A new gene therapy reprograms cancer cells to fight themselves

Cancer cells are insidious enemies.

Our body's immune system normally looks for signs of tumor cells. When it finds them, it sets killer T cells – a type of immune cell – in motion to seek out and destroy the threat. But it's a game of cat and mouse: As tumors grow, they form a protective barrier to ward off immune attacks. Within the protective zone, immune cells lose their targeting and killing power.

One solution is to genetically modify more powerful T cells. A relatively new and promising approach, called CAR-T therapy, adds additional “targeting markers” to the T cells taken from each patient to turn them into tailor-made cancer torpedoes.

So far, the FDA has approved six CAR-T therapies for various types of blood cancer. But they have an Achilles heel. Their number slowly decreases in the body and they gradually lose their ability to fight cancer.

Some scientists are working to make CAR-T cells more lethal. Others are turning T cells into Trojan horses that infiltrate tumors. One such therapy was approved in May 2024 and is the first cell therapy for a solid tumor – melanoma, an aggressive skin cancer.

Even with these improvements and alternatives, it is still difficult to penetrate a tumor's protective shield. This month, a team from Asgard Therapeutics and Lund University took a clever new approach to attack tumors from the inside. The work was

Using a technology called cellular reprogramming, the team transformed tumor cells in mice into a type of immune cell called cDC1 cells. These cells are the master regulators of the immune system. They are rare in tumors, but when present, they can trigger powerful immune responses that destroy the cancer's protective shield and recruit T cells to the target.

Mice treated with gene therapy remained cancer-free for at least 100 days and resisted cancer recurrence in a laboratory test.

“The data provide preclinical proof of concept for a ready-to-use, yet tumor-specific, unique cancer immunotherapy,” Asgard Therapeutics wrote in a press release.

Identity change

At the heart of the therapy is a technology called cellular reprogramming. In it, scientists use a combination of proteins called transcription factors to turn genes on or off. This process can change the identity of a cell.

The best-known example of cellular reprogramming is the Nobel Prize-winning creation of pluripotent cells (iPSCs). These cells have revolutionized regenerative medicine and the way we study disease. They use four transcription factors to convert mature skin cells back into stem cells. This cell type can develop into any other cell type in the body. Additional factors can then gently guide the newly created iPSCs to take on new identities – for example, brain organoids (“mini-brains”), egg and sperm precursor cells, or liver and bone cells.

Soon after its introduction, it became apparent that this groundbreaking technology held promise for gene therapy.

In 2008, a study found that administering three transcription factors directly into the pancreases of diabetic mice turned them into insulin-releasing cells that kept the animals' blood sugar levels under control. Another study, also in mice, converted heart cells that cause dangerous scarring after a heart attack into healthy heart muscle cells, leading to improved heart function. Scientists have also reprogrammed “supportive” brain cells into functional neurons in mice after brain injury or to treat neurodegenerative diseases.

But this cellular identity swap always started with relatively normal cells. Tumor cells function differently – and their abnormalities could torpedo the process.

Tumor makeover

The new study builds on the team's previous work reprogramming tumor cells in Petri dishes. Their goal was to convert these tumor cells into cDC1 cells, which play a “manager” role in coordinating immune responses.

First, they found three transcription factors that convert other cells into cDC1 cells. They then inserted genetic sequences of these factors into a virus that had been stripped of its pathogenic properties. These viral carriers can introduce genes into cultured cells or into the body.

As a proof of concept, the team grew melanoma cells in petri dishes, treated some with the gene therapy, and injected the engineered cells into healthy mice. Without the treatment, the melanoma cells proliferated rapidly. However, cells with the gene therapy could not grow as quickly.

The average survival rate increased from 19 days without treatment to 43 days with treatment. By adding conventional immunotherapeutics, all animals were freed of tumor cells.

The transformed cDC1 cells easily dismantled the tumor's protective shield. After nine days, additional immune cells populated the tumor, indicating that its protective barrier had begun to erode.

Classic immunotherapy drugs often exhaust T cells, limiting their spread and ability to attack. Reprogramming has reduced the risk of exhaustion in several T cell types by up to eight times.

At the same time, the treatment increased the number of memory T cells, which, as their name suggests, store records of previous attacks, including certain types of cancer. These cells protect the body from cancer recurring. Once they detect previously defeated tumors, they alert other components of the immune system to attack before the cancer cells can grow and spread again.

Can it work in the human body?

Tumors in mice are not exactly the same as those in humans. In another test, the team grew small balls of cells from different types of immortalized cancer cell lines in petri dishes. Some of these so-called “spheroids” contained cells and other factors from a tumor's protective shield.

Reprogramming the cancer cells into cDC1 cells reduced the size of the cancer balls, although the effectiveness varied depending on the type of cancer. The addition of common cancer drugs – which are known to reduce some immune responses – had no effect on the reprogramming and subsequent activation of the immune cells.

So far, so good. But could the therapy also work directly in the body – without having to remove tumor cells and reprogram them in the laboratory? In a final test, the team injected the drug into melanoma tumors in mice for two weeks.

Half of the treated mice remained cancer-free for 100 days, with large numbers of T cells infiltrating the tumor area. The treated mice also easily fought off an experimental model of cancer relapse, keeping malignant cells at bay for at least another 60 days – compared to control mice, which developed cancer within a month.

There is still a long way to go before the treatment reaches the clinics, but the team is already testing safety profiles and drug metabolism and optimizing manufacturing processes to prepare for clinical trials.

Turning tumor cells against themselves “offers the benefits of precise cell therapy while overcoming the challenges” of genetically manipulating immune cells outside the body, as is done with currently approved CAR-T therapies, the authors write. However, work manipulating CAR-T cells directly in the body is also increasing.

Nevertheless, the results pave the way for human trials. They lay “the foundation for a new class of immunotherapies based on the unique function” of different types of immune cells produced in the body through reprogramming, the authors concluded.

Image credit: T cells (red) attack cancer cells (white) / Rita Elena Serda, Duncan Comprehensive Cancer Center at Baylor College of Medicine, National Cancer Institute, National Institutes of Health