A new approach to cancer vaccine development could make immunotherapies more effective in acute myeloid leukemia

Acute myeloid leukemia (AML) is a form of blood cancer that forms in the soft bone marrow, typically attacking cells that would otherwise form the most important part of the body’s immune system: white blood cells.

In a new study published in Blood progressresearchers from the Hubbell Lab at the UChicago Pritzker School of Molecular Engineering created a novel approach to develop in-situ cancer vaccines that could increase the effectiveness of immunotherapies in AML and other blood cancers.

“We’re trying to come up with cancer vaccine approaches that are easier to scale and deploy, in other words, one type of vaccine that works across a number of cancers,” said Prof. Jeffrey Hubbell, Eugene Bell Professor of Tissue Engineering. at PME.

Powerful protection against pathogen attacks

Vaccination is a well-known method to prevent diseases caused by various pathogens, such as bacteria and viruses. It works by exposing a small part of the pathogen – usually a protein – to the immune system so that immune cells are ready to fight incoming pathogens.

Our immune system not only protects us from attacks by pathogens, but also protects against any abnormal changes in the body. For example, immune cells can identify abnormal mutated proteins or cancer cells and remove them from the system. Cancer vaccination has become a powerful tool for using the immune system to treat cancer.

Some vaccines work by preventing specific cancers from developing, such as the human papillomavirus (HPV) vaccine, which protects against a virus that can cause cervical cancer. Other vaccines are therapeutic vaccines, which are intended to boost immunity to attack existing cancers. This new research falls into the latter category.

From an immune perspective, cancer can often look exactly like healthy tissue, so the immune system doesn’t always respond to it without prompting, says Pritzker Molecular Engineering doctoral candidate Anna Slezak, the paper’s first author.

Slezak, who is also an intern at the University of Chicago Medicine Comprehensive Cancer Center, aims to identify key differences in cancer cells so that these unique properties can be harnessed to stimulate a specific immunological response against the cancer cells, as opposed to healthy tissues. .

Immune cell targets, or antigens, are usually the mutated proteins of the cancer cells. Scientists have been sequencing tumor biopsy samples for many years to identify target proteins that can be used to develop vaccines. This knowledge-based approach can be very useful in creating personalized vaccines, but it will be a laborious process.

Exploiting unique properties of cancer cells

Recently, Hubbell’s team took advantage of a unique characteristic of cancer cells to develop a generalized cancer vaccine. Tumor cells, unlike healthy cells, have unpaired cysteine ​​molecules on their surface due to metabolic and enzymatic dysregulation. These unpaired cysteines provide a tumor cell-enriched chemical signature that can be exploited to specifically target their material to cancer cells.

Attaching an adjuvant, usually a drug or chemical, to the material that labels free thiols can boost the immune response and turn the tumor cell itself into the vaccine, simply by injecting the material into the blood.

“Our material binds specifically to these free thiols and can covalently link our adjuvant to the tumor cell, tumor debris, whatever the thiol is attached to,” Slezak said. This is a way to label cancer cells or the waste of dying cancer cells in the circulating blood for immune recognition and to activate immunity against their mutated proteins.

The construct also contains mannose, a type of sugar moiety, and a Toll-like receptor-7 (TLR-7) agonist. The mannose moieties help transport the waste to antigen-presenting cells (APCs) located in the liver and spleen, and TLR-7 is required for immune system activation. Once APCs engulf the construct, it triggers a TLR-7-mediated immune response against the debris or cancer cells.

Chemotherapy enhances the effects of the cancer vaccine

To generate a more effective response, the researchers combined the administration of vaccines with treatment with cytarabine, a chemotherapy drug commonly administered to AML patients.

“Combination therapies are difficult to develop, but they are generally more effective than monotherapies,” Hubbell said.

In this study, combination treatment with low dose cytarabine significantly increased survival after intravenous administration of the vaccine. Because this vaccine approach does not target a specific cancer protein, the study authors said it could be applicable to other hematological malignancies.

“People have tried this concept before by using antibodies to target the tumor cell instead of the polymer, such as an antibody-drug conjugate or an antibody-adjuvant conjugate,” Hubbell said. “But here we come up with an approach that does not require a targeted antibody. That is a major advantage over what has been previously attempted in this tumor cell-targeted adjuvant concept.”

Future work from the Hubbell lab will focus on the chemistry of new vaccines, specifically asking questions about what kind of immune adjuvant or other molecules could be attached to the material that tags cancer cells to yield exciting results in cancer treatments. The researchers note that much more preclinical work is needed before the approach is ready for clinical testing.