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Rauf Bhat, PhD

Postdoctoral research fellow

Rauf Bhat, PhD

Project Director

Areas of scientific interest

Research in human Natural Killer (NK) cell immunology and development of anti-cancer immunotherapies

Past projects: As part of tumor virology research team (German Cancer Research Center, Heidelberg, Germany) I investigated the impact of oncolytic H1-PV parvovirus infection of tumor cells on their interaction with human Natural Killer cells. We reported that besides having an intrinsic oncolytic activity, parvovirus H-1PV is able to enhance Natural Killer cell-activity in pancreatic ductal adenocarcinoma (PDAC) and colon carcinoma model. Our data indicate that NK cells are endowed with anti-tumor potential against PDAC and colon carcinoma and that H-1PV-based oncolytic therapy could further boost NK cell-mediated immune responses and help to develop a combinatorial therapeutic approach against malignancies. I was also involved in the research accompanying the current human clinical trial of parvovirus H1-PV in glioma patients, specifically identifying T-cell epitope determinants of parvovirus H1-PV, in association with the group of Prof.Philipp Beckhove at NCT, Heidelberg. These data will later be used to measure anti-viral cellular immune responses in glioma patients treated with parvovirus, H1-PV. The responses observed will be included in the panel of surrogate markers of efficiency and will thus be quite essential for the final evaluation of the clinical trial. In addition, we also assessed recombinant H1-PV vectors encoding cytokines (IL-2) and chemokines (MCP-3, IP-10) in pancreatic cancer model.

Earlier, as part of Prof. Carsten Watzl lab, I investigated the dynamics of NK cell-mediated killing of tumor cells and mechanistic of co-stimulation of NK cell receptors and the resulting effect on cytotoxicity of NK cells against tumor cells.

 

Present project: Chimeric antigen receptor targeted oncoimmunotherapy with natural killer cells” (CAR–NK).

The major objective of this project is to develop new Chimeric antigen receptors (CARs) suited for NK cell based therapies and as a first step in developing anti-cancer personalised therapy in Romania. Natural killer (NK) cells represent an attractive lymphocyte population for cancer immunotherapy due to their ability to lyse tumor targets without prior sensitization and need for human leukocyte antigen–matching, unlike T cells. Chimeric antigen receptors (CARs) represent a novel tool for development of adoptive immunotherapy by enhancing lymphocyte targeting and activation towards malignancies. The primary aim of the project is to develop NK-CARs which recognise and target specific tumor antigens and can be used in an allogenic fashion. We also propose to create the first human CAR-NKs cellular bank which can be developed and applied for further clinical trials in support of personalized medicine in Romania.

 

Relevant publications

  1. Karsten Geletneky, Assia Angelova, Barbara Leuchs, David Capper, Andreas Bartsch, Jan Neumann,Tilman Schöning, Johannes Hüsing, Birgit Beelte, Irina Kiprianova, Mandy Roscher, Rauf Bhat, Alexandra Just, Veronika Frehtman, Stephanie Löbhard, Elena Ladwig, Jeremy Fry, Karin Jochims, Ottheinz Krebs, Michael Dahm, Bernard Huber, Andreas Unterberg, Jacek Hajda, Jean Rommelaere (2017). Oncolytic H-1 parvovirus shows safety and surrogate efficacy in a first glioblastoma trial. Journal of Clinical Investigation (submitted).
  2. Urlaub D, Bhat R, Messmer B, Watzl C (2016).Co-Activation of Cultured Human Natural Killer Cells: Enhanced Function and Decreased Inhibition. J Toxicol Environ Health A. 79(22-23):1078-1084 (equal contribution as first author).
  3. Rauf Bhat and Rommelaere J (2015).Emerging role of NK cells in Oncolytic Virotherapy. ImmunoTargets and Therapy.2015, 4:65-77 (corresponding author).
  4. Geletneky, A.Angelova, B.Leuchs, R.Bhat, A. Just, D.Capper, O.Krebs, M.Dahm, B.Huber, A.Unterberg, J.Hajda, J.Rommelaere (2014). ET-21 Combination of intravenous and intracerebral injection of oncolytic parvvirus H-1 in a phase I/II clinical trial of patients with recurrent glioblastoma multiforme:penetration of H-1 virus across the blood-brain barrier. Neuro-oncology 16 (suppl 5), v83-v84.
  5. Xiaojun Yu, Emmalene J. Bartlett, Josef Mautner, Marta Ilecka, Rauf Bhat, Regina Feederle and Henri-Jacques Delecluse (2015). Antigen-armed antibodies targeting B lymphoma cells effectively activate antigenspecific CD4+ T cells. Blood. 2015 Mar 5; 125 (10):1601-10.
  6. Bhat R, Rommelaere J (2013). NK cell-dependent killing of colon carcinoma cells is mediated by natural cytotoxicity receptors (NCRs) and stimulated by parvovirus infection of target cells. BMC Cancer. 2013 Jul 31; 13:367(corresponding author).
  7. Dempe S, Lavie M, Struyf S, Bhat R, Verbeke H, Paschek S, Berghmans N, Rommelaere J, Van Damme J, Dinsart C (2012).Antitumoral activity of parvovirus-mediated IL-2 and MCP-3/CCL7 delivery into human pancreatic cancer: implication of leucocyte recruitment. Cancer Immunol Immunother. Nov; 61(11):2113-23.
  8. Bhat R, Dempe S, Dinsart C and Rommelaere J (2011). Enhancement of NK cell anti-tumour responses using an oncolyticparvovirus. Int J Cancer. Feb 15; 128(4):908-19 (corresponding author).
  9. Bhat R, Watzl C (2007). Serial killing of tumor cells by human natural killer cells- enhancement by therapeutic antibodies. PLoS ONE. Mar 28; 2:e326.
  10. Claus M, Meinke S, Bhat R, Watzl C (2008). Regulation of Natural Killer Cell activity by 2B4, NTB-A and CRACC. (Review). Jan 1; 13:956-65. Frontiers Bioscience.
  11. Bhat R, Eissmann P, Endt J, Hoffmann S, Watzl C (2006). Fine-tuning of immune responses by SLAM related responses. J Leukoc Biol.79 (3):417-24. Review.
  12. Büttner M, Meinken C, Bastian M, Bhat R, Stößel R, Faller G, Cianciolo G, Ficker G, Wagner M, Röllinghoff M and Stenger S (2005). Inverse correlation of maturity and antibacterial activity in human dendritic cells. J Immunol. 1;174(7):4203-9.
  13. Stegelmann F, Bastian M, Swoboda K, Rauf Bhat, Kießler V, Krensky A, Röllinghoff M, Modlin R and Steffen Stenger (2005). Coordinate expression of CC chemokine ligand 5, granulysin, and perforin in CD8+ T cells provides a host defense mechanism against Mycobacterium tuberculosis. J Immunol. 175(11):7474-83.
  14. Bhat R, Kießler V, Röllinghoff M, Krensky A, Faller G, Niedobitek G and Stenger S. IL-15 upregulates granulysin and  antimicrobial activity of human natural killer cells (manuscript in prep.)

 

Affiliations

  1. Emergency Clinical County Hospital “Pius Brinzeu” Timisoara, Centre for Gene and cellular therapies in the treatment of cancer – OncoGen Center, Timisoara, Romania.
  2. Experimental Transfusions Medicine, Technical University, Dresden, Germany.
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