Reprogramming Cancer Cells into Immune Cells
Earlier research by the team showed that three specialized proteins, known as transcription factors—PU.1, IRF8, and BATF3—could reprogram skin cells into immune cells, called dendritic cells. These dendritic cells alert the immune system to attack foreign invaders, including cancer.
Last year, the team also showed that cancer cells reprogrammed into dendritic cells in petri dishes in the lab lost their ability to form tumors and could trigger an immune response against the cancer. These reprogrammed cancer cells could be injected back into tumors in mice, where they successfully activated the immune system to fight cancer. One question remained: Could this reprogramming be done directly within tumors?
“If we could reprogram tumor cells in the body, we could skip the whole process of collecting, reprogramming, and reinfusing the cells in patients. That would make the treatment more streamlined, off-the-shelf while personalized, and easier to apply to more people, and help in overcoming the hurdles of cell manufacturing,” explains Professor Filipe Pereira, leader of the research group behind the study at the Lund Stem Cell Center.
Delivering the “Trojan Horse” Inside Tumors
In their latest study, published in Science, the team has shown, for the first time using mice and human tumor models, that tumor cells inside a living organism can be reprogrammed into immune cells.
“The reprogramming process works within the body; and it works much better than we anticipated.”
By injecting the three transcription factors into tumors, the researchers were able to reprogram the tumor cells into type 1 conventional dendritic cells (cDC1s). The “Trojan Horse” proteins were delivered directly into tumors using a gene therapy based on adenoviral vectors - viruses engineered to carry therapeutic genes.
“We compared three different viral delivery systems to see which would be most effective for delivering the transcription factors and reprogramming cells inside tumors,” explains Filipe Pereira. “Adenoviral vectors proved to be the most efficient in both expressing the factors in vivo but also eliciting the reprogramming process within five to nine days.”
A New Type of Immunotherapy
In mouse models of melanoma, an aggressive form of skin cancer, this approach triggered the immune system to fight the cancer. “Half of the treated mice went into remission, and even after re-challenging them with cancer, they developed resistance against the cancer,” notes Filipe Pereira.
The reprogrammed cells developed long-term immunological memory that prevented the cancer from coming back. “Interestingly, CD4 T cells played an essential role in the immune response. We also observed the formation of tertiary lymphoid structures—large clusters of immune cells—within the tumors. These structures have been seen in patients responding well to immunotherapy, with better outcomes.”
The researchers also tested the therapy in human cancer models of melanoma, lung cancer, breast cancer, head and neck cancer, and sarcoma, and in spheroids—3D clusters of cells that mimic human tumors.
“We thought the tumor’s microenvironment might be an obstacle, but it actually helped by providing the right signals to speed up the reprogramming process.”
Even in conditions where the immune system is typically suppressed, a common challenge in cancer treatment, the reprogramming process was successful. “In all the conditions we tested, the cells responded well to reprogramming. In fact, it was better to have these more complex signals present to activate the cells and kill the cancer,” adds Filipe Pereira.
Bringing Reprogramming to the Clinic
Now, the team is eager to move toward clinical trials. Before that can happen, there are a few more steps to take. One will be to manufacture the viral vectors in GMP conditions for complete safety and toxicology studies with the final product. This work will be performed together with Asgard Therapeutics, a spin-out company from the lab that collaborated on this study.
“The thought of bringing in vivo reprogramming to patients for the first time is very exciting. Safety will be a key focus as we transition to the clinic,” reflects Filipe Pereira. “Now that we know we can deliver reprogramming factors to tumors using viral vectors, a future goal is to achieve the same result with RNA, which could make the treatment more affordable and easier to produce.”
“Our goal has been to turn cancer’s own cells against itself, using cell fate reprogramming. When we started eight years ago, we did not know how to do this. This has been a large team effort, building on our initial ideas step by step, from identifying factors to program immune cells from skin cells to converting cancer cells within tumors. It is incredible to see how far we have come, and that human clinical trials are now on the horizon,” says Filipe Pereira.