Abstract
CAR T cells have shown dramatic effects against blood cancers, but they have had little impact on solid tumors. Researchers increased the effectiveness of CAR T-cell therapy in solid tumors by injecting the cells near the tumors. A phase I trial using this approach will begin early next year.
Treatment with chimeric antigen receptor (CAR) T cells has shown promise against hematologic cancers, but it hasn't worked well against solid tumors. However, a study published this month shows that injecting the T cells into the area around the tumor improves the effectiveness of the therapy in mice.
CAR T-cell treatment involves removing some of a patient's T cells and genetically modifying them to carry a T-cell receptor that recognizes a specific antigen. After the reprogrammed T cells are returned to the patient's bloodstream, they destroy cancer cells they encounter that carry their target antigen.
Based on other research, one reason that the therapy hasn't performed as well against solid tumors as against hematologic cancers might be that few of the CAR T cells are reaching the tumors, notes Prasad Adusumilli, MD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York, NY. Consequently, a team led by Adusumilli and his MSKCC colleague Michel Sadelain, MD, PhD, decided to try placing the CAR T cells close to the tumors.
The researchers studied mice with malignant pleural mesothelioma, a difficult-to-treat tumor that grows on the pleura, the tissue that surrounds the lungs. For their antigen, the Adusumilli and colleagues chose mesothelin, a protein overexpressed by mesothelioma cells and by several other tumors that often metastasize to the pleura, including lung, ovarian, and breast cancers.
The team engineered human T cells to produce a mesothelin-targeting receptor and then injected the cells into the pleural cavities of the mice. The cells infiltrated the tumors, which became undetectable within 11 days, the researchers reported earlier this month in Science Translational Medicine. In contrast, CAR T cells infused into the bloodstream had little impact on the tumors.
In addition, the researchers found that CAR T cells injected into the pleural cavity replicated and persisted in the mice for at least 100 days. The CAR T cells also migrated away from the pleural cavity and attacked metastases.
“We found a novel way of targeting solid tumors,” says Adusumilli. He and his colleagues think that their delivery strategy might work not only for pleural tumors, but also for “accessible” peritoneal cavity tumors, such as those in the pancreas, ovaries, and stomach.
“CAR therapy for solid tumors is hard, and we need to improve it,” says Raffit Hassan, MD, of the NCI in Bethesda, MD, who wasn't connected to the research. He says the study is “a good first step” and justifies testing the regional delivery of CAR T cells in a phase I trial. Adusumilli and his colleagues plan to launch such a trial next year, enrolling 12 to 24 patients with pleural tumors.
In previous trials in humans, CAR T cells have caused serious side effects, including a surge in cytokines known as cytokine release syndrome, and it's possible that they would attack mesothelin on normal cells, Adusumilli says. For their clinical trial, Adusumilli's team plans to equip the CAR T cells with a suicide gene. If side effects become severe, they will give the patients a drug, AP1903, that turns the gene on, spurring the CAR T cells to self-destruct.
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