Researchers Demonstrate Ways to Improve CAR-T for Solid Tumors


Researchers with the Georgia Institute of Technology recently published work in Nature Biomedical Engineering that describes several new approaches to improving CAR-T, particularly for solid tumors.

CAR-T therapy, such as Gilead Sciences' Yescarta (axicabtagene ciloleucel) for non-Hodgkin lymphoma, acute lymphoblastic leukemia, mantle cell lymphoma and other indications, and Novartis' Kymriah (tisagenlecleucel), approved for acute lymphoblastic leukemia, chronic lymphoid leukemia, diffuse large B-cell lymphoma, as well as others, are very effective for hematologic cancers. However, getting CAR-T to work in solid tumors has been a tougher nut to crack.

In CAR-T (chimeric antigen receptor T-cell) therapy, T-cells are isolated from a cancer patient, engineered in the laboratory by adding a gene for a chimeric antigen receptor (CAR), grown, then infused back into the patient. There, they become a sort of living therapy highly tuned to attack the patient’s cancer.

“These therapies have proven to be remarkably effective for patients with liquid tumors — so, tumors that are circulating in the blood, such as leukemia,” Gave Kwong, associate professor in the Wallace H. Coulter Department of biomedical engineering at Georgia Tech and Emory, and senior study investigator told Genetic Engineering & Biotechnology News. “Unfortunately, for solid tumors — sarcomas, carcinomas — they don’t work well. There are many different reasons why. One huge problem is that the CAR T-cells are immunosuppressed by the tumor microenvironment.”

Kwong’s team is working to change the microenvironment to improve CAR-T in these cancers. One approach is to create an on-off switch that is sensitive to heat. 

Earlier work conducted by his research group precisely targets tumors with a local deposit of heat, which activates the CAR-T cells inside the tumor. To create heat, they used laser pulses from outside the body. Gold nanorods that are delivered to the tumor convert the light waves into localized heat, increasing the temperature to 40 to 42 degrees C, which activates the switch but doesn’t harm healthy tissues or the T-cells.

In addition to genetically engineering the CAR-T cells to respond to that switch, they have also redesigned them to manufactures immune stimulatory molecules. These cytokines and bispecific T-cell engagers are controlled carefully.

Kwong said, “These cancer-fighting proteins are really good at stimulating CAR T-cells, but they are too toxic to be used outside of tumors. They are too toxic to be delivered systemically. But with our approach, we can localize these proteins safely. We get all the benefits without the drawbacks.”

The study was conducted on mice. The research led to a 60-fold-higher expression of a reporter transgene without affecting the CAR-T cells’ proliferation, migration, and cytotoxicity. The system cured cancer in the mice, shrinking tumors and preventing relapse.

The researchers say that when they test it in humans, instead of the laser, they will use focused ultrasound, which is noninvasive while targeting any location in the body. Lasers don’t penetrate far enough into the body to be a practical approach in humans.

“So,” Kwong said, “if you have a deep-seated malignant tumor, that would be a problem. We want to eliminate problems.”

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