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T-Cells Engineered to Release Anti-Cancer Proteins

T-cells illustration

T-cells (NASA.gov)

14 Nov. 2019. A biotechnology company is developing modified immune system cells programmed to sense and respond to cancer cells with targeted therapeutic proteins. A team from Cellectis Inc. in New York and Paris reports on results of tests with these reprogrammed cells in lab mice, in yesterday’s issue of the journal Nature Communications.

Cellectis develops cancer treatments that harness the immune system by breaking down defenses tumors create to prevent the body’s immune system from fighting the disease. The company’s platform builds on recent developments that take T-cells, white blood cells from the immune system, and reprogram the cells through genetic engineering to find and kill cancer cells. The engineered T-cells become hunter cells, containing proteins known as chimeric antigen receptors that act like antibodies. These modified chimeric antigen receptor or CAR T-cells are infused into the patient, seeking out and binding to proteins associated with the cancer.

Most current CAR T-cell methods genetically engineer a patient’s own T-cells, then re-infuse the altered T-cells back into the individual. Cellectis’s process is designed to produce off-the-shelf CAR T-cell treatments, it calls Universal CAR T-cells, or UCARTs. These treatments use T-cells from healthy donors, rather than a patient’s own T-cells, then are genetically engineered to match the attributes of specific cancer types.

In their study, a Cellectis group led by Julien Valton, the company’s team leader for synthetic biology, reports on a next iteration of anti-cancer T-cells. The researchers aim to further reprogram T-cells beyond the addition of chimeric antigen receptors, to recognize the type of tumor encountered and secrete the appropriate cancer-fighting proteins in response. To modify the T-cells, the team edited critical genes responsible for immune system functions to express therapeutic proteins, under certain conditions.

The team used Cellectis’s gene-editing technology known as Talen, short for transcription activator-like effector nucleases, to modify the target genes. Talens are synthetic enzymes that Cellectis says provide highly precise editing of genomes. In this case, the researchers edited three genes enabling the T-cell to recognize the tumor environment, and under those conditions express chimeric antigen receptors. These newly empowered CAR T-cells then secrete the protein IL-12P70 in the Interleukin-12 family of immune system enzymes. The edited genes also prevent expression of programmed cell death or PD1, the so-called checkpoint protein that blocks the functioning of T-cells.

Valton and colleagues tested their programmed CAR T-cells in lab mice grafted with human lymphoma tumors. The modified CAR T-cells were delivered with adeno-associated virusesbenign and naturally occurring microbes that can infect cells, but do not integrate with the cell’s genome. The researchers programmed the CAR T-cells to find tumor cells expressing a specific surface protein known as CD22, with the tumor cells divided between those expressing or not expressing this protein.

The results show the modified CAR T-cells accumulated where the tumor cells expressed the target CD22 protein, but were absent from other tumor cells not expressing this protein. Likewise, the team found more secretion of cancer-fighting IL-12P70 proteins where tumors expressed CD22 proteins, than where these targets are not expressed. The researchers report more anti-tumor activity in mice receiving the programmed CAR T-cells, as well as longer survival times.

“These highly intelligent CAR T-cells can sense and remodel their microenvironment in a tailored, highly regulated, and antigen-specific manner,” says Valton in a company statement, “allowing us to have more control over increasingly potent treatments and less risk of general secretion into healthy tissues. This engineering strategy could bring smarter, safer and more effective treatments to the forefront for patients in need.”

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