"One injection on one side, and cancer on the other melted away"... A breakthrough against hard-to-treat cancer with a "30% survival rate" [Reading Science]

Gene circuit creates immune targets in chondrosarcoma cells... also blocks immunosuppressive factors
Shrinks distant tumors in mice implanted with human immune cells... points to potential for treating metastatic cancer

A new approach has been proposed to treat hard-to-treat cancers for which existing immunotherapies have been ineffective because immune cells lack targets to attack. The method prompts cancer cells to produce proteins that serve as targets for immune-cell attacks, while also blocking substances that suppress immune-cell activity. In animal experiments, tumors shrank even at sites where the treatment had not been directly administered.

Seoul National University announced on October 22 that a research team led by Professor Kim Jinhong of its Department of Biological Sciences had developed a new immunotherapy technology targeting chondrosarcoma, in collaboration with a team led by Professor Kim Yijun of Ewha Womans University College of Medicine and a team led by Professor Ming-Ru Wu of Harvard Medical School in the United States.

Mechanism of immunotherapy for chondrosarcoma using gene circuits and antibodies that modulate the tumor microenvironment. Provided by the research team.

Chondrosarcoma is a malignant tumor that develops in cartilage tissue and responds only to a limited extent to chemotherapy and radiation therapy. Surgery to remove the tumor is the primary treatment, but options are limited when surgery is not possible or the cancer has spread to other organs. According to the research team, the 10-year survival rate for these patients is below 30%.

Immunotherapies, including chimeric antigen receptor T-cell (CAR-T) therapy, which has recently been used to treat cancer, have also failed to achieve clear results against chondrosarcoma. This is because there are not enough target antigens for immune cells to recognize and attack cancer cells, and because an environment forms around the tumor that suppresses immune-cell activity.

Creating Targets for Immune Attacks in Cancer Cells and Blocking Immunosuppression

Rather than searching for existing targets on cancer cells, the research team devised a way to make cancer cells produce targets for immune-cell attacks themselves. To do so, they analyzed gene expression patterns in chondrosarcoma cells and designed an artificial genetic circuit that operates only under specific conditions.

The key is a logical structure called an "AND gate." Through large-scale screening, the team identified two types of promoters that respond to EGR1 and KLF13. A promoter is a region of DNA that regulates gene activity. The circuit was designed so that the therapeutic gene would activate only when both promoters were active, causing cancer cells to produce a "T-cell engager," a synthetic protein that activates immune cells.

In effect, the approach gives cancer cells, which were difficult for immune cells to target, a new target for attack. The team designed the circuit to suppress the expression of the therapeutic protein in normal cells.

The team also blocked substances that suppress immune-cell activity. By analyzing tissue from patients with chondrosarcoma, the researchers found that expression of MIF, an immunosuppressive factor, increased with tumor malignancy, and that patients with higher MIF expression had lower survival rates. Based on these findings, they combined an antibody that blocks MIF with the genetic-circuit therapy.

When the two treatments were administered together to mice implanted with human immune cells, the tumors shrank significantly. In particular, after tumors were implanted on both sides of the mice, the treatment was injected only on one side, yet the tumor on the untreated opposite side also shrank.

Research team photo. From left: Dr. Seo Juyeon (co-first author) and student Yuk Geunho (co-first author). Photo provided by Seoul National University.

This is an "abscopal effect," in which a localized treatment affects tumors at other sites, and it suggests that a systemic anticancer immune response may have been induced. However, the treatment has not been shown to be effective in patients with metastatic cancer. As the research is still at the animal-testing stage, further studies are needed to assess methods of delivering the treatment, its safety for normal tissue, and its long-term effects before it can be used in humans.

"Whereas existing immunotherapies seek out cancer cells that are deeply hidden, this study uses synthetic biology to make cancer cells reveal themselves and become targets for immune cells," said Kim Jinhong, a professor in Seoul National University's Department of Biological Sciences. "Rather than waiting to find good targets in cancer, this study demonstrates the potential of a new engineering approach that allows us to create the targets we need."

"Sarcomas are a classic example of 'cold tumors' that immune cells can barely penetrate, and they have remained outside the reach of immunotherapy," said Kim Yijun, a professor at Ewha Womans University College of Medicine. "This approach could also be extended to other cold tumors, such as pancreatic cancer and glioblastoma, and could serve as a starting point for broadening the range of cancers that can be treated with immunotherapy."

The findings were published in the international journal Trends in Biotechnology.

This content was produced with the assistance of AI translation services.