Many Crucial\u00a0 Findings<\/h3>\n
The recent paper offers what Sahin believes are \u201cmany crucial findings. The most important is that we systematically analyzed the immunogenicity of mutations, which resulted in the surprising finding that they are frequently recognized by CD4+ T cells. Before we published this paper, there were many studies showing that immune response against cancer mutations are extremely relevant for tumor control; for example, that checkpoint antibodies seem to work only if there are pre-existing mutation-specific T cells. Yet the understanding was, from the literature, that about one in 200 mutations are spontaneously recognized by the immune system. This is low.\u201d<\/p>\n
However, Sahin said, such work focused on CD8+ T cells, and on spontaneous immune responses. \u201cWe did it the other way,\u201d he said. \u201cWe looked in an unbiased fashion for both CD8+ and CD4+ cells and asked, \u2018Against which fractions of mutations is it possible to induce immune responses?\u2019 We came up with a much higher fraction: about 20 percent of cancer mutations are immunogenic.\u201d<\/p>\n
An even bigger question is, \u2018Which fraction of the immune mutations is able to control the tumor?\u2019 We found that six to seven percent of the total mutations need to be recognized by T cells to control tumor growth, or 35 to 40 percent of the immunogenic mutations. This number is at least ten fold higher than the initially reported number. And if you have 10 immunogenic mutations, 9 will be recognized by CD4+ cells. Crucial information.\u201d<\/p>\n
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Furthermore, generally CD8+ T cells are regarded as the \u201ckillers.\u201d But the Sahin group showed that CD4+ T cells enter the tumor and stimulate anti-tumor microenvironments. \u201cThey induce direct and indirect antitumor effects by attracting an influx of cytotoxic T cells, and by reducing the number of regulatory T cells,\u201d Sahin told Bioscience Technology.<\/p>\n
In 1998, Cornelius Melief of University Hospital Leiden in Leiden, Netherlands published work in Nature finding–for the first time–that CD4 T cells can have a strong anti-tumor effect. \u201cBut since then, CD4 T cells took a back seat,\u201d Sahin said. \u201cBecause of our study, I think CD4 cells may come into a Renaissance.\u201d<\/p>\n
Second Key Finding<\/h3>\n
His paper\u2019s second important presentation, Sahin said, was that of the relatively inexpensive RNA vaccines with which he demonstrates his findings. In a Science paper published earlier this month, a global team used synthetic peptide vaccines to arouse CD8+ T cell responses in patients. But peptides get complex as they get longer, Sahin explained. \u201cWe wanted to avoid stimulating the immune system with an artificial epitope, which could result in an immune response against a synthetic peptide not related to a tumor,\u201d he said.<\/p>\n
Instead the group kept the \u201cnatural configuration of the mutations by generating RNA from them, and flanking them with 13 amino acids at both sides in a natural configuration,\u201d Sahin said. This way, post-injection, he was giving in vivo antigen presenting cells (APCs) the chance to \u201cpick up our tumor epitopes and process them naturally. It can be extremely complicated to make peptides yourself. It can take up to a year to get long peptides of GMP quality. And ultimately the challenge is to get multiple peptides. So we decided to synthesize RNA by easy informatic approaches. We got our vaccine cassette in a few days. To produce synthetic RNA took one day. The whole process in animal models took a few days. For the clinical trial\u2014which has begun\u2014it takes three months.\u201d<\/p>\n
The group made cassettes of five mutations each, and used two cassette–for a total of 10 mutations–for each vaccine (although in other work they used 30 or 40.) \u201cWhat is really exciting is the flexibility of the approach.\u201d<\/p>\n
At length, they used an algorithm, and bioinformatics, to predict mutations, which they popped into a vaccine sans immunogenicity tests. \u201cWe showed we could sequence and identify immunogenic mutations, then synthesize the vaccine,” Sahin said. \u201cThe growing tumors were stopped, and established tumors rejected.\u201d<\/p>\n
The group then used the same approach on human cancers from a database. \u201cIn the last figure, we showed that our algorithms could identify relevant mutations in human cancers, and that they are extremely high.\u201d<\/p>\n
![\"Cancer](\"https:\/\/fomatmedical.com\/wp-content\/uploads\/2015\/04\/cancer-vaccine-illustration-of-doctor-and-patient.jpg\" "\\"Cancer")
<\/p>\n
The Clinic<\/h3>\n
For over a year, the approach has also been in clinic. A total of 15 patients have been enrolled; half have received the vaccine. Sahin is unable to reveal data mid-trial, but he noted that \u201cwe are excited to translate this to the patient setting.\u201d<\/p>\n
He said he will repeatedly vaccinate. \u201cWith infectious diseases, antibodies are raised for a lifetime by one or two shots. This is not the case for T cells, which are extremely aggressive, but stop attacking after a time. They need repeat vaccinations.\u201d<\/p>\n
Affordability<\/h3>\n
Synthetic RNA lets you produce vaccines that include both CD4+ and CD8+ epitopes in a relatively inexpensive way, Sahin said. By contrast, \u201ccolleagues told me that just getting ten long synthetic peptides means $700,000 in production costs. We want an affordable individual treatment. Individual treatment with RNA should not be more expensive than a standard antibody treatment. Our vision is to give this to everybody. We believe if we make this affordable, this may become a novel dominant approach in cancer immunotherapy.\u201d<\/p>\n
He added that both shared \u201cdriver\u201d mutations, and personal \u201cpassenger\u201d mutations, may be key to his vaccines.<\/p>\n
Interesting Questions<\/h3>\n
Overwijk said the study answers questions\u2014and raises them. An \u201cinteresting\u201d Nature Medicine paper recently looked at spontaneous CD4+ T cell responses to mutated antigens, Overwijk noted, where Sahin \u201clooked at vaccination-induced immune responses to mutated antigens. This suggests, but does not prove, that many mutated epitopes that could induce CD4+ T cell responses, probably don\u2019t, possibly due to the immunosuppressive action of the tumor.\u201d<\/p>\n
What should perhaps come next, Overwijik told Bioscience Technology, is investigation into \u201cthe degree to which spontaneous immunity to these epitopes is induced. A major open question is exactly how the CD4+ T cells are fighting the tumors. Induction of CD8+ T cells seems to be important in some, but not all, settings. Also, to what extent do currently active immunotherapies–anti-CTLA-4, anti-PD-1– promote immunity to these mutated epitopes? How many are required to be recognized for robust therapeutic activity? Is one epitope enough?\u201d<\/p>\n
Furthermore, Overwijik asked: \u201cDoes co-vaccination with peptides that induce CD4+ as well as CD8+ T cell responses work better than vaccination with either class of peptides alone?\u201d<\/p>\n
In the end, Overwijik said: \u201cOf 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.\u201d<\/p>\n","protected":false},"excerpt":{"rendered":"
En FOMAT, la inmunoterapia oncol\u00f3gica es una de las \u00e1reas m\u00e1s prometedoras que seguimos en la investigaci\u00f3n cl\u00ednica. Las vacunas personalizadas contra el c\u00e1ncer suponen un cambio fundamental en nuestra forma de abordar el tratamiento de los tumores, y esta investigaci\u00f3n de la Universidad Johannes Gutenberg representa un avance significativo\u2026<\/p>","protected":false},"author":3,"featured_media":30081,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"footnotes":""},"categories":[968,998,984,1074],"tags":[975,940,1046,938],"class_list":["post-4023","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-blogs-updates","category-cancer","category-research-studies","category-vaccines","tag-cancer","tag-medical-research","tag-oncology","tag-vaccine"],"acf":[],"_links":{"self":[{"href":"https:\/\/fomatmedical.com\/es\/wp-json\/wp\/v2\/posts\/4023","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/fomatmedical.com\/es\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/fomatmedical.com\/es\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/fomatmedical.com\/es\/wp-json\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/fomatmedical.com\/es\/wp-json\/wp\/v2\/comments?post=4023"}],"version-history":[{"count":2,"href":"https:\/\/fomatmedical.com\/es\/wp-json\/wp\/v2\/posts\/4023\/revisions"}],"predecessor-version":[{"id":73150,"href":"https:\/\/fomatmedical.com\/es\/wp-json\/wp\/v2\/posts\/4023\/revisions\/73150"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/fomatmedical.com\/es\/wp-json\/wp\/v2\/media\/30081"}],"wp:attachment":[{"href":"https:\/\/fomatmedical.com\/es\/wp-json\/wp\/v2\/media?parent=4023"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/fomatmedical.com\/es\/wp-json\/wp\/v2\/categories?post=4023"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/fomatmedical.com\/es\/wp-json\/wp\/v2\/tags?post=4023"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}