Michelson Prize Finalist Dr. Gabriele Casirati Makes Cancer Immunotherapies Safer through Genetic Engineering

Dr. Gabriele Casirati, 2024 Michelson Philanthropies & Science Prize Finalist

When Gabriele Casirati decided to specialize in hematology as a newly minted physician, the field was undergoing a revolution. In recent years, new techniques such as personalized immunotherapy, stem cell therapies, and the use of genetically modified immune cells known as CAR-T cells have expanded doctors’ options for treating blood cancers.

Casirati found himself collaborating closely with experts in the field as he and his colleagues tackled several of these challenges, including finding a way to effectively translate these innovative immunotherapies in the context of hematological malignancies.

The intersection of research and clinical practice held a profound fascination for him. “The study of the immune system and its interaction with cancer cells is one of the scientific fields where you get direct contact between what you see in patients and what you can model in the lab,” he reflects.

Using Gene Editing to Improve Bone Marrow Transplants

Gabriele Casirati, M.D., Ph.D.

Now a postdoctoral fellow at Boston Children’s Hospital, Casirati began working on ways to use gene editing to improve bone marrow transplants in leukemia patients – research that led to his being named a finalist for the 2024 Michelson Philanthropies and Science Prize for Immunology. The prize comes with a $10,000 award and the online publication of Casirati’s essay in Science.

Casirati received his MD from the University of Milan and his Ph.D. at the University of Milano-Bicocca before he began his research at the Dana Farber Cancer Institute and Boston Children’s Hospital.

His work led him to study acute myeloid leukemia (AML), a fast-progressing cancer that affects the blood and bone marrow.

Bone marrow stem cell transplants from donors can increase AML patients’ survival rates, but up to 50% of patients still relapse due to lingering cancerous cells. That means that oncologists often must devise a second treatment to kill the last of these cells.

CAR-T cells and antibody therapies are great at this. They recognize specific proteins known as epitopes that sit on the surface of cancerous cells, allowing them to find and kill those cells. But with AML, the epitopes on the cancerous cells are the same as those on the surface of the donor’s healthy bone marrow stem cells. That means that the treatment might kill the healthy cells that the patient depends on.

Casirati and his colleagues are developing ways to genetically engineer the donor cells before transplantation, altering their epitopes to hide them from CAR-T cells.

They modified three epitope genes using a technique called base editing that changes single letters in the DNA code. When they tested these modified stem cells in the lab, they found that the edits changed the epitopes’ structure enough that CAR-T cells no longer attacked them, but the cells still functioned as well as unmodified cells.

The team is now designing trials to test the technique in cancer patients. It’s still unclear whether the modified cells will work as well in the clinic as they do in the lab.

Still, Casirati is hopeful that they will open up more options for physicians who need to continue treating lingering cancer after transplantation. “We can probably spare some patients from chemotherapy or additional intense treatments. Especially older people who are more likely to die from AML because their health is too fragile for aggressive treatments,” he says. “It would be really fantastic if this research could at some point be translated back into the clinic and bring some potential benefits for the patients who right now have very poor prognoses.”

Casirati says the Michelson Prize will be helpful in supporting this research, especially because his team needs help from researchers across different scientific fields. “This is a great opportunity to get more visibility, discuss it with other experts, and see if there are other groups interested in collaborating and advancing the research,” he says. “It’s extremely fascinating: there is a lot still to discover and learn about how the immune system interacts with tumor cells.”

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