Acute myeloid leukemia AML is a type of blood cancer that forms in the soft marrow of the bones, typically attacking cells that would otherwise form the key component of the body’s immunodefense system, white blood cells.
In a new study published in Blood Advances, researchers from the UChicago Pritzker school of Molecular Engineering’s Hubbell Lab created with novel approach to develop in-situ cancer vaccines that could increase the effectiveness of immunotherapies in AML and other blood cancers.
“We are trying to come up with cancer vaccine approaches that could be more easily scaled and applied, in other words, one type of vaccine that works with a number of cancers.”: Said Prof. Jeffrey Hubbell, the Eugene Bell professor in Tissue Engineering at PME.
Strong protection against pathogen attacks
Vaccination is a well-established way to prevent diseases brought on by a range of pathogens, including bacteria an viruses. It functions by exposing a small portion of the pathogen to the immune system, so that immune cells are primed to fight off incoming pathogens. Our immune system not only protects us against threats from pathogens but also from any abnormal changes occurring within the body; for instance, immune cells are able to recognise abnormally mutated proteins or cancer cells and eradicate them from the body. As a result, cancer vaccination has emerged as a potent tool for utilising the immune system to that cancers.
Some vaccines work by preventing cancers from developing, such as the human papilloma virus (HPV) vaccine that protects against a virus that can cause cervical cancer. Other vaccines are therapeutic vaccines, meaning to prime immunity to attack existing cancers. This new research falls into the latter category.
From an immune prespective, cancer can often appear exactly like healthy tissue, so the immune system does not always initiate a response against it unprompted, said Pritzker Molecular Engineering doctoral candidate Anna Slezak, the first author of the paper.
Slezak, who is also a trainee associate member of the University of Chicago Medicine Comprehensive Cancer Center, is trying to identify key differences in cancer cells so those unique attributes can be targeted to drive a specific immunological response against the cancer cells as opposed to healthy tissues.
The altered proteins found in cancer cells are typically immune cell targets, also known as antigens. To find target proteins that can be utilized to create vaccines, scientists have been sequencing tumor biopsy samples for a long time. While creating customized vaccinations using this knowledge-based approach might be highly helpful, the procedure can become time-consuming.
Exploiting unique features of cancer cells
Recently, Hubbell’s team leveraged a unique feature of cancer cells to develop a generalized cancer vaccine. Tumor cells, unlike healthy cells, have unpaired cysteine molecules on their surfaces as a result of metabolic and enzymatic dysregulation. These unpaired cysteines provide a tumor cell-enriched chemical feature that can be exploited to target their material specifically to the cancer cells.
By injecting the material into the bloodstream, one can effectively transform the tumor cell into a vaccine by coupling the material that tags free thiols with an adjuvant, typically a chemical or medication.
“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 stated. This is a means of tagging cancer cells or the remains of dying cancer cells in the bloodstream so that their altered proteins will be recognised by the immune system and cause immunity.
The construct also contains mannose, a type of sugar group, and a toll-like receptor-7 (TLR-7) agonist. The mannose groups help traffic the debris to antigen-presenting cells (APCs) residing in their liver and spleen, and TLR-7 is required for immune system activation. Once APCs engulf the construct, it triggers TLR-7-mediated immune response against the debris or cancer cells.
Chemotherapy enhances the cancer vaccine effects
To generate a more effective response, the researchers combined vaccine delivery with cytarabine treatment, a chemotherapy commonly administered in AML patients.
“Combination therapies are hard to develop, but they tend to be more effective than monotherapies,” Hubbell said.
In this study, the combination treatment with low-dose cytarabine significantly increased the survival rate after intravenous administration of the vaccine. As this vaccine approach does not target any specific cancer protein, the study authors said it may have applicability in other hematological malignancies.
“People have tried this concept before with using antibodies to target the tumor cell rather than the polymer, like an antibody-drug conjugate or an antibody-adjuvant conjugate,” Hubbell said. “But here we are coming up with an approach that does not require a targeting antibody. That’s a big advantage over what’s been tried before in this tumor cell-targeted adjuvant concept.”
Future work of the Hubbell lab will focus on the chemistry of novel vaccines, particularly asking questions about what kind of an immune adjuvant or other molecules can be attached to the material that tags cancer cells to yield exciting outcomes in cancer treatments. The researchers note that there is much more preclinical work that is necessary before the approach would be ready for clinical testing.