein known as WT1 associated with several types of cancers. Named for its link to Wilms Tumor, a pediatric kidney cancer, it is now associated with a broad spectrum of malignancies ranging from leukemia to lung cancer.
Chapuis joined the Hutch faculty in 2014 and now works down the hall from Greenberg in her own laboratory, still savoring that American-style creative thinking. Her work today is focused on fine-tuning components of T-cell therapy — refining the T-cell receptors and selecting the cancer-specific molecules they target — to make sure that T cells and targets are not only well-matched, but that the immune cells can survive long enough to wipe out the cancer and keep it from returning.
Her approach, which she calls “T-cell receptor gene therapy,” is applicable not only to WT1 but to other tumor-associated proteins that originate inside cells and are displayed in bits and pieces on the cell surface for the immune system to assess. She aims to screen donor T cells for the receptors best suited to attack those targets. Then, immune cells bearing those receptors or modified versions of them can be infused in patients.
“We’re trying to find something which is safe, targets just the tumor, doesn’t involve chemotherapy... I think we are really on to something here.”
Clinical trials of those T-cell receptors chosen to go after WT1 are yielding promising results and a wealth of nuanced information that will help Chapuis and other immunotherapy researchers at Fred Hutch and beyond improve the approach further.
Chapuis is exploring new protein targets and crafting T-cell receptors that will zero in on them. Among those targets is one known as MAGE-A1 found in breast and lung tumors; others are viruses, including those that drive head and neck cancers, and a polyomavirus implicated in the rare skin cancer Merkel cell carcinoma. She is also developing strategies to speed the process of finding and isolating many new receptors on T cells so that therapies can target several other telltale proteins in tumors at once.
“It used to take four years to develop one T-cell receptor. Now we have the capability to develop 10 in two months,” she said. “We’re trying to find something which is safe, targets just the tumor, doesn’t involve chemotherapy, hopefully, to make the outcomes better. I think we are really on to something here.”
Getting there will involve tapping that bold, free-flowing thought that is encouraged at Fred Hutch. “There’s a lot less structure, convention, and a lot more freedom,” she said, reflecting on the differences in research cultures here and in Europe. “We’re completely free to do whatever jumps in our minds.”
— By Sabin Russell and Susan Keown, Dec. 3, 2016, updated Nov. 18, 2021
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