Two-phase vaccination can boost the immune system against cancer

 Our body's own defense system not only clears away bacteria and viruses, it can also fight cancer. However, not all tumor cells are easily recognizable by the immune system. In addition, they are constantly changing and camouflaging themselves to evade the defense system.

In order to treat tumor diseases better and more successfully, medical research is focusing on so-called therapeutic cancer vaccines. In this form of immunotherapy, people who already have cancer are vaccinated. It works in a similar way to vaccinations against pathogens and teaches the immune system to recognize tumor cells by certain typical characteristics—known as tumor antigens—and kill them.

One approach is to remove highly specialized immune cells from cancer patients and load them with tumor antigens outside the body. After these dendritic cells are injected back into the body, they can trigger and regulate antigen-specific immune responses.

In another approach, the vaccine, which is protein-based or peptide-based, contains only the protein of the tumor antigen or at least parts of it. This synthetic method is faster, cheaper and less complex. The problem with both methods is that the immune response triggered is often rather weak and the vaccination must be repeated frequently to activate the immune cells.

A research team led by associate professor Dr. Thomas Wirth and Dr. Dimitrij Ostroumov from the Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology at Hannover Medical School (MHH) has now developed a new two-phase liposomal peptide vaccine.

With this therapeutic immunotherapy, just two injections under the skin are enough to effectively mobilize the immune system against the tumor within only 14 days. The work has been published in the journal Cellular & Molecular Immunology

Vaccination takes place in two phases

Researchers have been working for 15 years to improve cancer vaccines. "The key lies in the dendritic cells," says Dr. Wirth. These cells are part of the innate immune system and constantly scan our bodies for viruses, bacteria and tumor cells. If they recognize structures as foreign or different, they absorb them completely or partially, eating them, so to speak.

As antigen-presenting cells, they are able to break down the foreign cell components into smaller pieces and then present them as peptides on their own cell surface. These mini-proteins show the specific T cells of our acquired immune system how to recognize the foreign structures, thereby activating the targeted immune response.

To achieve this as quickly and effectively as possible, the researchers opted for a two-phase vaccination schedule: a basic vaccination followed by a booster vaccination. In such heterologous prime-boost vaccines, the same antigens are injected into the organism twice in different compositions.

In this case, a single antigen peptide specifically produced by the tumor cells was sufficient to activate the dendritic cells directly in the body. However, because the peptide alone does not trigger a sufficiently strong immune response, the researchers added a so-called agonist in both vaccination phases to further activate the immune cells in the body.

"For the primary immunization, we package the peptide with the immune activator in a lipid shell," explains Dr. Wirth. This drives the dendritic cells in the body to present the tumor antigen to the specific T cells so that they can recognize and attack the tumor.

The liposomes used for primary immunization were developed as part of a collaboration in the Netherlands. "When boosting a week later, we also add an antibody that acts as an additional stimulator to ensure that the T cells directed against the tumor multiply ultra-fast."

Exceptional enhancement of the T-cell response

The vaccination regimen was tested in a mouse model for colon cancer. The effect astonished even the researchers. "After only two vaccinations, we observed an extremely strong immune response that led to a complete regression of the tumor," emphasizes Dr. Ostroumov.

"Our experiments not only show that liposomes can be used as peptide carriers without any problems, but also confirm the extraordinary enhancement of the T-cell response by stimulating antibodies in the heterologous vaccination regimen."

The rapid production of the vaccines and the early anti-tumor effect mean an extreme time advantage and thus also a survival advantage for people with cancer.

Another advantage of the vaccination regimen is that it is universal: the peptide building block can be exchanged like in a construction kit and adapted to the respective requirements.

"On the one hand, we can tailor the peptide to the genetic profile of the tumor, i.e., produce personalized vaccines that are individually tailored to each patient," says Dr. Wirth. "On the other hand, the peptide does not even have to be a tumor antigen, but can also carry other information, such as for the detection of parasites, bacteria or viruses."

However, there is still a long way to go before the vaccine becomes part of standard care. The next step would be clinical trials to prove its efficacy and safety for use in humans.

More information: Dmitrij Ostroumov et al, Sequential STING and CD40 agonism drives massive expansion of tumor-specific T cells in liposomal peptide vaccines, Cellular & Molecular Immunology (2025). DOI: 10.1038/s41423-024-01249-4

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