Novel Immunotherapy Selectively Targets Malignant T Cells

One major hurdle in the development of safe and effective immunotherapies has been the risk of depleting healthy T cells during CAR-T treatment that seeks out and kills cancerous T-cells.

In a new study published in Nature Communications, Yale Cancer Center researchers have developed a novel CAR-T cell therapy designed to efficiently kill cancerous T cells while leaving most healthy cells intact. Malignant T cells make up 10-20% of all T cells in non-Hodgkin's lymphoma patients and roughly 20% of T cells in patients with acute leukemias.

Malignant T cells in a patient's body tend to express a single dominant T cell receptor. By targeting that receptor — the receptor is named Vβ2 — the research team reports it can efficiently kill the cancer while protecting immune function of healthy T cells.

"It turns out that Vβ2 is more common than any other form of the T cell receptor for T cell leukemias and lymphomas that we've observed. So, we thought this was the best one to target first," says senior author of the study Michael Girardi, MD, the Evans Professor of Dermatology at Yale School of Medicine and a member of Yale Cancer Center.

Researchers used CRISPR, a gene editing tool, to create CAR-T cells tailored to attack only those cells expressing Vβ2 and that could be well tolerated by patients.

When used in multiple mouse models, the team found the treatment significantly reduced the number of Vβ2-positive cancerous cells while leaving behind the Vβ2-negative healthy cells.

"We've tried to target more specific components of the T cell receptor," Girardi says. "Which is going to, as opposed to wiping out all the T cells, maybe affect a very small percentage of the normal T cells that express that V-Beta. But hopefully eliminate all of the cancer cells that express that V-Beta."

The research was supported by grants from the R. S. Evans Foundation. Jingjing Ren and Xiaofeng Liao were co-first authors of the study. Julia M. Lewis, Jungsoo Chang, Rihao Qu, Kacie R. Carlson, and Francine Foss were Yale co-authors.