At FOMAT, oncology immunotherapy is one of the most exciting areas we follow in clinical research. The personalized cancer vaccine represents a fundamental shift in how we think about treating tumors, and this research from Johannes Gutenberg University represents a meaningful step forward in making that approach both scientifically sound and economically feasible.<\/p>\n
For the first time, it has been shown that many mutations in tumors \u2014 approximately 20 percent \u2014 are immunogenic, or able to rouse armies of T cells after vaccination. Also for the first time, it has been shown that most of those T cell armies are helper CD4+ T cells, not killer CD8+ T cells. A team from Johannes Gutenberg University in Mainz, Germany engineered a relatively affordable and comparatively easy to make personalized cancer vaccine using this new knowledge \u2014 and wiped out lung, skin, and colon cancer cells in mice.<\/p>\n
“This is a milestone paper,” said Gutenberg oncologist Ugur Sahin, senior author on the Nature paper. MD Anderson Cancer Center vaccine expert Willem Overwijk agreed: “This is a very good and convincing study. To my knowledge, it is a first. Most efforts have been focused on CD8+ T cells.”<\/p>\n
Overwijk added that a strength of the personalized cancer vaccine approach is that it is very fast, since it only uses tumor exome sequencing \u2014 which takes a few weeks \u2014 followed by bioinformatics and synthesis of RNA for the vaccine, which ideally takes a week. Based on the animal data and the previously reported power of CD4+ T cells in human cancer, he believes CD4 T cells are going to contribute substantially to the anti tumor effect of these personalized vaccines in patients.<\/p>\n
Sahin described many crucial findings in the paper. The most important is that the team systematically analyzed the immunogenicity of mutations, resulting in the surprising finding that they are frequently recognized by CD4+ T cells.<\/p>\n
Before this paper, the understanding from existing literature was that about one in 200 mutations are spontaneously recognized by the immune system. The Sahin group looked in an unbiased fashion for both CD8+ and CD4+ cells and asked which fractions of mutations could induce immune responses \u2014 arriving at a much higher fraction of approximately 20 percent of cancer mutations being immunogenic.<\/p>\n
Furthermore, the team found that six to seven percent of total mutations need to be recognized by T cells to control tumor growth, representing 35 to 40 percent of the immunogenic mutations. This number is at least ten times higher than the initially reported figure. And if there are 10 immunogenic mutations, 9 will be recognized by CD4+ cells \u2014 information Sahin described as crucial for personalized cancer vaccine design.<\/p>\n
While CD8+ T cells are generally regarded as the “killers,” the Sahin group showed that CD4+ T cells enter the tumor and stimulate anti tumor microenvironments. They induce direct and indirect anti tumor effects by attracting an influx of cytotoxic T cells and reducing the number of regulatory T cells.<\/p>\n
In 1998, Cornelius Melief of University Hospital Leiden published work in Nature finding for the first time that CD4 T cells can have a strong anti tumor effect. Since then, CD4 T cells had taken a back seat. “Because of our study, I think CD4 cells may come into a Renaissance,” Sahin said.<\/p>\n
The second major contribution of the paper is the relatively inexpensive RNA vaccine approach. Instead of stimulating the immune system with an artificial epitope, the group kept the natural configuration of mutations by generating RNA and flanking them with 13 amino acids at both sides in a natural configuration. This allows in vivo antigen presenting cells to pick up tumor epitopes and process them naturally.<\/p>\n
The group made cassettes of five mutations each and used two cassettes \u2014 for a total of 10 mutations \u2014 per vaccine. Using an algorithm and bioinformatics to predict mutations, they synthesized the vaccine in a few days, producing synthetic RNA in one day. For the clinical trial, the process takes approximately three months.<\/p>\n
The personalized cancer vaccine using RNA lets researchers include both CD4+ and CD8+ epitopes in a relatively inexpensive way. By contrast, getting ten long synthetic peptides through traditional methods costs approximately $700,000 in production. “We want an affordable individual treatment,” Sahin said. “Our vision is to give this to everybody.”<\/p>\n
For over a year, the approach had also been in clinical use at the time of publication. A total of 15 patients were enrolled, with half having received the personalized cancer vaccine. While Sahin was unable to reveal mid trial data, he noted that the team was excited to translate the approach into the patient setting.<\/p>\n
He also noted that repeated vaccinations would be necessary. Unlike infectious diseases where antibodies are raised for a lifetime by one or two shots, T cells \u2014 while extremely aggressive \u2014 stop attacking after a time and require repeat vaccinations.<\/p>\n
Overwijk noted that while the study answers key questions about the personalized cancer vaccine, it also raises important new ones \u2014 including the degree to which spontaneous immunity to these epitopes is induced, exactly how CD4+ T cells fight tumors, and whether co vaccination with peptides that induce both CD4+ and CD8+ T cell responses works better than vaccination with either class alone.<\/p>\n
“Of course, we really want to see if vaccination of patients using this algorithm will result in clinical efficacy, either as monotherapy or in combination with checkpoint blockade,” Overwijk said.<\/p>\n
To understand how personalized cancer vaccine research moves from animal studies into patient trials, our introduction to clinical trials<\/a> explains the full development pathway from Phase I through Phase IV studies.<\/p>\n For those interested in the broader landscape of cancer research breakthroughs, our article on the halichondrin anti cancer agent<\/a> covers another landmark synthesis achievement that is already in Phase I clinical trials.<\/p>\n