KU Leuven researchers discover how to break the negative feedback loop to improve cancer immunotherapy

Immunotherapy focuses on activating the patient’s own immune system to respond against the tumor(s) by administering a specific therapy. One of these drugs can be seen as a form of vaccination. While conventional vaccines are used to prevent infectious diseases, vaccines against cancer aim to kill the existing cancer cells and prevent metastasis. These so-called “cancer vaccines” are made from patients’ own immune cells, which are prepared in the lab to combat specific cancer cells. A type of immune cell that is often used are dendritic cells (DCs) – a key component of the human and, more generally, the mammalian immune system.

Unfortunately, not all tumors respond to current immunotherapies. This is especially the case with tumors that have a low amount of T cells, a type of white blood cells that is responsible for killing cancer cells. Tumors with less T cells occur mostly in the brain, liver, ovaries, prostate and pancreas – although this can vary between patients. Not surprisingly, these are all cancers that are difficult to treat, generally resulting in a poor outlook for the patient.

This problem of immunotherapy resistance has been investigated over the past years, and specific DC vaccines have been designed that would elicit stronger immunogenic responses in low T cell tumors. However, these improved vaccines have not yet led to convincing results in the clinic.

Negative feedback loop

An international team of cancer researchers, led by KU Leuven, is following a different path. Instead of only focusing on the preparation of DC vaccines in the lab, the researchers zoomed in on what actually happens when they are administered to the patients or to preclinical tumor models. They discovered that the vaccines stimulate the creation of a specific type of macrophages (another kind of white blood cells) that can block the immune response to the vaccines.

“We found a negative feedback loop in the host response to the vaccines”, says principal investigator Abhishek Garg, assistant research professor at the Department of Cellular Molecular Medicine and member of LKI - KU Leuven Cancer Institute. “In a successful immunotherapy, this negative effect is overcome probably due to the rich presence of T cells in the tumor. But in low T cell tumors we have to somehow deal with it.”

The team was also able to identify an important mechanism behind the creation of the immune-suppressing macrophages: the production of a protein called PD-L1. This protein has an immune-suppressing role in situations where the immune system should not ‘overreact’, such as in pregnancy or to prevent destructive autoimmunity. In the case of cancer, macrophages can use the PD-L1 protein to block an immune response against the cancer cells. Importantly, the negative feedback loop and its underlying mechanism were both found in humans and in mice.

'Next-generation' strategy

The discovery encouraged the researchers to develop a prototype of a new, ‘next-generation’, vaccination-driven strategy: a combination of a DC vaccine with a blockade of PD-L1 activity in the tumors. They tested this preclinical therapy in mice, which showed promising results.

“It looks like we got rid of the negative feedback loop, so that the low T cell tumors respond like tumors that are currently treated with immunotherapy”, says Jenny Sprooten, lead researcher of the study.

The research is published in the leading translational medicine journal Cell Reports Medicine.

Will the discovery and the initial development of the next-generation vaccine therapy improve cancer immunotherapy? The team will now collaborate with oncologists to start human clinical trials, more specifically with patients with glioblastoma, a severe form of brain cancer.

Garg: “Glioblastoma is a very aggressive cancer, with generally short survival times. If we manage to prolong survival and improve life quality, that would already be a big win.”

The human trials will be performed at the University Hospitals Leuven (UZ Leuven) as well as at a hospital in Germany. The trials are supported by the EU-funded GLIOMATCH consortium program.