Dr. Rauf Bhat

Domenii de interes științific

Cercetare în domeniul imunologiei celulelor Natural Killer (NK) umane și al dezvoltării de imunoterapii anti-cancer

Proiecte încheiate: În calitate de membru al echipei de cercetare în virusologie tumorală (German Cancer Research Center, Heidelberg, Germania) am investigat impactul infecției celulelor tumorale cu parvovirusul oncolitic H1-PV asupra interacțiunii acestora cu celulele Natural Killer. impact of oncolytic H1-PV parvovirus infection of tumor cells on their interaction with human Natural Killer cells. Am raportat că, pe lângă activitatea oncolitică intrinsecă, parvovirusul H-1PV este capabil să crească activitatea celulară a celulelor Natural Killer în adenocarcinoamele pancreatice ductale (ACPD) și pe un model de carcinom de colon. Datele noastre indică faptul că celuele NK au potențial anti-tumoral față de ACPD și carcinoamele de colon și că terapia oncolitică bazată pe H-1PV ar putea stimula răspunsurile imune mediate de celulele NK și ar servi la dezvoltarea unei abordări terapeutice combinate împotriva cancerului. Am fost implicat și în cercetarea  accompanying actualul studiu clinic asupra parvovirusului H1-PV la pacienții cu gliom, și anume în identificarea determinanților epitopului celulei T-cell ai parvovirusului H1-PV, în colaborare cu grupul Prof. Philipp Beckhove de la NCT, Heidelberg. Aceste date vor fi utilzate pentru a măsura răspunsurile imune celulare anti-virale la pacienții cu gliom tratați cu parvovirusul H1-PV. Răspunsurile observate vor fi incluse în panelul de markerui surogat ai eficienței și, astfel, vor fi esențiali în evaluarea finală a studiului clinic. În plus, am evaluat vectorii H1-PV recombinat care codifică citokine (IL-2) și chemokine (MCP-3, IP-10) pe un model de cancer pancreatic.

Înainte de acest proiect, în calitate de membru al laboratorului Prof. Carsten Watzl, 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.

Experimental Transfusions Medicine, Technical University, Dresden, Germany.