Acute myeloid leukemia (AML) is a type of blood cancer that forms in the soft bone marrow, usually attacking cells that would otherwise be the main component of the body’s immune defense system, the white blood cells.
In a new study published in blood advances, researchers from the Hubbell Laboratory of the UChicago Pritzker School of Molecular Engineering have come up with a new approach to developing on the spot 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 could be scaled up and implemented more easily, in other words, a type of vaccine that works across a range of cancers.”
Prof. Jeffrey Hubbell, the Eugene Bell Professor of Tissue Engineering at PME
Strong protection against pathogen attacks
Vaccination is a well-known method for preventing diseases caused by a variety of pathogens such as bacteria and viruses. It works by exposing a small part of the pathogen -? usually a protein – in the immune system so that immune cells are primed to fight incoming pathogens.
Our immune system not only protects us from attacks by pathogenic microorganisms, but also protects against any abnormal changes that occur within the body. For example, immune system cells can recognize abnormal mutated proteins or cancer cells and eliminate them from the system. Thus, cancer vaccination has emerged as a powerful tool for harnessing the immune system to treat cancers.
Some vaccines work by preventing the development of certain cancers, such as the human papillomavirus (HPV) vaccine that protects against a virus that can cause cervical cancer. Other vaccines are therapeutic vaccines, ie boosting immunity to attack existing cancers. This new research falls into the latter category.
From an immune perspective, cancer can often appear just like healthy tissue, so the immune system doesn’t always launch a response against it unprompted, said Pritzker Molecular Engineering PhD candidate Anna Slezak, first author of the paper.
Slezak, who is also a fellow in training at the University of Chicago Cancer Center, is trying to identify key differences in cancer cells so that these unique characteristics can be targeted to drive a specific immune response against cancer cells as opposed to normal ones. healthy tissues.
Immune cell targets, or antigens, are usually the mutated proteins of cancer cells. For many years, scientists have been sequencing tumor biopsy samples to identify target proteins that can be used to develop vaccines. This knowledge-based approach can be very useful for making personalized vaccines, but it becomes a laborious process.
Harnessing the unique characteristics of cancer cells
Recently, Hubbell’s team used a unique characteristic of cancer cells to develop a generalized cancer vaccine. Cancer cells, unlike healthy cells, have unpaired cysteine ​​molecules on their surfaces as a result of metabolic and enzymatic dysregulation. These unpaired cysteines provide a cancer cell-enriched chemical signature that can be exploited to target their material specifically 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 cancer cell itself into the vaccine, simply by injecting the material into the blood.
“Our material specifically binds to these free thiols and can covalently bind our adjuvant to the cancer cell, tumor debris, whatever the thiol is attached to,” Slezak said. This is a way to mark cancer cells or dead cancer cell debris in circulating blood for immune recognition and trigger immunity to their mutated proteins.
The construct also contains mannose, a type of sugar group, and a Toll-like receptor-7 (TLR-7) agonist. The mannose groups help transport the residues to antigen-presenting cells (APC) found in the liver and spleen, and TLR-7 is required to activate the immune system. Once the APCs engulf the construct, it activates the TLR-7-mediated immune response against the debris or tumor cells.
Chemotherapy enhances the effects of the cancer vaccine
To create a more effective response, the researchers combined vaccine administration with treatment with cytarabine, a chemotherapy commonly given to AML patients.
“Combination therapies are difficult to develop, but they tend to be more effective than monotherapies,” Hubbell said.
In this study, combination therapy with low-dose cytarabine significantly increased the survival rate after intravenous administration of the vaccine. Because this vaccine approach does not target any specific cancer protein, the study authors said it may have application in other hematologic malignancies.
“People have tried this idea in the past using antibodies to target the cancer cell rather than the polymer, such as an antibody-drug conjugate or an antibody-enhancer conjugate,” Hubbell said. “But here we come up with an approach that doesn’t require a targeting antibody. That’s a big advantage over what’s been tried before in this tumor cell-targeting adjuvant concept.”
Future work in the Hubbell lab will focus on the chemistry of innovative vaccines, particularly asking questions about what kind of adjuvant or other molecules can be attached to the material that tags cancer cells to produce exciting results in cancer treatments. The researchers note that there is much more preclinical work that is necessary before the approach is ready for clinical testing.
Source:
Journal Reference:
Slezak, AJ, et al. (2024). Cysteine-binding adjuvant enhances survival and promotes immune function in a murine model of acute myeloid leukemia. The blood goes on. doi.org/10.1182/bloodadvances.2023012529.
