Şahin has worked with Türeci as a physician-scientist couple since they met in 1992. Their early work focussed on identifying and characterizing new target molecules (antigens) for the immunotherapy of cancer. They discovered tumor antigens relevant for treatment of various types of cancers, e.g.
stomach cancer,
pancreatic cancer,
breast cancer,
ovarian cancer,
prostate cancer,
lung cancer and other dangerous cancers. Şahin and his team established strategies that allow different layers of mRNA vaccine optimization, including optimizations of the various structural backbone elements of mRNA molecules, ways to utilize uridine-based as well as nucleoside-modified mRNA chemistries, and different lipid-based compositions and administration routes to deliver mRNA. Systematically combining mRNA modifications achieved an exponential improvement in the potency of mRNA vaccines and its adaption to various purposes. Building on this toolbox of improvements of RNA molecules, Şahin successfully used mRNA for applications in humans.
RNA vaccines targeting individual cancer mutations One application Sahin's team pioneered are mRNA vaccines for personalized
cancer therapy that are based on non-nucleoside modified mRNA. This technology relies on targeting tumor-specific mutations that are not present in normal cells. Each patient's tumor has a unique set of mutations. Since mRNA vaccines can be easily designed to target any antigen, the team could use the mutation fingerprint of cancers for engineering mRNA-based personalized neo-antigen vaccines. This application offers the possibility of targeting each patient's tumor mutations with an individually tailored mRNA vaccine of unique composition that is produced "on demand".
RNA vaccines targeting tumor-associated antigens To apply their RNA cancer vaccine to tumor-associated antigens (TAAs) shared between patients, Sahin and his team developed RNA vaccine nanoparticle delivery strategies that target tissue-derived dendritic cells body-wide. They pioneered the first intravenous nanoparticle delivery of mRNA vaccines in humans. They observed strong tumor-antigen-specific immune responses induced by their uridine-based non-nucleoside modified mRNA vaccines, even though the utilized TAAs are self-antigens. This was a critical step toward the development of effective, potent cancer vaccines targeting a broad range of antigens for
immunotherapy.
RNA vaccines to improve CAR-T therapy Chimeric
antigen receptor (CAR)-T cell therapies (CARVAC) are promising immunotherapies for treating B-cell-derived hematologic cancers. Achieving long-term patient responses in solid tumors remains a challenge due to poor activity of CAR-T cells against solid cancer. Sahin and his team have developed ways to use RNA vaccine technology for
in vivo expansion and enhanced engraftment of genetically engineered, adoptively transferred CAR-T cells. This has been effective in inducing regression of large tumors in challenging mouse cancer models. The approach is now in clinical trials for the treatment of patients with various cancers.
RNA vaccines to induce antigen-specific tolerance in autoimmune disease during the honorary doctorate ceremony given by the
University of Cologne Faculty of Medicine, 2021
Autoimmune diseases, such as
multiple sclerosis (MS), result from tissue damage caused by self-reactive T
lymphocytes. Combating autoimmune diseases is challenging and can lead to systemic immunosuppression and side effects such as increased risk of infection. Şahin and his team developed a novel therapeutic strategy that circumvents systemic immunosuppression by inhibiting only the immune cells that mediate
autoimmune disease. They used a different version of
lipid nanoparticles to deliver MS
autoantigens encoded by a non-inflammatory RNA into
dendritic cells. This approach expands a specific type of immune cells, called antigen-specific regulatory effector
T cells, which suppress autoreactivity against the targeted autoantigens and also promote inhibition of
autoreactive T cells against other
myelin-specific autoantigens. The
RNA vaccine used for tolerance induction contained
1-methylpseudouridine (m1Ψ) instead of uridine, a modification previously described by
Katalin Karikó and colleagues that does not stimulate
Toll-like receptors. In mouse models of MS, the novel RNA vaccine approach delayed onset and reduced severity of established disease without inducing generalized
immunosuppression.
RNA vaccine against COVID-19 In January 2020, Sahin and his teams pivoted from cancer to COVID-19 vaccine development. The rapid publication of the
sequence of SARS-COV-2 enabled them to initiate an RNA vaccine discovery program. The versatile nature of their mRNA technology and the groundwork Sahin's team had done in the area of cancer vaccines allowed them to develop, produce and test multiple mRNA vaccine candidates in parallel.
BNT162b2 was discovered as the best candidate for the particular purpose of vaccinating for COVID19 prevention. BNT162b2 is a
lipid nanoparticle encapsulated, nucleoside-modified RNA vaccine encoding SARS-CoV-2
spike protein and combines multiple features for optimized vaccine activity derived from Sahin, Türeci and their teams prior work. BNT162b2 became the first mRNA drug approved for human use and the fastest vaccine developed against a new pathogen in the history of medicine. == Memberships ==