Cancer vaccines that prime the immune system to recognize and eliminate cancer cells have gained traction lately. Scientists are pursuing a wide range of strategies including making vaccines from immune cells, tumor cells, tumor-associated proteins or their smaller components.
Now, a team at Stanford University has demonstrated that a cancer vaccine made from induced pluripotent stem cells (iPSCs), together with an immune adjuvant, could protect against pancreatic cancer in mouse models. The findings were published in the journal Stem Cell Reports.
Because iPSC vaccination trains the immune system using a broad range of non-mutated tumor antigens, the approach could potentially be applicable not just to pancreatic cancer, but also to other cancers with low tumor mutational burdens, the researchers said.
The Stanford team previously discovered that iPSCs, which can be generated by reprogramming mature skin or blood cells, share similar gene expression profiles with cancer cells but not with normal tissue. They hypothesized that an iPSC-based cancer vaccine could be used to elicit an immune response against tumors.
The researchers designed a mouse iPSC-based cancer vaccine and tested it in a model of pancreatic ductal adenocarcinoma. The iPSCs were irradiated so they wouldn’t divide, and they were paired with a vaccine adjuvant called CpG, which can promote the function of antigen-presenting cells and boost immune responses.
While solo CpG or iPSCs didn’t work, 75% of mice that got the combo before being injected with pancreatic cancer cells completely rejected the cancer cells, the team reported.
In the combo group, researchers noted an increase of CD8+ killer T cells compared with control, and those T cells appeared to have enhanced activation. The combo vaccine dialed up the production of inflammatory molecules IFN-gamma and IL-2 in CD8+ T cells, CD4+ memory T cells and circulating dendritic cells, suggesting a broad immune activation.
What’s more, the treatment reduced the number of regulatory T cells, or Tregs, which can accumulate in the tumor microenvironment and suppress the immune response, while neither the iPSCs alone nor CpG alone did that. The combo also suppressed other tumor-promoting immune cells such as T helper 17 cells, which have been linked to poor survival in human patients.
The team also examined the expression levels of these so-called iPSC-cancer signature genes in human tumors from The Cancer Genome Atlas database and found high levels of mRNA upregulation across different tumor types, ranging from 68.1% to 88.7%. These data suggest over-expression of these genes is common in human solid tumors, the researchers said.
Stem cells have been used in cancer vaccine research, but most often as a delivery platform. For example, Mayo Clinic is working with the National Cancer Institute on a cancer vaccine that infects mesenchymal stem cells with a modified measles virus encoding a thyroid membrane protein.
The Stanford team suggests that iPSCs could serve as the core component of a cancer vaccine for tumors with enriched iPSC-cancer signature genes. And, if expressions of those tumor-associated antigens in the iPSCs are validated, new peptide-based cancer vaccines could be developed based on them, the team said.
“Compared with other immunological modalities, iPSC vaccination presents a broad-spectrum of non-mutated tumor antigens to the immune system, potentially making this approach applicable to PDAC and other cancers with low tumor mutational burdens,” the researchers wrote in the study.