OpTcell

The OpTcell Unit is primarily focused on cancer immunotherapy. Both patients and science have high hopes for this field in terms of modern cancer therapies. Particularly relevant aspects of cancer immunotherapy are dealt with under three core areas of activity. The aim is to create technological innovations which will potentially increase the efficacy of cancer immunotherapeutics and which may also be used to treat solid tumors.

OpTcell – procedure for optimizing T-cell therapeutics for the treatment of solid tumors

The immune system not only keeps infectious agents at bay but also degenerative cells, which can otherwise give rise to cancer. If, however, individual degenerative cells escape this immune control, tumors emerge which may lead to severe forms of cancer. Supported by the Fraunhofer's internal ATTRACT program, genetic procedures for producing cellular cancer immunotherapeutics are to be optimized in this project on the one hand while control mechanisms which enable regulation of the therapeutic cells are to be developed on the other.

Blocking inhibition of T-cells for anti-tumor therapy (BITCAT)

Logo EU Marie Curie

As part of a Marie Skłodowska-Curie award provided by the European Union, and in cooperation with the Fraunhofer project center "Biomedical Engineering and Advanced Manufacturing" (BEAM) and McMaster University (Hamilton, Canada), the BITCAT project pursues the aim of boosting anti-tumor immunity.

At present, immunotherapeutics tend to be protein based (e.g. using antibodies) or cell based (e.g. cancer vaccines).

The immune checkpoint control mechanism – a vital mechanism in regulating the anti-tumor T-cell response – has proven to be especially promising. As part of the BITCAT project, a completely new class of immunotherapeutics, based on nucleic acids, is to be developed and tested with a view to its effect in interaction with existing cell therapies.

Development of immunomodulatory, oligonucleotide-based drugs

The balance between potentially over-activating yet also inhibiting signals plays a decisive role for the functionality of the immune system. Immunological signals can usually be traced back to the interaction between protein and / or peptide signals (e.g. immune cell receptors, cytokines). The cell's own production of these signals can therefore be influenced not only on a protein level but also on a genetic level, using state-of-the-art, nucleic-acid-based technologies. A number of elements have to be considered when developing these types of drugs: The design of the potentially bioactive sequence, the possible chemical modification of the nucleic-acid-based drug with regard to bioavailability and toxicity, and the testing of biological activity in vitro and in vivo. The unit has expert knowledge of oligonucleotides in particular (e.g. siRNA, antisense, shRNA) for use in human and murine immune cells, as well as in murine immunological animal models (e.g. GvHD, graft versus host disease).

Biodistribution of nanoparticle gene therapeutics / oligonucleotides in vivo

The therapeutic efficacy of nanoparticle or gene-therapeutic agents is often decisively influenced primarily by their effective tissue distribution. A therapeutic molecule is only able to take effect when not only the target tissue but also individual target cells are reached. Moreover, in the case of nucleic-acid-based drugs, a number of additional barriers have to be negotiated, such as getting past the vascular endothelium and penetrating into the target cells, as well as the stable release inside a cell. The intra-cellular, tissue-specific distribution (biodistribution) of various marked agents is recorded using modern monitoring methods, based on histological and flow cytometric analysis (FACS).

Immunophenotyping, immunological profile and pharmacological toxicity in vivo

Potential immunological interference and toxicity is hugely significant, especially in terms of the tolerability and potential side effects profile of nucleic-acid-based drugs. With the help of various molecular biological and clinical-chemical methods, immunological parameters (e.g. cytokine production, cell populations) and toxicological parameters, which may also bear relevance with regard to a clinical use on human subjects, can be investigated.

Publications

  • Lipka J, Semmler-Behnke M, Wenk A, Burkhardt J, Aigner A, Kreyling W. Biokinetic datasets of PEI F25-LMW complexed and non-complexed 32P-siRNA within different lung compartments. Data in Brief 7 (2016), pp.1175-1178. DOI dx.doi.org/10.1016/j.dib.2016.03.092
  • Ewe A, Przybylski S, Burkhardt J, Janke A, Appelhans D, Aigner A. A novel tyrosine-modified low molecular weight polyethylenimine (P10Y) for efficient siRNA delivery in vitro and in vivo. J Control Release. 2016 May 28;230:13-25. DOI dx.doi.org/10.1016/j.jconrel.2016.03.034. Epub 2016 Apr 7.
  • Lipka J, Semmler-Behnke M, Wenk A, Burkhardt J, Aigner A, Kreyling W. Biokinetic studies of non-complexed siRNA versus nano-sized PEI F25-LMW/siRNA polyplexes following intratracheal instillation into mice. Int J Pharm. 2016 Mar 16;500(1-2):227-35. DOI dx.doi.org/10.1016/j.ijpharm.2016.01.038. Epub 2016 Jan 21.
  • Burkhardt J, Blume M, Petit-Teixeira E, Hugo Teixeira V, Steiner A, Quente E, Wolfram G, Scholz M, Pierlot C, Migliorini P, Bombardieri S, Balsa A, Westhovens R, Barrera P, Radstake TR, Alves H, Bardin T, Prum B, Emmrich F, Cornelis F, Ahnert P, Kirsten H. Cellular Adhesion Gene SELP Is Associated with Rheumatoid Arthritis and Displays Differential Allelic Expression. PLoS One. 2014 Aug 22;9(8):e103872. DOI dx.doi.org/10.1371/journal.pone.0103872. eCollection 2014.
  • Burkhardt J, Emmrich F, Aigner A. Nanopartikel zur Einschleusung kleiner RNA-Moleküle: Gen-Knockdown als neue Therapiestrategie bei immunologischen Erkrankungen. Deutsche Zeitschrift für Klinische Forschung DZKF, 03/2014
  • Burkhardt J, Kirsten H, Wolfram G, Quente E, Ahnert P. Differential Allelic Expression of Asthma associated IL13 and CSF2 genes. Genet Mol Biol. 2012 Jul;35(3):567-74. DOI dx.doi.org/10.1590/S1415-47572012005000055. Epub 2012 Aug 2.

Patents

  • Burkhardt J, Kirsten H. T-Cell Modulation by Exon Skipping. PCT/EP2013/076518