Labor
Ein wichtiges Ziel der klinisch orientierten Forschung ist, ein tieferes Verständnis der zellulären und molekularen Mechanismen zu erlangen, die auf der Regulation von T-Zell-vermittelten immunologischen Prozessen beruhen, insbesondere der Verwendung von NKT-Lymphozyten bei malignen Erkrankungen und dem Verhalten von Tumorzellen sowie Strategien zur Induktion einer effizienten Antitumor-Immunantwort in vitro.
Die adoptive zelluläre Immuntherapie konzentriert sich auf die Antigen-präsentierende Funktion menschlicher dendritischer Zellen (DC) und die Verwendung von NKT-Lymphozyten bei der gezielten Behandlung von hämatologischen Neoplasmen und soliden Tumoren. Andere Arten der Verbesserung der Immuntherapie sind Chemotherapie, molekulare Zieltherapien und intrinsische Immun-Checkpoint-Blockaden, die Schlüsselmechanismen des Lymphozytenaktivierungsprozesses sind.
Experimental Oncology
The central interest of our research group is adoptive T cell based immunotherapies, in particular cytokine-induced killer (CIK) cell immunotherapy, which is actively involved in the treatment of cancer for almost three decades (Sharma, J Exp Clin Cancer Res 2021). Being inherently heterogeneous, CIK cells can be easily characterized phenotypically as CD3+CD56- (T cells), CD3+CD56+(NKT cells) and CD3-CD56+ (NK cells) subpopulations, all of which have a strong impact on the target (tumor) cells. CIK cells are compatible with almost all types of immune checkpoint inhibitors, epigenetic drugs or commercial compounds. Numerous clinical trials and preclinical studies have been conducted over the past three decades, and thousands of patients with more than 30 tumor types have benefited from this approach. With the newly established International Society of CIK Cells (ISCC, https://iscc-info.org/) in 2024, a stronger scientific network integrating the preclinical research and clinical trials to benefit patients around the globe can be foreseen. (Sharma, Cancer Immunology Immunotherapy 2024). In our lab, we currently pursue the following main research projects:
Synergistic effects and molecular insights of CIK cells in the cancer landscape: Using diverse cancer types, we have evident that CIK cells are highly compatible to epigenetics/histone deacetylase inhibitors (Pu, Clin Transl Immunology 2024), immune check point inhibitors/PD-1 inhibitors (Li, Front Oncol. 2023), cannabidiols (Li, Front Immunol. 2024), and even non-oncology drug like meticrane (Wang, Front Oncol. 2023). We also demonstrated that clinically applicable HSP90 inhibitors can synergistically enhance CIK cell-mediated killing across hematological malignancies via multiple pathways i.e., Fas/FasL pathway in Burkitt lymphoma (Ge, IJMS 2023) and NKG2D/NKG2D ligand axis in multiple myeloma and acute lymphoblastic leukemia (Ge, under review). In addition, we showed that NKG2D (natural killer group 2D) engagement alone is sufficient to trigger and activate CIK cells, while 2B4 (CD244, another well-characterized NK cell activation receptor) only provides limited co-activation (Wu, Front Immunol. 2021). Our team is continuously engaged in understanding the molecular interplay underlying the function of CIK cells (Sharma, Cell Mol Immunol. 2023) and finding suitable determinants to further improve their therapeutic effect in the clinic.
CIK cell therapy & associated advanced derivatives: In addition to CIK cells, our research also undermines the potential clinical impact of its advanced derivatives (DC-CIK, CAR-CIK). We recently showed that agonistic anti-CD40 antibody rather than CTLA-4 inhibitor may improve the antitumor response of DC-CIK cells in renal cell carcinoma (Zhang, Front Immunol. 2022). For CNS (central nervous system) malignancies, where no effective treatment exists to date, we have recently suggested the potential of CIK cell therapy and adjuvant NKT immunotherapy with invariant NKT (iNKT) for improving the clinical outcome of glioblastoma (GBM), a fast-growing and aggressive brain tumour (Li, IJMS 2022). Moreover, we have demonstrated that balancing CIK cell cancer immunotherapy with peroxisome proliferator-activated receptor (PPAR) ligands may be a more focused and potential therapeutic application for CNS malignancies (Vordermark, Cancer Scinece.2024). Furthermore, in a preclinical evaluation, we have now experimentally demonstrated that the cytotoxic ability of dendritic cells in combination with cytokine-induced killer cells (DC-CIKs) can be used as an effective immunotherapy model for investigating treatment options for GBM (Lück, under review).
Bioinformatics roadmap for therapy selection in cancer: Using machine learning frameworks, we designed the very first study in which the transcriptome of CIK cells was used to successfully stratify the clinical features of renal cell carcinoma (Chen, under review). Of interest, we have made the first attempt in the literature to systematically predict the potential interaction between the three key determinants (m6A/epi transcriptome, autophagy, lncRNA) to establish a prognostic signature for GBM (Sharma, Scientific Reports 2023). Our lab has also provided evidence of a potential new prognostic marker that may influence the immune response in cancer (Zhao, Discov Oncol. 2024; Ge, Curr Med Chem. 2024; Ge, Front Genet. 2023). To keep the research community up-to-date on the unprecedented advances in the field of cellular immunotherapies and cancer, we continue to publish updates in the literature (Pu, Exp Hematol Oncol. 2024; Li, Mol Cancer. 2024; Chen, J Exp Clin Cancer Res. 2024; Vaseq, IJMS 2023; Hu, Front Immunol. 2023; Dakal, MedComm 2024).
Underlying distant molecular mechanisms in cancer and neurodegeneration: Cancer and neurodegenerative diseases (NDD) appear mechanistically distinct, i.e., the former acquires mechanisms to resist and evade cell death in order to proliferate, while the latter is characterized by progressive cellular demise and degeneration in specific neuronal populations. Our lab is investigating overlapping/inversely related molecular mechanisms involved in the development of cancer and NDDs (Sharma, Front Mol Neurosci. 2023, Pu, Epigenomics. 2023, Liu, under review).
Selected publications (last 4 years):
Sharma, A., Schmidt-Wolf, I.G.H. 30 years of CIK cell therapy: recapitulating the key breakthroughs and future perspective. J Exp Clin Cancer Res 40, 388 (2021). https://doi.org/10.1186/s13046-021-02184-2
Sharma A, Ren X, Rosato A, Sangiolo D, Wang Z, Tettamanti S, Zhang Y, Rettinger E, Fenix KA, Sommaggio R, Cappuzzello E, Schmidt-Wolf IGH. Cytokine-induced killer (CIK) cells, successes and challenges: report on the first international conference dedicated to the clinical translation of this unique adoptive cell immunotherapy. Cancer Immunol Immunother. 2024 Jan 27;73(2):21. doi: 10.1007/s00262-023-03605-1.
Pu J, Sharma A, Liu T, Hou J, Schmidt-Wolf IG. Synergistic integration of histone deacetylase inhibitors apparently enhances the cytokine-induced killer cell efficiency in multiple myeloma via the NKG2D pathway. Clin Transl Immunology. 2024 Mar 25;13(3):e1500. doi: 10.1002/cti2.1500.
Li Y, Sharma A, Hoffmann MJ, Skowasch D, Essler M, Weiher H, Schmidt-Wolf IGH. Discovering single cannabidiol or synergistic antitumor effects of cannabidiol and cytokine-induced killer cells on non-small cell lung cancer cells. Front Immunol. 2024 Mar 14;15:1268652. doi: 10.3389/fimmu.2024.1268652
Wang Y, Sharma A, Ge F, Chen P, Yang Y, Liu H, Liu H, Zhao C, Mittal L, Asthana S, Schmidt-Wolf IGH. Non-oncology drug (meticrane) shows anti-cancer ability in synergy with epigenetic inhibitors and appears to be involved passively in targeting cancer cells. Front Oncol. 2023 May 19;13:1157366. doi: 10.3389/fonc.2023.1157366.
Li Y, Sharma A, Wu X, Weiher H, Skowasch D, Essler M, Schmidt-Wolf IGH. A Combination of Cytokine-Induced Killer Cells With PD-1 Blockade and ALK Inhibitor Showed Substantial Intrinsic Variability Across Non-Small Cell Lung Cancer Cell Lines. Front Oncol. 2022 doi: 10.3389/fonc.2022.713476.
Ge F, Wang Y, Sharma A, Yang Y, Liu H, Essler M, Jaehde U, Schmidt-Wolf IGH. Cytokine-Induced Killer Cells in Combination with Heat Shock Protein 90 Inhibitors Functioning via the Fas/FasL Axis Provides Rationale for a Potential Clinical Benefit in Burkitt's lymphoma. Int J Mol Sci. 2023 Aug 5;24(15):12476. doi: 10.3390/ijms241512476.
Wu X, Sharma A, Oldenburg J, Weiher H, Essler M, Skowasch D, Schmidt-Wolf IGH. NKG2D Engagement Alone Is Sufficient to Activate Cytokine-Induced Killer Cells While 2B4 Only Provides Limited Coactivation. Front Immunol. 2021 Oct 7;12:731767. doi: 10.3389/fimmu.2021.731767.
Sharma A, Schmidt-Wolf IGH. Tempering of exhausted T cells to comprehend their adaptive response for suitable clinical translation. Cell Mol Immunol. 2023 Dec;20(12):1401-1402. doi: 10.1038/s41423-023-01031-y.
Zhang Y, Wu X, Sharma A, Weiher H, Schmid M, Kristiansen G, Schmidt-Wolf IGH. Anti-CD40 predominates over anti-CTLA-4 to provide enhanced antitumor response of DC-CIK cells in renal cell carcinoma. Front Immunol. 2022 Aug 25;13:925633. doi: 10.3389/fimmu.2022.925633.
Li Y, Sharma A, Maciaczyk J, Schmidt-Wolf IGH. Recent Development in NKT-Based Immunotherapy of Glioblastoma: From Bench to Bedside. Int J Mol Sci. 2022 Jan 24;23(3):1311. doi: 10.3390/ijms23031311.
Vordermark K, Pu JJ, Sharma A, Maciaczyk J , Schmidt-Wolf IGH, Balancing CIK Cell Cancer Immunotherapy and PPAR Ligands: One Potential Therapeutic Application for CNS Malignancies, Cancer Medicine (in press)
Sharma A, Wang Y, Ge F, Chen P, Dakal TC, Carro MS, Schmidt-Wolf IGH, Maciaczyk J. Systematic integration of m6A regulators and autophagy-related genes in combination with long non-coding RNAs predicts survival in glioblastoma multiforme. Sci Rep. 2023 Oct 11;13(1):17232. doi: 10.1038/s41598-023-44087-6
Zhao C, Wang Y, Wang H, Sharma A, Wu Y, Schmidt-Wolf IGH, Wang Z. CSRP1 gene: a potential novel prognostic marker in acute myeloid leukemia with implications for immune response. Discov Oncol. 2024 Jun 27;15(1):248. doi: 10.1007/s12672-024-01088-9.
Ge F, Wang Y, Chen P, Sharma A, Huang X, Dakal TC, Wang Z, Jaehde U, Essler M, Schmid M, Schmidt-Wolf IGH. FOXN3-AS1: A Candidate Prognostic Marker and Epigenetic Target with Immunotherapeutic Implications in Acute Myeloid Leukemia. Curr Med Chem. 2024 Oct 11. doi: 10.2174/0109298673311108240926062214.
Ge F, Wang Y, Sharma A, Jaehde U, Essler M, Schmid M, Schmidt-Wolf IGH. Computational analysis of heat shock proteins and ferroptosis-associated lncRNAs to predict prognosis in acute myeloid leukemia patients. Front Genet. 2023 Aug 1;14:1218276. doi: 10.3389/fgene.2023.1218276.
Pu J, Liu T, Sharma A, Jiang L, Wei F, Ren X, Schmidt-Wolf IGH, Hou J. Advances in adoptive cellular immunotherapy and therapeutic breakthroughs in multiple myeloma. Exp Hematol Oncol. 2024 Oct 28;13(1):105. doi: 10.1186/s40164-024-00576-6. PMID: 39468695; PMCID: PMC11514856.
Li Y, Sharma A, Schmidt-Wolf IGH. Evolving insights into the improvement of adoptive T-cell immunotherapy through PD-1/PD-L1 blockade in the clinical spectrum of lung cancer. Mol Cancer. 2024 Apr 24;23(1):80. doi: 10.1186/s12943-023-01926-4.
Chen P, Sharma A, Weiher H, Schmidt-Wolf IGH. Biological mechanisms and clinical significance of endoplasmic reticulum oxidoreductase 1 alpha (ERO1α) in human cancer. J Exp Clin Cancer Res. 2024 Mar 8;43(1):71. doi: 10.1186/s13046-024-02990-4.
Vaseq R, Sharma A, Li Y, Schmidt-Wolf IGH. Revising the Landscape of Cytokine-Induced Killer Cell Therapy in Lung Cancer: Focus on Immune Checkpoint Inhibitors. Int J Mol Sci. 2023 Mar 15;24(6):5626. doi: 10.3390/ijms24065626.
Hu C, Liu M, Li Y, Zhao Y, Sharma A, Liu H, Schmidt-Wolf IGH. Recent advances and future perspectives of CAR-T cell therapy in head and neck cancer. Front Immunol. 2023 Jun 29;14:1213716. doi: 10.3389/fimmu.2023.1213716.
Dakal TC, Bhushan R, Xu C, Gadi BR, Cameotra SS, Yadav V, Maciaczyk J, Schmidt-Wolf IGH, Kumar A, Sharma A. Intricate relationship between cancer stemness, metastasis, and drug resistance. MedComm (2020). 2024 Sep 21;5(10):e710. doi: 10.1002/mco2.710.
Sharma A, Wüllner U, Schmidt-Wolf IGH, Maciaczyk J. Marginalizing the genomic architecture to identify crosstalk across cancer and neurodegeneration. Front Mol Neurosci. 2023 Feb 27;16:1155177. doi: 10.3389/fnmol.2023.1155177.
Pu J, Sharma A, Hou J, Schmidt-Wolf IG. Histone deacetylase 6: at the interface of cancer and neurodegeneration. Epigenomics. 2023 Nov;15(22):1195-1203. doi: 10.2217/epi-2023-0373. Epub 2023 Dec 7. PMID: 38059314.
Extended list of publications: PubMed
Lab Members
Univ.-Prof. Dr. med. Ingo Schmidt-Wolf
Head of research group
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Prof. Dr. Hans Weiher
Scientific advisor
Dr. Amit Sharma
Senior scientist
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Dr. Yutao Li
Postdoc
PhD Students
Oliver Rudan
Maria Setiawan
Rohulla Vaseq
Peng Chen
Yin hao chen
Linlin Chen
Xiang Ruan
Medical, master students
Kira Vordermark
Annika Simone Lück
Leandros Andreou
Marc Pullan
Nahid Mahleqa
Marian Unger
Johanna Schäfer
Nóra Kálmán
Alumni
Dr. Jingjing Pu
Dr. Yulu Wang
Dr.FangFang Ge
Dr. Ying Zhang
Dr. Xiaolong Wu
Dr.Francesca Garofano
David Stephan
Berthila Ferkamchwi
Sara Rezaeigoharchaghaei
Collaborations (selection):
Dr. Maria A Gonzalez-Carmona, University Hospital Bonn, Germany
Prof. Jaroslaw Maciaczyk, University Hospital Bonn, Germany
Prof. Adrian A Achuthan, University of Melbourne, Australia
We are always looking for talented Postdocs, MD/PhDs and Master’s students to join our team. For inquiries about current positions, please contact Enable JavaScript to view protected content.
