Carbon ion radiotherapy (CIRT) alone leads to a reduction of lung metastases in an osteosarcoma in vivo model, which is not the case for conventional photon therapy (XRT), when compared to untreated negative controls (NC). Addition of immunotherapy (Figure 8: a mix checkpoint inhibitors, CPI) fosters the immunogenic response, leading to further reduction of lung metastases. This shows the vast potential for CIRT as a match in combination with immunotherapy in terms of checkpoint blockade [17].

Dr. Daniela Kraft

Secondary cancer occurs months to years after exposure and is an important issue in radiation protection, for radiotherapy and manned space missions. The interference in the process of self-renewal and differentiation of hematopoietic stem and progenitor cells (HSPC) via radiation exposure is considered to increase the risk for radiation induced leukaemia (rAML). However, risk assessment for radiation induced leukemogenesis needs an improved knowledge about the radiation response of HSPC and, in particular, their genetic stability. Therefore, we investigated the transmission of chromosomal changes in HSPC exposed to low and higher LET irradiation (up to 85 keV/µm). In view of known differences in genetic stability and DNA repair between murine and human HSPC, we used human HSPC, provided in collaboration with Prof. H. Bönig (Frankfurt University) (Figure 10, click to enlarge). Our results showed, independent of LET, no chromosomal instability, but a considerable frequency of clonal chromosomal aberrations in the descendants of irradiated HSPC [19, 20]. To elucidate the capacity for correct DNA repair in HSPC, we assessed in collaboration with Prof. L. Wiesmüller (Ulm University), the quality and molecular components of DSB (double strand break-) repair compared to mature peripheral blood lymphocytes using an EGF plasmid reporter systems (developed by Prof. L. Wiesmüller). We could show that HSPC bear a deficiency for DSB repair (homologous recombination) due to diminished NF-κB signaling, which was confirmed for heavy ion exposure and could explain the occurrence of clonal aberrations in the following generations after exposure [21, 22]. More recently, we started to investigate the combined influence of micro-gravity and high LET exposure in HSPC.

Dr. Felicitas Rapp

For longer manned space missions, for example a mission to Mars, it is important to know about risks for the astronauts. In our project, we investigate the radiation induced neuroinflammation, and if it can be reduced by test substances. We are funded by ESA and DLR. To induce neuroinflammation, we use an organotypic hippocampal slice culture model from mice. These slice cultures are irradiated with heavy ions occurring in space (iron ions, Fe) ex vivo and treated with our test substances afterwards (Fig. 11 A+B). At several timepoints up to 29 days after irradiation, samples are taken and analyzed regarding an inflammatory reaction. Inflammation in the brain is mediated by the innate immune cells, microglia, so they are in focus in this project. We developed a system where microglia are stained and their inflammatory activation and morphology are analyzed by confocal microscopy (Fig 11 C+D). This project is a collaboration with Dr. Sonja Kallendrusch and Prof. Ingo Bechmann (Institute of Anatomy, University of Leipzig). In the next step, we will use a mouse model based on our findings, and test the effect of space irradiation in combination with a treatment with our test substances on their cognitive performance. In addition, we will test new shielding materials in collaboration with Prof. Chiara LaTessa (University of Trento, Italy)

Dr. Julia Wiedermann

In other projects, our research group studies late effects induced by exposure to heavy ions. Radiation induced non-cancer effects include impact on the functionality of tissues and organs, which is often caused by loss of functional cells or modifications in the differentiation process and subsequent reorganisation of the tissue. The resulting changes can evoke inflammation, a physiological “repair” process, which may turn into a chronic process, as in the case of fibrosis. The increasing application of charged particles in radiotherapy requires a better understanding of these processes for charged particles, in particular for carbon ions.

Especially skin is exposed in all scenarios of radiation exposure. We investigate in another project the early skin response after carbon ion exposure, whose molecular and cellular basis is not well understood. In order to complement previous RBE data sets obtained in a pig model [23] by cellular and molecular studies, we use mono- and co-cultures of epidermal cells, a full skin 3D tissue equivalent, and ex vivo exposed human skin from healthy donors, provided by our collaboration partners PD Dr. M. Podda and M. Kovacs (Darmstadt Hospital) (Figure 12, click to enlarge). Similar to photon exposure, epidermal tissue organization was modified at low doses and differentiation at high doses of carbon ions, with a moderate release of inflammatory cytokines [24]. In ongoing experiments, the results are verified in carbon ion irradiated pig skin.

Theses pig skin samples were obtained in experiments performed in collaboration with MD I. Lehmann and MD D. Packer (Mayo Clinics, Rochester), dedicated to investigate the possibility to treat cardiac arrhythmias by targeted charged particle irradiation. In a first step, isolated pig hearts were irradiated, and cellular and molecular changes were analysed [25]. Then, pigs were irradiated with carbon ions to demonstrate the efficiency of targeted small volume irradiation of structures in the heart which are responsible for electrophysiological conductivity. We then analysed the induced damage in the targeted and non-targeted areas (with Dr. P. Simoniello, Parthenope University of Naples) [29]. (Figure 13, click to enlarge)