6 results on '"Junghanss, Christian"'
Search Results
2. Chemo-immunotherapy improves long-term survival in a preclinical model of MMR-D-related cancer
- Author
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Maletzki, Claudia, Wiegele, Leonie, Nassar, Ingy, Stenzel, Jan, and Junghanss, Christian
- Published
- 2019
- Full Text
- View/download PDF
3. Short-term immune-checkpoint inhibition partially rescues perturbed bone marrow hematopoiesis in mismatch-repair deficient tumors.
- Author
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Krone, Paula, Wolff, Annabell, Teichmann, Julia, Maennicke, Johanna, Henne, Julia, Engster, Leonie, Salewski, Inken, Bergmann, Wendy, Junghanss, Christian, and Maletzki, Claudia
- Subjects
IMMUNE checkpoint inhibitors ,BONE marrow ,HEMATOPOIESIS ,MYELOID-derived suppressor cells ,REGULATORY T cells ,HEREDITARY nonpolyposis colorectal cancer - Abstract
Wide-spread cancer-related immunosuppression often curtails immune-mediated antitumoral responses. Immune-checkpoint inhibitors (ICIs) have become a state-of-the-art treatment modality for mismatch repair-deficient (dMMR) tumors. Still, the impact of ICI-treatment on bone marrow perturbations is largely unknown. Using anti-PD1 and anti-LAG-3 ICI treatments, we here investigated the effect of bone marrow hematopoiesis in tumor-bearing Msh2
loxP/loxP;TgTg(Vil1- cre) mice. The OS under anti-PD1 antibody treatment was 7.0 weeks (vs. 3.3 weeks and 5.0 weeks, control and isotype, respectively). In the anti-LAG-3 antibody group, OS was 13.3 weeks and thus even longer than in the anti-PD1 group (p = 0.13). Both ICIs induced a stable disease and reduced circulating and splenic regulatory T cells. In the bone marrow, a perturbed hematopoiesis was identified in tumor-bearing control mice, which was partially rescued by ICI treatment. In particular, B cell precursors and innate lymphoid progenitors were significantly increased upon anti-LAG-3 therapy to levels seen in tumor-free control mice. Additional normalizing effects of ICI treatment were observed for lin− c-Kit+ IRF8+ hematopoietic stem cells, which function as a "master" negative regulator of the formation of polymorphonuclear-myeloid-derived suppressor cell generation. Accompanying immunofluorescence on the TME revealed significantly reduced numbers of CD206+ F4/80+ and CD163+ tumor-associated M2 macrophages and CD11b+ Gr1+ myeloid-derived suppressor cells especially upon anti-LAG-3 treatment. This study confirms the perturbed hematopoiesis in solid cancer. Anti-LAG-3 treatment partially restores normal hematopoiesis. The interference of anti-LAG-3 with suppressor cell populations in otherwise inaccessible niches renders this ICI very promising for subsequent clinical application. [ABSTRACT FROM AUTHOR]- Published
- 2023
- Full Text
- View/download PDF
4. Combined Gemcitabine and Immune-Checkpoint Inhibition Conquers Anti-PD-L1 Resistance in Low-Immunogenic Mismatch Repair-Deficient Tumors
- Author
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Salewski, Inken, Henne, Julia, Engster, Leonie, Schneider, Bjoern, Lemcke, Heiko, Skorska, Anna, Berlin, Peggy, Henze, Larissa, Junghanss, Christian, and Maletzki, Claudia
- Subjects
QH301-705.5 ,immune checkpoint inhibitor ,DNA Mismatch Repair ,Deoxycytidine ,Article ,B7-H1 Antigen ,Mice ,Lymphocytes, Tumor-Infiltrating ,Neoplastic Syndromes, Hereditary ,Animals ,Humans ,tumor microenvironment ,Biology (General) ,Chemokine CCL4 ,Immune Checkpoint Inhibitors ,QD1-999 ,coding microsatellite mutations ,Interleukin-13 ,Brain Neoplasms ,Tumor Necrosis Factor-alpha ,Myeloid-Derived Suppressor Cells ,MMR deficiency ,Colorectal Neoplasms, Hereditary Nonpolyposis ,Gemcitabine ,Disease Models, Animal ,Chemistry ,Drug Resistance, Neoplasm ,genetic model ,in vivo imaging ,Colorectal Neoplasms ,MutL Protein Homolog 1 ,T-Lymphocytes, Cytotoxic - Abstract
Tumors arising in the context of Lynch Syndrome or constitutional mismatch repair deficiency are hypermutated and have a good response towards immune-checkpoint inhibitors (ICIs), including α-PD-L1 antibodies. However, in most cases, resistance mechanisms evolve. To improve outcomes and prevent resistance development, combination approaches are warranted. Herein, we applied a combined regimen with an α-PD-L1 antibody and gemcitabine in a preclinical tumor model to activate endogenous antitumor immune responses. Mlh1−/− mice with established gastrointestinal tumors received the α-PD-L1 antibody (clone 6E11, 2.5 mg/kg bw, i.v., q2wx3) and gemcitabine (100 mg/kg bw, i.p., q4wx3) in mono- or combination therapy. Survival and tumor growth were recorded. Immunological changes in the blood were routinely examined via multi-color flow cytometry and complemented by ex vivo frameshift mutation analysis to identify alterations in Mlh1−/−-tumor-associated target genes. The combined therapy of α-PD-L1 and gemcitabine prolonged median overall survival of Mlh1−/− mice from four weeks in the untreated control group to 12 weeks, accompanied by therapy-induced tumor growth inhibition, as measured by [18F]-FDG PET/CT. Plasma cytokine levels of IL13, TNFα, and MIP1β were increased and also higher than in mice receiving either monotherapy. Circulating splenic and intratumoral myeloid-derived suppressor cells (MDSCs), as well as M2 macrophages, were markedly reduced. Besides, residual tumor specimens from combi-treated mice had increased numbers of infiltrating cytotoxic T-cells. Frameshift mutations in APC, Tmem60, and Casc3 were no longer detectable upon treatment, likely because of the successful eradication of single mutated cell clones. By contrast, novel mutations appeared. Collectively, we herein confirm the safe application of combined chemo-immunotherapy by long-term tumor growth control to prevent the development of resistance mechanisms.
- Published
- 2021
5. Establishment and characterization of patient-derived head and neck cancer models from surgical specimens and endoscopic biopsies.
- Author
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Strüder, Daniel, Momper, Theresa, Irmscher, Nina, Krause, Mareike, Liese, Jan, Schraven, Sebastian, Zimpfer, Annette, Zonnur, Sarah, Burmeister, Ann-Sophie, Schneider, Björn, Frerich, Bernhard, Mlynski, Robert, Große-Thie, Christina, Junghanss, Christian, and Maletzki, Claudia
- Subjects
SQUAMOUS cell carcinoma ,HEAD & neck cancer ,INDIVIDUALIZED medicine ,TUMOR microenvironment ,HISTOLOGY ,BIOPSY - Abstract
Background: Head and neck squamous cell carcinoma (HNSCC) is heterogeneous in etiology, phenotype and biology. Patient-derived xenografts (PDX) maintain morphology and molecular profiling of the original tumors and have become a standard "Avatar" model for human cancer research. However, restricted availability of tumor samples hindered the widespread use of PDX. Most PDX-projects include only surgical specimens because reliable engraftment from biopsies is missing. Therefore, sample collection is limited and excludes recurrent and metastatic, non-resectable cancer from preclinical models as well as future personalized medicine. Methods: This study compares the PDX-take rate, -growth, histopathology, and molecular characteristics of endoscopic specimens with surgical specimens. HNSCC samples (n = 55) were collected ad hoc, fresh frozen and implanted into NOD.Cg-Prkdc
scid Il2rgtm1Wjl /SzJ mice. Results: Engraftment was successful in both sample types. However, engraftment rate was lower (21 vs. 52%) and growth delayed (11.2 vs. 6.7 weeks) for endoscopic biopsies. Following engraftment, growth kinetic was similar. Comparisons of primary tumors and corresponding PDX models confirmed preservation of histomorphology (HE histology) and molecular profile (Illumina Cancer Hotspot Panel) of the patients' tumors. Accompanying flow cytometry on primary tumor specimens revealed a heterogeneous tumor microenvironment among individual cases and identified M2-like macrophages as positive predictors for engraftment. Vice versa, a high PD-L1 expression (combined positive score on tumor/immune cells) predicted PDX rejection. Conclusion: Including biopsy samples from locally advanced or metastatic lesions from patients with non-surgical treatment strategies, increases the availability of PDX for basic and translational research. This facilitates (pre-) clinical studies for individual response prediction based on immunological biomarkers. [ABSTRACT FROM AUTHOR]- Published
- 2021
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6. Arginine-Depleting Enzymes - An Increasingly Recognized Treatment Strategy for Therapy-Refractory Malignancies.
- Author
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Riess, Christin, Shokraie, Fatemeh, Friedrich Classen, Carl, Kreikemeyer, Bernd, Fiedler, Tomas, Junghanss, Christian, and Maletzki, Claudia
- Subjects
AUXOTROPHY ,ARGININE deiminase ,AUTOPHAGY ,TUMOR microenvironment ,ANTINEOPLASTIC agents - Abstract
Arginine auxotrophy occurs in certain tumor types and is usually caused by the silencing of argininosuccinate synthetase 1 or arginine lyase genes. Such tumors are often associated with an intrinsic chemoresistance and thus a poor prognosis. Arginine auxotrophy however renders these tumors vulnerable to treatment with arginine-degrading enzymes. Among the most frequently applied arginine-degrading agents are bacterial arginine deiminases (ADI). The anti-cancerous effects of ADI derived from different bacteria were extensively studied in numerous preclinical cell culture and xenograft models. Mycoplasma-derived ADI-PEG20 is most commonly used and is currently under clinical investigation as a single agent therapeutic as well as in combination with different antineoplastic compounds. Mechanistically, ADI is capable of reducing metabolic activity in tumor cells, contributing to autophagy, senescence and apoptosis in arginine auxotrophic cells. Although clinical trials are promising, the resistance development upon initial treatment response is an increasing challenge. Furthermore, interference of ADI with the tumor microenvironment is poorly understood. In the present review, we outline recent experimental ADI-based treatment approaches and their translation into the clinic. Furthermore, we summarize new insights into the molecular mechanisms underlying the anti-cancer effects of ADI that might facilitate the refinement of ADI-based combination therapy approaches. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
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