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Caroline Diorio

Children’s Hospital of Philadelphia

Caroline Diorio’s interest in medicine started at her own bedside. As a kid, she had a rare blood disorder called chronic ITP, where the immune system attacks its own platelets. “I was taken care of by pediatric hematologist oncologists, and I thought they were like the coolest people I ever met,” she said.

Through undergrad, medical school, and residency, Diorio never found a specialty that suited her better. During her medical training, Diorio became more interested in studying cellular therapy like CAR-T. One particular problem drew her in.

“It’s incredibly unfair. We really badly need better therapies for these kids.”

Because T cells in T cell leukemia patients are malignant, these patients can’t use their own cells for CAR-T therapy like patients with B-cell acute lymphoblastic leukemia, or B-ALL, can. So for T-cell acute lymphoblastic leukemia patients, the engineered cells must come from a donor. That introduces a host of new problems, Diorio said, including the need for more gene editing to get someone else’s cells to work and be accepted in the patient.

“With more edits, the more likely you are to have an error,” Diorio said.

But Diorio is using a new gene editing tool called cytosine base editing to create a CAR-T therapy for T-ALL patients at Children’s Hospital of Philadelphia. This tool can make gene edits by only breaking one of the DNA strands, rather than both like CRISPR-Cas9. That means fewer DNA repairs have to be made after editing, and less chances for errors. In her work, Diorio found creating a CAR-T with this tool led to more genomic stability and better cell proliferation than CAR-T cells made with CRISPR-Cas9.

That CAR-T was also active against T-ALL in mice. The work might help researchers develop the first allogeneic CAR-T therapy, and it may one day offer some hope for T-ALL patients for whom chemotherapy wasn’t effective.

“T-ALL is a particularly hard problem. Most kids are cured, but if they relapse, we have nothing to offer,” Diorio said. “It’s incredibly unfair. We really badly need better therapies for these kids.”

— Angus Chen