Department of Fundamental Oncology with Genetic Engineering and Cell Therapy Group

 

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Alexei Petukhov
Head of Group

Principal activity

The Genetic Engineering and Cell Therapy Group focuses on research of the efficacy and safety of genetically modified lymphocytes for cancer treatment. The laboratory is equipped with bioreactors used for scaling up the production of vectors for genetic modification of T cells, the equipment for the production of cell products, their analysis and cryopreservation.

Newly developed and implemented technologies

In order to determine a strategy for improving the design of CAR-T cells, the Research Laboratory of Onco-Hematology is currently working on the identification of genes associated with tumor resistance to CAR-T therapy. Another area is the development of allogeneic universal CAR-T cells to increase the availability of therapy for patients. The Genetic Engineering and Cell Therapy Group has been carrying out the work on the domestic development of CAR-T cells.

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Participation in State Assignments 

Experimental research «Development of allogeneic tumor-specific T cells with an anti-CD19 chimeric antigen receptor» (State Assignment of the Russian Health Ministry).

Supervised by: Prof. Andrey Zaritskey.

Grants

  • «Study of the efficacy mechanisms of T cells with chimeric antigen receptor (CAR-T) in cell-based and animal models of solid tumors» (ongoing project).
  • “Pathophysiological significance of the PPM1D gene and its therapeutic modulation in a xenograft model of human acute myeloid leukemia” (ongoing project).
  • “Reprogramming of myeloid suppressor cells by genomic editing to increase the effectiveness of antitumor immunotherapy (ongoing project).
  • “Works in the area of diagnosing significant mutations of acute myeloid leukemia (IDH, FLT3, DNMT3a, etc.) ” (ongoing project).
  • Tumor resistance genes for MHC-independent immunotherapy (completed in 2019).

Major results: CAR-T therapy is effective in treating hematologic malignancies, but the chance of relapse may still be high. Our objective was to identify genes that help tumor cells suppress the effectiveness of CAR-T cell therapy or to identify genes that can alter the expression profile in tumor cells after CAR-T exposure. To identify such resistance genes, we performed genomic screening with the CRISPR / Cas9 Synergistic Activation Mediator (SAM) library and next generation sequencing. We used Hela cells that exogenously express CD19 as a model system. The studies have identified immunosuppressive genes that may be associated with the effectiveness of CAR-T therapy. CD19 + Hela cells were incubated with CAR-T cells (anti-CD19 with 4-1BB or CD28). The surviving clones were sequenced. The results were validated by screening in several rounds of library enrichment (surviving clones of tumor cells were again incubated with CAR-T cells) and further bioinformatic analysis, as well as by overexpression of candidate genes in the Hela tumor line followed by incubation with CAR-T cells. The results can be used to boost the effectiveness of CAR-T therapy.

International collaboration 

The Genetic Engineering and Cell Therapy Group collaborates with the French National Institute of Health and Medical Research (INSERM), the Bourgogne Franche Comté University (France); the University of Texas MD Anderson Cancer Center (USA).

Major publications

2020 

Titov A, Valiullina A, Zmievskaya E, Zaikova E, Petukhov A, Miftakhova R, Bulatov E, Rizvanov A. Advancing CAR T-Cell Therapy for Solid Tumors: Lessons Learned from Lymphoma Treatment. Cancers (Basel). 2020 Jan 3;12 (1). doi: 10.3390/cancers12010125. Review. PubMed PMID: 31947775; PubMed Central PMCID: PMC7016531. IF 6,162

Zaytsev, D., Girshova, L., Ivanov, V., Budaeva, I., Motorin, D., Badaev, R., Mirolubova, J., Grobovenko, E., Chitanava, T., Zaykova, E., Alexeeva, J. and Zaritskey, A. Rapid Efficacy of Gemtuzumab Ozogamicin in Refractory AML Patients with Pulmonary and Kidney Failure. Biology (Basel). 2020; 9 (2):28. doi:10.3390/biology9020028 IF 3,05

Vasileva E, Shuvalov O, Petukhov A, Fedorova O, Daks A, Nader R, Barlev N. KMT Set7/9 is a new regulator of Sam68 STAR-protein. Biochem Biophys Res Commun. 2020 May 14;525 (4):1018—1024. doi: 10.1016/j.bbrc.2020.03.017. Epub 2020 Mar 13. PubMed PMID: 32178870. IF 2,705

2019 

Suvorova II, Knyazeva AR, Petukhov AV, Aksenov ND, Pospelov VA. Resveratrol enhances pluripotency of mouse embryonic stem cells by activating AMPK/Ulk1 pathway. Cell Death Discov. 2019;5:61. doi: 10.1038/s41420-019-0137-y. eCollection 2019. PubMed PMID: 30729040; PubMed Central PMCID: PMC6361884. IF 8,5

Deryabin P, Griukova A, Shatrova A, Petukhov A, Nikolsky N, Borodkina A. Optimization of lentiviral transduction parameters and its application for CRISPR-based secretome modification of human endometrial mesenchymal stem cells. Cell Cycle. 2019 Mar — Apr;18 (6-7):742-758. doi: 10.1080/15384101.2019.1593650. Epub 2019 Mar 28. PubMed PMID: 30880567; PubMed Central PMCID: PMC6464586. IF 3,304

2018 

Shuvalov O, Kizenko A, Shakirova A, Fedorova O, Petukhov A, Aksenov N, Vasileva E, Daks A, Barlev N. Nutlin sensitizes lung carcinoma cells to interferon-alpha treatment in MDM2-dependent but p53-independent manner. Biochem Biophys Res Commun. 2018 Jan 1;495 (1):1233—1239. doi: 10.1016/j.bbrc.2017.11.118. Epub 2017 Nov 23. PubMed PMID: 29175211. IF 2,705

Kulemzin SV, Gorchakov AA, Chikaev AN, Kuznetsova VV, Volkova OY, Matvienko DA, Petukhov AV, Zaritskey AY, Taranin AV. VEGFR2-specific FnCAR effectively redirects the cytotoxic activity of T cells and YT NK cells. Oncotarget. 2018 Feb 6;9 (10):9021—9029. doi: 10.18632/oncotarget.24078. eCollection 2018 Feb 6. PubMed PMID: 29507671; PubMed Central PMCID: PMC5823625. IF 3,710

Kalinin RS, Petukhov AV, Knorre VD, Maschan MA, Stepanov AV, Gabibov AG. Molecular Approaches to Safe and Controlled Engineered T-cell Therapy. Acta Naturae. 2018 Apr-Jun;10 (2):16-23. PubMed PMID: 30116611; PubMed Central PMCID: PMC6087824. IF 0,82

Canfarotta F, Lezina L, Guerreiro A, Czulak J, Petukhov A, Daks A, Smolinska-Kempisty K, Poma A, Piletsky S, Barlev NA. Specific Drug Delivery to Cancer Cells with Double-Imprinted Nanoparticles against Epidermal Growth Factor Receptor. Nano Lett. 2018 Aug 8;18 (8):4641—4646. doi: 10.1021/acs.nanolett.7b03206. Epub 2018 Jul 9. PubMed PMID: 29969563. IF 12,334

Titov A, Petukhov A, Staliarova A, Motorin D, Bulatov E, Shuvalov O, Soond SM, Piacentini M, Melino G, Zaritskey A, Barlev NA. The biological basis and clinical symptoms of CAR-T therapy-associated toxicites. Cell Death Dis. 2018 Sep 4;9 (9):897. doi: 10.1038/s41419-018-0918-x. Review. PubMed PMID: 30181581; PubMed Central PMCID: PMC6123453. IF 5,910

Fedorova O, Daks A, Petrova V, Petukhov A, Lezina L, Shuvalov O, Davidovich P, Kriger D, Lomert E, Tentler D, Kartsev V, Uyanik B, Tribulovich V, Demidov O, Melino G, Barlev NA. Novel isatin-derived molecules activate p53 via interference with Mdm2 to promote apoptosis. Cell Cycle. 2018;17 (15):1917—1930. doi: 10.1080/15384101.2018.1506664. Epub 2018 Sep 5. PubMed PMID: 30109812; PubMed Central PMCID: PMC6152504. IF 3,304

Bulatov E, Sayarova R, Mingaleeva R, Miftakhova R, Gomzikova M, Ignatyev Y, Petukhov A, Davidovich P, Rizvanov A, Barlev NA. Isatin-Schiff base-copper (II) complex induces cell death in p53-positive tumors. Cell Death Discov. 2018;4:103. doi: 10.1038/s41420-018-0120-z. eCollection 2018. PubMed PMID: 30455989; PubMed Central PMCID: PMC6234212. IF 3,304

Zhiduleva E, Irtyuga O, Shishkova A, Ignat’eva E, Kostina A, Levchuk K, Golovkin A,  Rylov, A, Kostareva A, Moiseeva O, Malashicheva A, Gordeev M. Cellular Mechanisms of Aortic Valve Calcification. Bulletin of Experimental Biology and Medicine. 2018. 164. 10.1007/s10517-0183992-2. IF 0,34

Fedorova O, Petukhov A, Daks A, Shuvalov O, Leonova T, Vasileva E, Aksenov N, Melino G, Barlev NA. Orphan receptor NR4A3 is a novel target of p53 that contributes to apoptosis. Oncogene. 2019 Mar;38 (12):2108—2122. doi: 10.1038/s41388-018-0566-8. Epub 2018 Nov 19. PubMed PMID: 30455429. IF 6,854

Sullivan G.P., Davidovich P.B., Sura‐Trueba S., Belotcerkovskaya E., Henry C.M., Clancy D.M., Zinoveva A., Mametnabiev T., Garabadzhiu A.V., Martin S.J. Identification of small molecule elastase inhibitors as antagonists of IL‐36 cytokine activation// FEBS Open Bio. 2018. DOI: 10.1002/2211—5463.12406 IF 2,101

G.P. Sullivan, C.M. Henry, D.M. Clancy, T. Mametnabiev, E. Belotcerkovskaya, P. Davidovich, S. Sura-Trueba, A.V. Garabadzhiu, S.J. Martin. Suppressing IL-36-driven inflammation using peptide pseudosubstrates for neutrophil proteases// Cell Death and Disease. 2018;9 (3):378. IF 2,705

Lomert E, Turoverova L, Kriger D, Aksenov ND, Nikotina AD, Petukhov A, Mittenberg AG, Panyushev NV, Khotin M, Volkov K, Barlev NA, Tentler D. Co-expression of RelA/p65 and ACTN4 induces apoptosis in non-small lung carcinoma cells. Cell Cycle. 2018;17 (5):616-626. doi: 10.1080/15384101.2017.1417709. Epub 2018 Jan 22. PubMed PMID: 29251177; PubMed Central PMCID: PMC5969568. IF 3,304

2017 год

Kostina A, Shishkova A, Ignatieva E, Irtyuga O, Bogdanova M, Levchuk K, Golovkin A, Zhiduleva E, Uspenskiy V, Moiseeva O, Faggian G, Vaage J, Kostareva A, Rutkovskiy A, Malashicheva A. Different Notch signaling in cells from calcified bicuspid and tricuspid aortic valves. J Mol Cell Cardiol., 2017 Nov 20;114:211-219. doi: 10.1016/j.yjmcc.2017.11.009 IF 5,055

Shuvalov O, Petukhov A, Daks A, Fedorova O, Vasileva E, Barlev NA. One-carbon metabolism and nucleotide biosynthesis as attractive targets for anticancer therapy. Oncotarget. 2017 Apr 4;8 (14):23955-23977. doi: 10.18632/oncotarget.15053. Review. PubMed PMID: 28177894; PubMed Central PMCID: PMC5410357. IF 3,710

2016 

Daks A, Petukhov A, Fedorova O, Shuvalov O, Merkulov V, Vasileva E, Antonov A, Barlev NA. E3 ubiquitin ligase Pirh2 enhances tumorigenic properties of human non-small cell lung carcinoma cells. Genes Cancer. 2016 Nov;7 (11-12):383-393. doi: 10.18632/genesandcancer.123. PubMed PMID: 28191284; PubMed Central PMCID: PMC5302039. IF 4,041

M. Clancy, C. M. Henry, P. B. Davidovich, G. P. Sullivan, E. Belotcerkovskaya, S. J. Martin. Production of biologically active IL-36 family cytokines through insertion of N-terminal caspase cleavage motifs// FEBS Open bio. 2016;6 (4):338 – 348. IF 2,101

2015 

Shuvalov O, Petukhov A, Daks A, Fedorova O, Ermakov A, Melino G, Barlev NA. Current genome editing tools in gene therapy: new approaches to treat cancer. Curr Gene Ther. 2015;15 (5):511-29. doi: 10.2174/1566523215666150818110241. Review. PubMed PMID: 26282844. IF 1,943

Shuvalov OY, Fedorova OA, Petukhov AV, Daks AA, Vasilieva EA, Grigorieva TA, Ivanov GS, Barlev NA. [NEGATIVE REGULATORS OF TUMOR SUPPRESSOR P53 IN THE CONTEXT OF ANTICANCER THERAPY]. Tsitologiia. 2015;57 (12):847-54. Review. PubMed PMID: 26995961. IF 0,817

Daks AA, Petukhov AV, Shuvalov OY, Vasilieva EA, Melino G, Barlev NA, Fedorova OA. [TUMOR SUPPRESSOR p63 REGULATES EXPRESSION OF UBIQUITIN LIGASE Pirh2]. Tsitologiia. 2015;57 (12):876-9. PubMed PMID: 26995965. IF 0,817