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1. A New Pharmacokinetic Model Describing the Biodistribution of Intravenously and Intratumorally Administered Superparamagnetic Iron Oxide Nanoparticles (SPIONs) in a GL261 Xenograft Glioblastoma Model

Author

Klapproth AP, Shevtsov M, Stangl S, Li WB, and Multhoff G

Subjects
mathematical modeling, spions, superparamagnetic iron oxide nanoparticles, pharmacokinetic model, glioblastoma, biodistribution, Medicine (General), R5-920
Abstract

Alexander P Klapproth,1,2,* Maxim Shevtsov,1,3– 7,* Stefan Stangl,1 Wei Bo Li,2 Gabriele Multhoff1 1Center for Translational Cancer Research Technische Universität München (TranslaTUM), Klinikum Rechts Der Isar, Munich, Germany; 2Institute of Radiation Medicine, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Munich, Germany; 3Institute of Cytology of the Russian Academy of Sciences (RAS), St. Petersburg, Russia; 4Department of Biotechnology, First Pavlov State Medical University of St. Petersburg, St. Petersburg, Russia; 5Almazov National Medical Research Centre, Russian Polenov Neurosurgical Institute, St. Petersburg, Russia; 6National Center for Neurosurgery, Nur-Sultan, Kazakhstan; 7Department of Biomedical Cell Technologies, Far Eastern Federal University, Vladivostok, Russia*These authors contributed equally to this workCorrespondence: Maxim Shevtsov; Wei Bo Li Email maxim.shevtsov@tum.de; wli@helmholtz-muenchen.deBackground: Superparamagnetic iron oxide nanoparticles (SPIONs) have displayed multifunctional applications in cancer theranostics following systemic delivery. In an effort to increase the therapeutic potential of local therapies (including focal hyperthermia), nanoparticles can also be administered intratumorally. Therefore, the development of a reliable pharmacokinetic model for the prediction of nanoparticle distribution for both clinically relevant routes of delivery is of high importance.Materials and Methods: The biodistribution of SPIONs (of two different sizes – 130 nm and 60 nm) radiolabeled with zirconium-89 or technetium-99m following intratumoral or intravenous injection was investigated in C57/Bl6 mice bearing subcutaneous GL261 glioblastomas. Based on PET/CT biodistribution data, a novel pharmacokinetic model was established for a better understanding of the pharmacokinetics of the SPIONs after both administration routes.Results: The PET image analysis of the nanoparticles (confirmed by histology) demonstrated the presence of radiolabeled nanoparticles within the glioma site (with low amounts in the liver and spleen) at all investigated time points following intratumoral injection. The mathematical model confirmed the dynamic nanoparticle redistribution in the organism over a period of 72 h with an equilibrium reached after 100 h. Intravenous injection of nanoparticles demonstrated a different distribution pattern with a rapid particle retention in all organs (particularly in liver and spleen) and a subsequent slow release rate.Conclusion: The mathematical model demonstrated good agreement with experimental data derived from tumor mouse models suggesting the value of this tool to predict the real-time pharmacokinetic features of SPIONs in vivo. In the future, it is planned to adapt our model to other nanoparticle formulations to more precisely describe their biodistribution in in vivo model systems.Keywords: mathematical modeling, SPIONs, superparamagnetic iron oxide nanoparticles, pharmacokinetic model, glioblastoma, biodistribution

Published
2020

2. A JWST Medium Resolution MIRI Spectrum and Models of the Type Ia supernova 2021aefx at +415 d

Author

Ashall, C., Hoeflich, P., Baron, E., Shahbandeh, M., DerKacy, J. M., Medler, K., Shappee, B. J., Tucker, M. A., Fereidouni, E., Mera, T., Andrews, J., Baade, D., Bostroem, K. A., Brown, P. J., Burns, C. R., Burrow, A., Cikota, A., de Jaeger, T., Do, A., Dong, Y., Dominguez, I., Fox, O., Galbany, L., Hsiao, E. Y., Krisciunas, K., Khaghani, B., Kumar, S., Lu, J., Maund, J. R., Mazzali, P., Morrell, N., Patat, F., Pfeffer, C., Phillips, M. M., Schmidt, J., Stangl, S., Stevens, C. P., Stritzinger, M. D., Suntzeff, N. B., Telesco, C. M., Wang, L., and Yang, Y.

Subjects
Astrophysics - Solar and Stellar Astrophysics, Astrophysics - High Energy Astrophysical Phenomena
Abstract

We present a JWST MIRI/MRS spectrum (5-27 $\mathrm{\mu}$m) of the Type Ia supernova (SN Ia), SN 2021aefx at $+415$ days past $B$-band maximum. The spectrum, which was obtained during the iron-dominated nebular phase, has been analyzed in combination with previous JWST observations of SN 2021aefx, to provide the first JWST time series analysis of an SN Ia. We find the temporal evolution of the [Co III] 11.888 $\mathrm{\mu}$m feature directly traces the decay of $^{56}$Co. The spectra, line profiles, and their evolution are analyzed with off-center delayed-detonation models. Best fits were obtained with White Dwarf (WD) central densities of $\rho_c=0.9-1.1\times 10^9$g cm$^{-3}$, a WD mass of M$_{\mathrm{WD}}$=1.33-1.35M$_\odot$, a WD magnetic field of $\approx10^6$G, and an off-center deflagration-to-detonation transition at $\approx$ 0.5 $M_\odot$ seen opposite to the line of sight of the observer (-30). The inner electron capture core is dominated by energy deposition from $\gamma$-rays whereas a broader region is dominated by positron deposition, placing SN 2021aefx at +415 d in the transitional phase of the evolution to the positron-dominated regime. The formerly `flat-tilted' profile at 9 $\mathrm{\mu}$m now has significant contribution from [Ni IV], [Fe II], and [Fe III] and less from [Ar III], which alters the shape of the feature as positrons excite mostly the low-velocity Ar. Overall, the strength of the stable Ni features in the spectrum is dominated by positron transport rather than the Ni mass. Based on multi-dimensional models, our analysis is consistent with a single-spot, close-to-central ignition with an indication for a pre-existing turbulent velocity field, and excludes a multiple-spot, off-center ignition., Comment: Accepted for publication in ApJ

Published
2024

3. JWST NIRSpec+MIRI Observations of the nearby Type IIP supernova 2022acko

Author

Shahbandeh, M., Ashall, C., Hoeflich, P., Baron, E., Fox, O., Mera, T., DerKacy, J., Stritzinger, M. D., Shappee, B., Law, D., Morrison, J., Pauly, T., Pierel, J., Medler, K., Andrews, J., Baade, D., Bostroem, A., Brown, P., Burns, C., Burrow, A., Cikota, A., Cross, D., Davis, S., de Jaeger, T., Do, A., Dong, Y., Hsiao, E., Dominguez, I., Galbany, L., Janzen, D., Jencson, J., Hoang, E., Karamehmetoglu, E., Khaghani, B., Krisciunas, K., Kumar, S., Lu, J., Mazzali, P., Morrell, N., Patat, F., Pearson, J., Pfeffer, C., Wang, L., Yang, Y., Cai, Y. Z., Camacho-Neves, Y., Elias-Rosa, N., Lundquist, M., Maund, J., Phillips, M., Rest, A., Retamal, N., Stangl, S., Shrestha, M., Stevens, C., Suntzeff, N., Telesco, C., Tucker, M., Foley, R., Jha, S., Kwok, L., Larison, C., LeBaron, N., Moran, S., Rho, J., Salmaso, I., Schmidt, J., and Tinyanont, S.

Subjects
Astrophysics - High Energy Astrophysical Phenomena, Astrophysics - Solar and Stellar Astrophysics
Abstract

We present JWST spectral and photometric observations of the Type IIP supernova (SN) 2022acko at ~50 days past explosion. These data are the first JWST spectral observations of a core-collapse SN. We identify ~30 different H I features, other features associated with products produced from the CNO cycle, and s-process elements such as Sc II and Ba II. By combining the JWST spectra with ground-based optical and NIR spectra, we construct a full Spectral Energy Distribution from 0.4 to 25 microns and find that the JWST spectra are fully consistent with the simultaneous JWST photometry. The data lack signatures of CO formation and we estimate a limit on the CO mass of < 10^{-8} solar mass. We demonstrate how the CO fundamental band limits can be used to probe underlying physics during stellar evolution, explosion, and the environment. The observations indicate little mixing between the H envelope and C/O core in the ejecta and show no evidence of dust. The data presented here set a critical baseline for future JWST observations, where possible molecular and dust formation may be seen.

Published
2024

4. JWST MIRI/MRS Observations and Spectral Models of the Under-luminous Type Ia Supernova 2022xkq

Author

DerKacy, J. M., Ashall, C., Hoeflich, P., Baron, E., Shahbandeh, M., Shappee, B. J., Andrews, J., Baade, D., Balangan, E. F, Bostroem, K. A., Brown, P. J., Burns, C. R., Burrow, A., Cikota, A., de Jaeger, T., Do, A., Dong, Y., Dominguez, I., Fox, O., Galbany, L., Hoang, E. T., Hsiao, E. Y., Janzen, D., Jencson, J. E., Krisciunas, K., Kumar, S., Lu, J., Lundquist, M., Evans, T. B. Mera, Maund, J. R., Mazzali, P., Medler, K., Retamal, N. E. Meza, Morrell, N., Patat, F., Pearson, J., Phillips, M. M., Shrestha, M., Stangl, S., Stevens, C. P., Stritzinger, M. D., Suntzeff, N. B., Telesco, C. M., Tucker, M. A., Valenti, S., Wang, L., and Yang, Y.

Subjects
Astrophysics - High Energy Astrophysical Phenomena, Astrophysics - Solar and Stellar Astrophysics
Abstract

We present a JWST mid-infrared spectrum of the under-luminous Type Ia Supernova (SN Ia) 2022xkq, obtained with the medium-resolution spectrometer on the Mid-Infrared Instrument (MIRI) $\sim130$ days post-explosion. We identify the first MIR lines beyond 14 $\mu$m in SN Ia observations. We find features unique to under-luminous SNe Ia, including: isolated emission of stable Ni, strong blends of [Ti II], and large ratios of singly ionized to doubly ionized species in both [Ar] and [Co]. Comparisons to normal-luminosity SNe Ia spectra at similar phases show a tentative trend between the width of the [Co III] 11.888 $\mu$m feature and the SN light curve shape. Using non-LTE-multi-dimensional radiation hydro simulations and the observed electron capture elements we constrain the mass of the exploding white dwarf. The best-fitting model shows that SN 2022xkq is consistent with an off-center delayed-detonation explosion of a near-Chandrasekhar mass WD (M$_{\rm ej}$ $\approx 1.37$ M$_{\odot}$) of high-central density ($\rho_c \geq 2.0\times10^{9}$ g cm$^{-3}$) seen equator on, which produced M($^{56}$Ni) $= 0.324$ M$_{\odot}$ and M($^{58}$Ni) $\geq 0.06$ M$_{\odot}$. The observed line widths are consistent with the overall abundance distribution; and the narrow stable Ni lines indicate little to no mixing in the central regions, favoring central ignition of sub-sonic carbon burning followed by an off-center DDT beginning at a single point. Additional observations may further constrain the physics revealing the presence of additional species including Cr and Mn. Our work demonstrates the power of using the full coverage of MIRI in combination with detailed modeling to elucidate the physics of SNe Ia at a level not previously possible., Comment: 31 pages, 18 figures, accepted to ApJ; updated to accepted version

Published
2023

5. Imaging of Hsp70-positive tumors with cmHsp70.1 antibody-conjugated gold nanoparticles

Author

Gehrmann MK, Kimm MA, Stangl S, Schmid TE, Noël PB, Rummeny EJ, and Multhoff G

Subjects
Medicine (General), R5-920
Abstract

Mathias K Gehrmann,1 Melanie A Kimm,2 Stefan Stangl,1 Thomas E Schmid,1 Peter B Noël,2 Ernst J Rummeny,2 Gabriele Multhoff11Department of Radiation Oncology, 2Department of Diagnostic and Interventional Radiology, Klinikum rechts der Isar, Technische Universität München, Munich, GermanyAbstract: Real-time imaging of small tumors is still one of the challenges in cancer diagnosis, prognosis, and monitoring of clinical outcome. Targeting novel biomarkers that are selectively expressed on a large variety of different tumors but not normal cells has the potential to improve the imaging capacity of existing methods such as computed tomography. Herein, we present a novel technique using cmHsp70.1 monoclonal antibody-conjugated spherical gold nanoparticles for quantification of the targeted uptake of gold nanoparticles into membrane Hsp70-positive tumor cells. Upon binding, cmHsp70.1-conjugated gold nanoparticles but not nanoparticles coupled to an isotype-matched IgG1 antibody or empty nanoparticles are rapidly taken up by highly malignant Hsp70 membrane-positive mouse tumor cells. After 24 hours, the cmHsp70.1-conjugated gold nanoparticles are found to be enriched in the perinuclear region. Specificity for membrane Hsp70 was shown by using an Hsp70 knockout tumor cell system. Toxic side effects of the cmHsp70.1-conjugated nanoparticles are not observed at a concentration of 1–10 µg/mL. Experiments are ongoing to evaluate whether cmHsp70.1 antibody-conjugated gold nanoparticles are suitable for the detection of membrane-Hsp70-positive tumors in vivo.Keywords: heat shock protein 70, tumor biomarker, theranostics, multimodal CT, multispectral CT, k-edge

Published
2015

6. JWST Low-Resolution MIRI Spectral Observations of SN~2021aefx: High-density Burning in a Type Ia Supernova

Author

DerKacy, J. M., Ashall, C., Hoeflich, P., Baron, E., Shappee, B. J., Baade, D., Andrews, J., Bostroem, K. A., Brown, P. J., Burns, C. R., Burrow, A., Cikota, A., de Jaeger, T., Do, A., Dong, Y., Dominguez, I., Galbany, L., Hsiao, E. Y., Karamehmetoglu, E., Krisciunas, K., Kumar, S., Lu, J., Evans, T. B. Mera, Maund, J. R., Mazzali, P., Medler, K., Morrell, N., Patat, F., Phillips, M. M., Shahbandeh, M., Stangl, S., Stevens, C. P., Stritzinger, M. D., Suntzeff, N. B., Telesco, C. M., Tucker, M. A., Valenti, S., Wang, L., Yang, Y., Jha, S. W., and Kwok, L. A.

Subjects
Astrophysics - High Energy Astrophysical Phenomena
Abstract

We present a JWST/MIRI low-resolution mid-infrared (MIR) spectroscopic observation of the normal Type Ia supernova (SN Ia) SN 2021aefx at +323 days past rest-frame B-band maximum light. The spectrum ranges from 4-14 um, and shows many unique qualities including a flat-topped [Ar III] 8.991 um profile, a strongly tilted [Co III] 11.888 um feature, and multiple stable Ni lines. These features provide critical information about the physics of the explosion. The observations are compared to synthetic spectra from detailed NLTE multi-dimensional models. The results of the best-fitting model are used to identify the components of the spectral blends and provide a quantitative comparison to the explosion physics. Emission line profiles and the presence of electron capture (EC) elements are used to constrain the mass of the exploding white dwarf (WD) and the chemical asymmetries in the ejecta. We show that the observations of SN 2021aefx are consistent with an off-center delayed-detonation explosion of a near-Chandrasekhar mass (Mch) WD at a viewing angle of -30 degrees relative to the point of the deflagration-to-detonation transition. From the strength of the stable Ni lines we determine that there is little to no mixing in the central regions of the ejecta. Based on both the presence of stable Ni and the Ar velocity distributions, we obtain a strict lower limit of 1.2 Msun of the initial WD, implying that most sub-Mch explosions models are not viable models for SN 2021aefx. The analysis here shows the crucial importance of MIR spectra for distinguishing between explosion scenarios for SNe Ia., Comment: 21 pages, 9 figures, 4 tables, accepted to ApJL; updated to accepted version

Published
2023
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8. Intercomparison of dose enhancement ratio and secondary electron spectra for gold nanoparticles irradiated by X-rays calculated using multiple Monte Carlo simulation codes

Author

Li, W.B., Belchior, A., Beuve, M., Chen, Y.Z., Di Maria, S., Friedland, W., Gervais, B., Heide, B., Hocine, N., Ipatov, A., Klapproth, A.P., Li, C.Y., Li, J.L., Multhoff, G., Poignant, F., Qiu, R., Rabus, H., Rudek, B., Schuemann, J., Stangl, S., Testa, E., Villagrasa, C., Xie, W.Z., and Zhang, Y.B.

Published
2020
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9. Extracellular heat shock protein 70 levels in tumour‐bearing dogs and cats treated with radiation therapy and hyperthermia

Author

Nytko, K. J., primary, Weyland, M. S., additional, Dressel‐Böhm, S., additional, Scheidegger, S., additional, Salvermoser, L., additional, Werner, C., additional, Stangl, S., additional, Carpinteiro, A. C., additional, Alkotub, B., additional, Multhoff, G., additional, Bodis, S., additional, and Rohrer Bley, C., additional

Published
2023
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11. JWST Low-resolution MIRI Spectral Observations of SN 2021aefx: High-density Burning in a Type Ia Supernova

Author

DerKacy, J. M., primary, Ashall, C., additional, Hoeflich, P., additional, Baron, E., additional, Shappee, B. J., additional, Baade, D., additional, Andrews, J., additional, Bostroem, K. A., additional, Brown, P. J., additional, Burns, C. R., additional, Burrow, A., additional, Cikota, A., additional, de Jaeger, T., additional, Do, A., additional, Dong, Y., additional, Dominguez, I., additional, Galbany, L., additional, Hsiao, E. Y., additional, Karamehmetoglu, E., additional, Krisciunas, K., additional, Kumar, S., additional, Lu, J., additional, Evans, T. B. Mera, additional, Maund, J. R., additional, Mazzali, P., additional, Medler, K., additional, Morrell, N., additional, Patat, F., additional, Phillips, M. M., additional, Shahbandeh, M., additional, Stangl, S., additional, Stevens, C. P., additional, Stritzinger, M. D., additional, Suntzeff, N. B., additional, Telesco, C. M., additional, Tucker, M. A., additional, Valenti, S., additional, Wang, L., additional, Yang, Y., additional, Jha, S. W., additional, and Kwok, L. A., additional

Published
2023
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12. Extracellular heat shock protein 70 levels in tumour-bearing dogs and cats treated with radiation therapy and hyperthermia

Author

Nytko, K. J., Weyland, M., Dressel-Böhm, S., Scheidegger, S., Salvermoser, L., Werner, C., Stangl, S., Carpinteiro, A. C., Alkotub, B., Multhoff, G., Bodis, S., Rohrer Bley, C., Nytko, K. J., Weyland, M., Dressel-Böhm, S., Scheidegger, S., Salvermoser, L., Werner, C., Stangl, S., Carpinteiro, A. C., Alkotub, B., Multhoff, G., Bodis, S., and Rohrer Bley, C.

Abstract

Hyperthermia is a form of a cancer treatment which is frequently applied in combination with radiotherapy (RT) to improve therapy responses and radiosensitivity. The mode of action of hyperthermia is multifactorial; the one hand by altering the amount of the blood circulation in the treated tissue, on the other hand by modulating molecular pathways involved in cell survival processes and immunogenic interactions. One of the most dominant proteins induced by hyperthermia is the major stress-inducible heat shock protein 70 (Hsp70). Hsp70 can be found in the blood either as a free-protein (free HSP70) derived from necrotic cells, or lipid-bound (liposomal Hsp70) when it is actively released in extracellular vesicles (EVs) by living cells. The aim of the study was to evaluate the levels of free and liposomal Hsp70 before and after treatment with RT alone or hyperthermia combined with radiotherapy (HTRT) in dogs and cats to evaluate therapy responses. Peripheral blood was collected from feline and canine patients before and at 2, 4, 6 and 24 h after treatment with RT or HTRT. Hsp70 enzyme-linked immunosorbent assays (ELISAs) were performed to determine the free and liposomal Hsp70 concentrations in the serum. The levels were analysed after the first fraction of radiation to study immediate effects and after all applied fractions to study cumulative effects. The levels of free and liposomal Hsp70 levels in the circulation were not affected by the first singular treatment and cumulative effects of RT in cats however, after finalizing all treatment cycles with HTRT free and liposomal Hsp70 levels significantly increased. In dogs, HTRT, but not treatment with RT alone, significantly affected liposomal Hsp70 levels during the first fraction. Free Hsp70 levels were significantly increased after RT, but not HTRT, during the first fraction in dogs. In dogs, on the other hand, RT alone resulted in a significant increase in liposomal Hsp70, but HTRT did not significantly affect th

Published
2023

13. Properties of a Small Active Region in the Solar Photosphere

Author

Stangl, S., Hirzberger, J., Burton, W.B., editor, Kuijpers, J. M. E., editor, Van Den Heuvel, E. P. J., editor, Van Der Laan, H., editor, Appenzeller, I., editor, Bahcall, J. N., editor, Bertola, F., editor, Cassinelli, J. P., editor, Cesarsky, C. J., editor, Engvold, O., editor, McCray, R., editor, Murdin, P. G., editor, Pacini, F., editor, Radhakrishnan, V., editor, Sato, K., editor, Shu, F. H., editor, Somov, B. V., editor, Sunyaev, R. A., editor, Tanaka, Y., editor, Tremaine, S., editor, Weiss, N. O., editor, Hanslmeier, Arnold, editor, Veronig, Astrid, editor, and Messerotti, Mauro, editor

Published
2005
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15. Exosomal Hsp70 in Liquid Biopsies - A Biomarker for Prediction and Response Monitoring in Cancer

Author

Wang F, Multhoff G, Salvermoser L, Xanthopoulos A, Skerra A, Werner C, Schlapschy M, Schwab M, Bache M, Shevstov M, Medenwald D, Windberg M, and Stangl S

Subjects
business.industry, allergology, medicine, Cancer research, Biomarker (medicine), Cancer, Liquid biopsy, medicine.disease, business, Microvesicles, Glioblastoma
Abstract

In contrast to normal cells, tumor cells of multiple entities overexpress the Heat Shock Protein 70 (Hsp70) not only in the cytosol, but also present it on their plasma membrane in a tumor-specific manner. Furthermore, membrane-Hsp70 positive tumor cells actively release Hsp70 into lipid microvesicles termed exosomes into the blood. Due to conformational changes of Hsp70 in the lipid environment, most commercially available antibodies fail to detect membrane-bound and exosomal Hsp70. To fill this gap and to assess the role of exosomal Hsp70 in the circulation as a potential tumor biomarker, we established the novel complete Hsp70 (compHsp70) sandwich ELISA using two monoclonal antibodies (mAbs) that are able to recognize both, free and lipid-associated Hsp70 on the cell surface of viable tumor cells and exosomes. The epitopes of the mAbs cmHsp70.1 (aa 451-461) and cmHsp70.2 (aa 614-623) that are conserved among different species reside in the substrate-binding domain of Hsp70, with measured affinities of 0.42 nM and 0.44 nM, respectively. Validation of the compHsp70 ELISA revealed a high intra- and inter-assay precision, linearity in a concentration range of 1.56 to 25 ng/ml, high recovery rates of ‘spiked’ liposomal Hsp70 (>84%), comparable values between human serum and plasma samples, and no interference by food intake or age of the donors. Hsp70 concentrations in the circulation of patients with glioblastoma, squamous cell or adeno non-small cell lung carcinoma (NSCLC) at diagnosis were significantly higher than those of healthy volunteers. Hsp70 concentrations dropped concomitantly with the decrease in viable tumor mass on irradiation of patients with approximately 20 Gy (range 18 – 22.5 Gy) or after completion of radiotherapy (60 - 70 Gy). In summary, the compHsp70 ELISA presented herein provides a highly sensitive and reliable tool for measuring free and exosomal Hsp70 in liquid biopsies of tumor patients, levels of which can be used as a predictive tumor-specific biomarker, risk assessment and for monitoring therapeutic outcome.

Published
2021

23. Membrane Hsp70—A Novel Target for the Isolation of Circulating Tumor Cells After Epithelial-to-Mesenchymal Transition

Author

Breuninger, S, Stangl, S, Werner, C, Sievert, W, Lobinger, D, Foulds, GA, Wagner, S, Pickhard, A, Piontek, G, Kokowski, K, Pockley, AG, and Multhoff, G

Subjects
EpCAM (CD326), Oncology, circulating tumor cells (CTCs), membrane Hsp70, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, lcsh:RC254-282, epithelial-to-mesenchymal transition (EMT), Original Research, cmHsp70.1 antibody
Abstract

The presence of circulating tumor cells (CTCs) in the peripheral blood is a pre-requisite for progression, invasion, and metastatic spread of cancer. Consequently, the enumeration and molecular characterization of CTCs from the peripheral blood of patients with solid tumors before, during and after treatment serves as a valuable tool for categorizing disease, evaluating prognosis and for predicting and monitoring therapeutic responsiveness. Many of the techniques for isolating CTCs are based on the expression of epithelial cell surface adhesion molecule (EpCAM, CD326) on tumor cells. However, the transition of adherent epithelial cells to migratory mesenchymal cells (epithelial-to-mesenchymal transition, EMT)—an essential element of the metastatic process—is frequently associated with a loss of expression of epithelial cell markers, including EpCAM. A highly relevant proportion of mesenchymal CTCs cannot therefore be isolated using techniques that are based on the “capture” of cells expressing EpCAM. Herein, we provide evidence that a monoclonal antibody (mAb) directed against a membrane-bound form of Hsp70 (mHsp70)—cmHsp70.1—can be used for the isolation of viable CTCs from peripheral blood of tumor patients of different entities in a more quantitative manner. In contrast to EpCAM, the expression of mHsp70 remains stably upregulated on migratory, mesenchymal CTCs, metastases and cells that have been triggered to undergo EMT. Therefore, we propose that approaches for isolating CTCs based on the capture of cells that express mHsp70 using the cmHsp70.1 mAb are superior to those based on EpCAM expression.

Published
2018

26. Heat shock protein 70 and tumor-infiltrating NK cells as prognostic indicators for patients with squamous cell carcinoma of the head and neck after radiochemotherapy: A multicentre retrospective study of the German Cancer Consortium

Author

Stangl, S., Tontcheva, N., Sievert, W., Shevtsov, M., Niu, M., Schmid, T., Pigorsch, S., Combs, S., Haller, B., Balermpas, P., Rödel, F., Rödel, C., Fokas, E., Krause, M., Linge, A., Lohaus, F., Baumann, M., Tinhofer, I., Budach, V., Stuschke, M., Grosu, A., Abdollahi, A., Debus, J., Belka, C., Maihöfer, C., Mönnich, D., Zips, D., and Multhoff, G.

Subjects
NK cells, prognostic biomarker, Hsp70, IHC, SCCHN, retrospective trial
Abstract

Tumor cells frequently overexpress heat shock protein 70 (Hsp70) and present it on their cell surface, where it can be recognized by pre-activated NK cells. In our retrospective study the expression of Hsp70 was determined in relation to tumor-infiltrating CD56+ NK cells in formalin-fixed paraffin embedded (FFPE) tumor specimens of patients with SCCHN (N = 145) as potential indicators for survival and disease recurrence. All patients received radical surgery and postoperative cisplatin-based radiochemotherapy (RCT). In general, Hsp70 expression was stronger, but with variable intensities, in tumor compared to normal tissues. Patients with high Hsp70 expressing tumors (scores 3-4) showed significantly decreased overall survival (OS; p = 0.008), local progression-free survival (LPFS; p = 0.034) and distant metastases-free survival (DMFS; p = 0.044), compared to those with low Hsp70 expression (scores 0-2), which remained significant after adjustment for relevant prognostic variables. The adverse prognostic value of a high Hsp70 expression for OS was also observed in patient cohorts with p16- (p = 0.001), p53- (p = 0.0003) and HPV16 DNA-negative (p = 0.001) tumors. The absence or low numbers of tumor-infiltrating CD56+ NK cells also correlated with significantly decreased OS (p = 0.0001), LPFS (p = 0.0009) and DMFS (p = 0.0001). A high Hsp70 expression and low numbers of tumor-infiltrating NK cells have the highest negative predictive value (p = 0.00004). In summary, a strong Hsp70 expression and low numbers of tumor-infiltrating NK cells correlate with unfavorable outcome following surgery and RCT in patients with SCCHN, and thus serve as negative prognostic markers.

Published
2018

30. Immunohistochemical and Flow Cytometric Analysis of Intracellular and Membrane-Bound Hsp70, as a Putative Biomarker of Glioblastoma Multiforme, Using the cmHsp70.1 Monoclonal Antibody

Author

Stangl, S., Foulds, G.A., Fellinger, H., Pilkington, G.J., Pockley, A.G., and Multhoff, G.

Subjects
Male, Cytoplasm, Cell Membrane, Antibodies, Monoclonal, Middle Aged, Flow Cytometry, Immunohistochemistry, Cytosol, Cell Line, Tumor, Biomarkers, Tumor, Humans, Female, HSP70 Heat-Shock Proteins, Formalin Fixed Paraffin-embedded (ffpe) Sections, Glioblastoma Multiforme, Hsp70 Antibody Epitope, Intracellular And Membrane-bound Heat Shock Protein 70 (hsp70), Glioblastoma, Aged
Abstract

The major stress-inducible 70kDa heat shock (stress) protein 70 (Hsp70) is frequently overexpressed in highly aggressive tumor cells and thus might serve as a tumor-specific biomarker of aggressive disease. We have previously shown that, in contrast to normal cells, tumor cells present Hsp70 on their plasma membrane. In order to elucidate the role of intracellular and membrane-bound Hsp70 as a potential tumor biomarker in glioblastoma multiforme, herein, we describe protocols for the staining of cytosolic Hsp70 in tumor formalin fixed paraffin-embedded (FFPE) sections using immunohistochemistry, and for plasma membrane-bound Hsp70 by multi-parametric flow cytometry using the cmHsp70.1 monoclonal antibody (mAb).

Published
2017

31. The PD-1/PD-L1 axis and human papilloma virus in patients with head and neck cancer after adjuvant chemoradiotherapy: A multicentre study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG)

Author

Balermpas, P., Rödel, F., Krause, M., Linge, A., Lohaus, F., Baumann, M., Tinhofer, I., Budach, V., Sak, A., Stuschke, M., Gkika, E., Grosu, A.-L., Abdollahi, A., Debus, J., Stangl, S., Ganswindt, U., Belka, C., Pigorsch, S., Multhoff, G., Combs, S. E., Welz, S., Zips, D., Lim, S. Y., Rödel, C., and Fokas, E.

Subjects
Male, HPV, Papillomavirus Infections, Programmed Cell Death 1 Receptor, Medizin, CD8, Chemoradiotherapy, Adjuvant, Middle Aged, Prognosis, PD-1/PD-L1, B7-H1 Antigen, SCCHN, chemoradiotherapy, Survival Rate, Head and Neck Neoplasms, Biomarkers, Tumor, Carcinoma, Squamous Cell, Humans, Female, Neoplasm Grading, prognostic, Papillomaviridae, Follow-Up Studies, Neoplasm Staging
Abstract

We examined the prognostic role of PD-1+ and CD8+ tumor infiltrating lymphocytes (TILs), and PD-L1+ cells in patients with squamous cell carcinoma of the head and neck (SCCHN) treated with surgery and postoperative chemoradiotherapy (CRT). FFPE samples from 161 patients were immunohistochemically stained for PD-1, CD8 and PD-L1. The immune marker expression was correlated with clinicopathologic characteristics, and overall survival (OS), local progression-free survival (LPFS) and distant metastases free-survival (DMFS), also in the context of HPV16 DNA/p16 status. The median follow-up was 48 months (range: 4-100). The 2-year-OS was 84.1% for the entire cohort. High PD-1 and PD-L1 expression were more common in patients with positive HPV16 DNA (p

Published
2017

36. OC-0324: Immune contexture in SCCHN and outcome after chemoradiotherapy in an uni- and multicentric cohort

Author

Mueller-von der Gruen, J., primary, Rödel, F., additional, Fokas, E., additional, Tinhofer, I., additional, Budach, V., additional, Krause, M., additional, Linge, A., additional, Lohaus, F., additional, Sak, A., additional, Stuschke, M., additional, Grosu, A., additional, Gkika, E., additional, Abdollahi, A., additional, Debus, J., additional, Ganswindt, U., additional, Belka, C., additional, Stangl, S., additional, Pigorsch, S., additional, Multhoff, G., additional, Combs, S., additional, Welz, S., additional, Zips, D., additional, Baumann, M., additional, Rödel, C., additional, and Balermpas, P., additional

Published
2018
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37. Correlation of Hsp70 serum levels with gross tumor volume and composition of lymphocyte subpopulations in patients with squamous cell and adeno non-small cell lung cancer

Author

Gunther, S., Ostheimer, C., Stangl, S., Specht, H.M., Mozes, P., Jesinghaus, M., Vordermark, D., Combs, S.E., Peltz, F., Jung, M.P., and Multhoff, G.

Subjects
lcsh:Immunologic diseases. Allergy, gross tumor volume, Immunology, Nsclc, Biological, Biomarker, Gross Tumor Volume, Heat-shock Protein 70, Immune Responses, Lymphocytes, Tumor Markers, heat-shock protein 70, Immune responses, NSCLC, tumor markers, Tumor Markers, Biological, biomarker, heat shock protein 70, lcsh:RC581-607, biological, Original Research
Abstract

Heat shock protein 70 (Hsp70) is frequently found on the plasma membrane of a large number of malignant tumors including non-small cell lung cancer (NSCLC) and gets released into the blood circulation in lipid vesicles. On the one hand a membrane (m)Hsp70-positive phenotype correlates with a high aggressiveness of the tumor, on the other hand, mHsp70 serves as a target for natural killer (NK) cells that had been pre-stimulated with Hsp70-peptide TKD plus low dose interleukin-2 (TKD/IL-2). Following activation, NK cells show an up-regulated expression of activatory C-type lectin receptors, such as CD94/NKG2C, NKG2D and natural cytotoxicity receptors (NCRs; NKp44, NKp46, NKp30) and thereby gain the capacity to kill mHsp70-positive tumor cells. With respect to these results, the efficacy of ex vivo TKD/IL-2 stimulated, autologous NK cells is currently tested in a proof-of-concept phase II clinical trial in patients with squamous cell NSCLC after RCT at the TUM. Inclusion criteria are histological proven, non-resectable NSCLC in stage IIIA/IIIB, clinical responses to RCT and a mHsp70-positive tumor phenotype. The mHsp70 status is determined in the serum of patients using the lipHsp70 ELISA test which enables the quantification of liposomal and free Hsp70. Squamous cell and adeno NSCLC patients had significantly higher serum Hsp70 levels than healthy controls. A significant correlation of serum Hsp70 levels with the gross tumor volume (GTV) was shown for adeno and squamous cell NSCLC. However, significantly elevated ratios of activated CD69+/CD94+ NK cells that are associated with low serum Hsp70 levels were observed only in patients with squamous cell lung cancer. These data might provide a first hint that the innate immune system might get activated by soluble Hsp70 in squamous cell but not adeno NSCLC.

Published
2015

41. CD8+ tumour-infiltrating lymphocytes in relation to HPV status and clinical outcome in patients with head and neck cancer after postoperative chemoradiotherapy: A multicenter study of the German cancer consortium radiation oncology group (DKTK-ROG)

Author

Balermpas, P., Rödel, F., Rödel, C., Krause, M., Linge, A., Lohaus, F., Baumann, M., Tinhofer, I., Budach, V., Gkika, E., Stuschke, M., Avlar, M., Grosu, A.-L., Abdollahi, A., Debus, J., Bayer, C., Stangl, S., Belka, C., Pigorsch, S., Multhoff, G., Combs, S. E., Mönnich, D., Zips, D., Fokas, E., Balermpas, P., Rödel, F., Rödel, C., Krause, M., Linge, A., Lohaus, F., Baumann, M., Tinhofer, I., Budach, V., Gkika, E., Stuschke, M., Avlar, M., Grosu, A.-L., Abdollahi, A., Debus, J., Bayer, C., Stangl, S., Belka, C., Pigorsch, S., Multhoff, G., Combs, S. E., Mönnich, D., Zips, D., and Fokas, E.

Abstract

We examined the prognostic value of tumour-infiltrating lymphocytes (TILs) in patients with squamous cell carcinoma of the head and neck (SCCHN) after surgery and postoperative cisplatin-based chemoradiotherapy. FFPE-tissue originating from the surgery of 161 patients treated in 8 DKTK partner sites was immunohistochemically stained for CD3 and CD8. Their expression was correlated with clinicopathological characteristics as well as overall survival (OS), local progression-free survival (LPFS) and distant metastases free-survival (DMFS), also in the context of the HPV16-DNA/p16 status. After a median follow-up of 48 months (range: 4100 months), OS at 4 years was 46.5% for the entire cohort. In multivariate analysis, high CD8 expression was confirmed as an independent prognostic parameter for OS (p 5 0.002), LPFS (p 5 0.004) and DMFS (p 5 0.006), while CD3 expression lacked significance. In multivariate analysis HPV16 DNA positivity was associated with improved OS (p 5 0.025) and LPFS (p 5 0.013) and p16-positive patients showed improved DMFS (p 5 0.008). Interestingly, high CD8 expression was a prognostic parameter for the clinical outcome in both HPV16 DNA-positive and HPV16 DNA-negative patients. Similar findings were observed in the multivariate analysis for the combined HPV16 DNA/p16 status. Altogether, CD81 TILs constitute an independent prognostic marker in SCCHN patients treated with adjuvant chemoradiotherapy. These data indicate that CD8-positive TILs have antitumour activity and could be used for treatment stratification. Further validation of the prognostic value of CD81 TILs as a biomarker and its role in the immune response in SCCHN patients after adjuvant chemoradiotherapy is warranted and will be performed in the prospective DKTK-ROG study. What’s new? Squamous cell carcinomas of the head and neck (SCCHN) are not a homogenous group of tumors. This means that biomarkers are urgently needed, so that prognosis and treatment can be individualised. In this

Published
2016

42. Selective in vivo imaging of tumors with a tumor cell-specific Hsp70 peptide-based probe

Author

Stangl, S., Varga, J., Freysoldt, B., Trajkovic-Arsic, M., Siveke, J.T., Greten, F.R., Ntziachristos, V., and Multhoff, G.

Abstract

Although in vivo targeting of tumors using fluorescently-labeled probes has greatly gained in importance over the last few years, most of the clinically applied reagents lack tumor cell specificity. Our novel tumor cell-penetrating peptide-based probe (TPP) recognizes an epitope of Hsp70 that is exclusively present on the cell surface of a broad variety of human and mouse tumors and metastases, but not on normal tissues. Due to the rapid turn-over rate of membrane-Hsp70, fluorescently-labeled TPP is continuously internalized into syngeneic, spontaneous, chemically/genetically induced and xenograft tumors following intravenous administration, thereby enabling site-specific labeling of primary tumors and metastases. In contrast to the commercially available non-peptide small molecule alpha v beta3-integrin antagonist IntegriSense (trademark), TPP exhibits a significantly higher tumor-to-background contrast and stronger tumor-specific signal intensity in all tested tumor models. Moreover, in contrast to IntegriSense (trademark), TPP reliably differentiates between tumor cells and cells of the tumor microenvironment, such as tumor-associated macrophages and fibroblasts which were found to be membrane-Hsp70 negative. Therefore, TPP provides a useful tool for multimodal imaging of tumors and metastases that might help to improve our understanding of tumorigenesis and allow the establishment of improved diagnostic procedures and more accurate therapeutic monitoring. TPP might also be a promising platform for tumor-specific drug delivery and other Hsp70- based targeted therapies.

Published
2014

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