Engineered T cells turn cancer’s strength against itself

T cell therapy harnesses the power of the immune system to fight cancer, driving major breakthroughs in treating liquid tumors like leukemia and lymphoma. However, T cell therapy can be prohibitively expensive, carries the risk of severe side effects, and still has trouble treating solid tumors, which represent 90% of cancers.

Now, a new technique called “Judo T cell therapy,” recently described in Nature, aims to change that (1). Inspired by the martial arts technique of turning opponents’ strengths against themselves, the treatment exploits a gene mutation found in lymphoma to improve the fitness of engineered T cells.

“Cancer has evolved in order to overcome all of these checks and balances in the body,” said study coauthor Kole Roybal, an immunologist at the University of California, San Francisco. While cancer cells are uniquely positioned to thrive in the low-oxygen, immunosuppressive solid tumor microenvironment, noncancerous engineered T cells struggle to survive, which drastically limits their efficacy.

Judo T cell therapy employs gene mutations found in cancer to improve the fitness of engineered T cells.

credit: istock.com/luismmolina

“It took some outside-the-box thinking to take what we find in cancer cells and cancerous T cells, and to move some of that activity into cellular therapies,” said Michael Girardi, a dermatologist at Yale School of Medicine who was not associated with the study.

CARD11–PIK3R3, a gene fusion found in CD4+ cutaneous T cell lymphoma, stood out to the researchers as a leading candidate for strengthening engineered T cells. Out of Roybal’s team’s initial screens of more than 70 mutations, the gene fusion showed the most promise in altering multiple T cell signaling pathways of interest. The team found that engineered T cells expressing this mutation were 100 times more potent at killing cancer cells in a mouse model; the modified cells cleared an aggressive form of cancer, Nalm6 leukemia, that typically causes death within weeks.

Although transferring a gene found in cancer into engineered T cells may prompt concerns that those therapeutic cells will become cancerous, the researchers found no evidence of malignant transformation in mice over one year of monitoring.

“It’s really hard to take a T cell, put a mutation in, and make it turn into cancer,” said coauthor Julie Garcia, a founding scientist at Moonlight Bio.

Roybal and Garcia hope that T cell therapies employing this mutation will be more efficient at combating solid tumors and will require lower doses, leaving patients with milder side effects and lower bills. The researchers believe that this study represents the beginning of “judo” therapies; they have already identified a handful of other cancer gene mutations to target.

“The work we've done makes all of the process easier and potentially cheaper,” said Roybal. “What that means is that we could treat a greater number of patients.”