Adoptitive immunotherapy with genetically engineered T lymphocytes modified to express chimeric antigen receptors

Pavlova, A.; Maschan, Michael; Пономарев, В. Б.

doi:10.17650/1818-8346-2017-12-1-17-32

Cited by 11 publications

(11 citation statements)

References 77 publications

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“…Чтобы создать уни-версальные CAR T-лимфоциты для уменьшения воз-можных побочных эффектов, представляется целесо-образной дальнейшая модификация клеток -умень-шение экспрессии нативного TCR молекул главного комплекса гистосовместимости I класса. Кроме того, возможно включение в геном CAR T-лимфоцитов так называемых суицидальных генов, позволяющих при необходимости осуществить быструю элиминацию клеток путем применения определенных препаратов, например ганцикловира [21,51,52].…”

Section: Discussionunclassified

“…Внутри-клеточная часть рецептора состоит из ζ-цепи CD3 и до-полнительных сигнальных доменов костимуляторных белков, чаще всего CD28 или 4-1ВВ (CD137). Внутри-клеточные домены отвечают за передачу сигнала при связывании с антигеном-мишенью и эффективную активацию CAR T-лимфоцитов [9,20,21].…”

Section: Introductionunclassified

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Manufacturing of CD19 Specific CAR T-Cells and Evaluation of their Functional Activity in Vitro

Петухов¹,

Маркова²,

Моторин³

et al. 2018

Клиническая онкогематология

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Background. The most promising variant of adoptive immunotherapy of the B-line oncohematological diseases includes the use of cells with the chimeric antigen receptor (CAR T-cells), that showed extraordinary results in clinical studies. Aim. To manufacture CAR T-cells for the clinical use and to study their cytotoxicity in vitro. Methods. Human T-lymphocytes were transduced by the lentiviral vector containing anti-CD19-CAR, RIAD, and GFP genes. The T-cell transduction efficacy was assessed on the basis of GFP protein signal by flow cytometry. Propidium iodide was used to analyse the cell viability. Cytotoxic activity of the manufactured CAR T-cells was studied in the presence of the target cells being directly co-cultivated. Analysis of the number and viability of CAR T-cells and cytokine expression was performed by flow cytometry. Results. The viability of the transduced T-cells and GFP expression reached 91.87 % and 50.87 % respectively. When cultured in the presence of IL-2 and recombinant CD19 (the target antigen), the amount of CAR-T after 120 h of the process was 1.4 times larger compared with the period of 48 h. In the cytotoxic test of co-cultivation CART with the K562-CD19+ cells the percentage of CAR-T increased to 57 % and 84.5 % after 48 h and 120 h of exposure respectively. When cultured with the K562 cells (test line not expressing CD19) the number of CAR T-cells decreased to 36.2 % within 48 h while the number of K562 cells increased to 58.3 %. The viability of target cells in the experimental and control groups was 3.5 % and 36.74 % respectively. Comparison of IL-6 level in the control and experimental groups revealed that the differences are insignificant, as opposed to the level of other cytokines (IFN-y, IL-2, TNF) which proved to be different in both groups. Conclusion. The present work resulted in the production of anti-CD19 CAR T-cells with adequate viability. The in vitro model demonstrated their cytotoxicity. Manufacturing of CAR T-cells for clinical use is the first step of the development of adoptive immunotherapy in the Russian Federation.

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Section: Discussionunclassified

Section: Introductionunclassified

Manufacturing of CD19 Specific CAR T-Cells and Evaluation of their Functional Activity in Vitro

Петухов¹,

Маркова²,

Моторин³

et al. 2018

Клиническая онкогематология

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“…Российский журнал ДЕТСКОЙ ГЕМАТОЛОГИИ и ОНКОЛОГИИ R u s s i a n J o u r n a l o f P e d i a t r i c H e m a t o l o g y а n d O n c o l o g y 2 О б з о р ы л и т е р а т у р ы || L i t e r a t u r e r e v i e w s Введение Онкологические заболевания уверенно занимают 2-е место не только в структуре смертности населения планеты, уступая лишь сердечно-сосудистым заболеваниям [1], но и в структуре все чаще применяемого показателя лет жизни, скорректированных по нетрудоспособности (Disability-adjusted life years; DALY). По данным Всемирной организации здравоохранения, DALY от онкозаболеваний в 2017 г. оценено в 233,5 млн лет [2].…”

Section: том | Volunclassified

“…На основании этого ученые объединили антигенсвязывающий вариабельный фрагмент антитела и константную часть Т-клеточного рецептора. Получился химерный рецептор, способный распознавать антигены на поверхности опухолевых клеток независимо от соединения эпитопа с MHC I. При этом все внутриклеточные сигнальные пути, характерные для Т-лимфоцитов, такой рецептор точно так же, как и TCR, способен активировать [1].…”

Section: том | Volunclassified

The latest trends in improving CAR-T cell therapy: from leukemia to solid malignant tumors

Ершов

Демьянов

Насруллаева

et al. 2021

Ross. ž. det. gematol. onkol.

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CAR-Т cell therapy with the use of cytotoxic lymphocytes with chimeric antigen receptors occupies an important place among modern approaches to the cancer treatment. This therapy has established itself as an effective method of the treatment of CD19+ acute lymphoblastic leukemia. Nevertheless, the recurrences of the illness are not uncommon; the treatment of solid tumors with genetically engineered lymphocytes shows modest results and it is accompanied by the high toxicity. One thing, however, is certain: CAR-Т cell therapy has great potential in the treatment of cancer and further improving of the structure and functions of genetically engineered lymphocytes with chimeric Т cell receptors help greatly increase the efficiency of antitumor treatment.The review includes the current data on the structure of chimeric lymphocytes of different generations and the trends in improving CAR-Т cell therapy. It includes also the fundamental platform for formation of ideology of use CAR-Т cells for the treatment of solid malignant tumors.

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“…Furthermore, given the broad availability of appropriate targets, the application of CAR T-cell therapy now actively expands into the management of R/R multiple myeloma [1][2][3][4][5] and acute myeloid leukemia (AML) [6]. A phase I clinical trial of anti-CD123 CAR T-cells in AML reported three complete remissions (CR) and two stable disease (SD) cases in 12 infused patients without significant toxicity [7], while other clinical trials continue recruiting.…”

Section: Introductionmentioning

confidence: 99%

Advancing CAR T-Cell Therapy for Solid Tumors: Lessons Learned from Lymphoma Treatment

Titov

Valiullina

Zmievskaya

et al. 2020

Cancers

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Chimeric antigen receptor (CAR) immunotherapy is one of the most promising modern approaches for the treatment of cancer. To date only two CAR T-cell products, Kymriah® and Yescarta®, have been approved by the Food and Drug Administration (FDA) for the treatment of lymphoblastic leukemia and B-cell lymphoma. Administration of CAR T-cells to control solid tumors has long been envisaged as one of the most difficult therapeutic tasks. The first two clinical trials conducted in sarcoma and neuroblastoma patients showed clinical benefits of CAR T-cells, yet multiple obstacles still hold us back from having accessible and efficient therapy. Why did such an effective treatment for relapsed and refractory hematological malignancies demonstrate only relatively modest efficiency in the context of solid tumors? Is it due to the lucky selection of the “magic” CD19 antigen, which might be one of a kind? Or do lymphomas lack the immunosuppressive features of solid tumors? Here we review the existing knowledge in the field of CAR T-cell therapy and address the heterogeneity of solid tumors and their diverse strategies of immunoevasion. We also provide an insight into prospective developments of CAR T-cell technologies against solid tumors.

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Adoptitive immunotherapy with genetically engineered T lymphocytes modified to express chimeric antigen receptors

Cited by 11 publications

References 77 publications

Manufacturing of CD19 Specific CAR T-Cells and Evaluation of their Functional Activity in Vitro

Manufacturing of CD19 Specific CAR T-Cells and Evaluation of their Functional Activity in Vitro

The latest trends in improving CAR-T cell therapy: from leukemia to solid malignant tumors

Advancing CAR T-Cell Therapy for Solid Tumors: Lessons Learned from Lymphoma Treatment

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