Kliniken & Institute ... Institute Pathologisches Institut... Abteilungen Angewandte... Forschung ... Tumorvakzine

Cancer vaccines to treat and prevent MSI-H cancers

Background

MSI-H cancers are particularly immunogenic tumors. During their development, they accumulate a huge abundance of immunogenic target structures, which result from an abundance of mutations associated with microsatellite instability.

Why are MSI-H cancer so special?

In contrast to most other tumors, MSI-H cancers follow a precisely defined molecular pathway  that encompasses a step-by-step progression. This process of defined mutation accumulation is the reason, why the majority of MSI-H cancers carry the same tumor antigens, which are derived from critical driver mutations. The presence of shared, relevant tumor antigens make MSI-H cancers a unique target for the development and evaluation of cancer vaccines.

What we do

Our group has deciphered the molecular progression of MSI- H cancer and over many years developed a vaccine that shall in the future help to treat MSI-H cancers more efficiently. Moreover, we want to develop a vaccine that can prevent MSI-H tumor formation in Lynch syndrome. The basic science part of our research aims to understand better why tumors can evade the attack of the immune system.

Central part of our current activities is the development of a mouse model for Lynch syndrome immunology.

Why we do it

The development of a cancer preventive vaccine in Lynch syndrome may not only significantly improve the life of people affected by the most common tumor syndrome. It also bears the potential to test whether cancer prevention by vaccination is possible. If successful, we plan to broaden our approach and develop new cancer vaccines for other common forms of cancer. Achievements In collaboration with the Krankenhaus Nordwest in Frankfurt (Prof. E. Jäger), we have recently completed a clinical phase I/IIa trial that demonstrated the successful induction of strong immune responses against MSI-H tumor-specific frameshift peptide antigens. This marks a major milestone on the way towards the clinical introduction of preventive cancer vaccines.

Key publications

  • Janikovits J, Müller M, Krzykalla J, Körner S, Echterdiek F, Lahrmann B, Grabe N, Schneider M, Benner A, von Knebel Doeberitz M, Kloor M. High numbers of PDCD1 (PD-1)-positive T cells and B2M mutations in microsatellite-unstable colorectal cancer. Oncoimmunology. 2017 Nov 6;7(2):e1390640
  • Kloor M, von Knebel Doeberitz M. The Immune Biology of Microsatellite-Unstable Cancer. Trends Cancer. 2016 Mar;2(3):121-133. doi: 10.1016/j.trecan.2016.02.004. Review.
  • Echterdiek F, Janikovits J, Staffa L, Müller M, Lahrmann B, Frühschütz M, Hartog B, Nelius N, Benner A, Tariverdian M, von Knebel Doeberitz M, Grabe N, Kloor M.  Low density of FOXP3-positive T cells in normal colonic mucosa is related to the presence of beta2-microglobulin mutations in Lynch syndrome-associated colorectal cancer. OncoImmunology 2015 Nov 11;5(2):e1075692.
  • Surmann EM, Voigt AY, Michel S, Bauer K, Reuschenbach M, Ferrone S, von Knebel Doeberitz M, Kloor M. Association of high CD4-positive T cell infiltration with mutations in HLA class II-regulatory genes in microsatellite-unstable colorectal cancer. Cancer Immunology Immunotherapy 2015;64, 357-366.
  • Bauer K, Nelius N, Reuschenbach M, Koch M, Weitz J, Steinert G, Kopitz J, Beckhove P, Tariverdian M, von Knebel Doeberitz M, Kloor M. T cell responses against microsatellite instability-induced frameshift peptides and influence of regulatory T cells in colorectal cancer. Cancer Immunol Immunother. 2013 Jan;62 (1): 27-37.  
  • Kloor M, Michel S, von Knebel Doeberitz M. Immune evasion of microsatellite unstable colorectal cancers. Int J Cancer. 2010 Sep 1;127(5):1001-10.
  • Michel S, Linnebacher M, Alcaniz J, Voss M, Wagner R, Dippold W, Becker C, von Knebel Doeberitz M, Ferrone S, Kloor M. Lack of HLA class II antigen expression in microsatellite unstable colorectal carcinomas is caused by mutations in HLA class II regulatory genes. Int J Cancer. 2009 Dec 9;127(4):889-898.