The Principles of Engineering Immune Cells to Treat Cancer

Lim, Wendell A.; June, Carl H.

doi:10.1016/j.cell.2017.01.016

Cited by 904 publications

(823 citation statements)

References 149 publications

(162 reference statements)

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“…Possibly, this reflects, (1) the high sensitivity of several hematological tumors to standard-of-care treatments, and/or (2) the fact that hematological malignancies often stem from components of the immune system, resulting in compromised immune functions and limited susceptibility to multiple forms of immunotherapy and immunogenic chemotherapy. 279,280 In multiple clinical studies, bona fide ICD-inducing chemotherapeutic regimens are combined with agents that elicit ICD per se, such as radiation therapy (2 trials), or considerably boost the immunogenicity of cancer cells, such as taxanes or zoledronic acid (10 trials). Finally, in a limited amount of trials, ICD inducers are combined with targeted anticancer agents, including the inhibitor of JAK kinases ruxolitinib (1 trial) and the inhibitor of mechanistic target of rapamycin kinase (MTOR) rapamycin 281,282 (also known as sirolimus, or its derivative everolimus) (2 trials) ( Tables 1 and 2).…”

Section: Ongoing Clinical Trialsmentioning

confidence: 99%

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics

et al. 2017

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The expression "immunogenic cell death" (ICD) refers to a functionally unique form of cell death that facilitates (instead of suppressing) a T cell-dependent immune response specific for dead cell-derived antigens. ICD critically relies on the activation of adaptive responses in dying cells, culminating with the exposure or secretion of immunostimulatory molecules commonly referred to as "damage-associated molecular patterns". Only a few agents can elicit bona fide ICD, including some clinically established chemotherapeutics such as doxorubicin, epirubicin, idarubicin, mitoxantrone, bleomycin, bortezomib, cyclophosphamide and oxaliplatin. In this Trial Watch, we discuss recent progress on the development of ICD-inducing chemotherapeutic regimens, focusing on studies that evaluate clinical efficacy in conjunction with immunological biomarkers.

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Section: Ongoing Clinical Trialsmentioning

confidence: 99%

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics

et al. 2017

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“…Этот вид лечения совмещает в себе технологии клеточной терапии и генной инженерии [6]. Адоптивная клеточная терапия основана на введении в организм пациента аутологичных или аллогенных Т-лимфоцитов, ко-торые подверглись ex vivo генетической модификации и экспрессируют на своей поверхности химерный антигенный рецептор (Chimeric Antigen Receptor, CAR) [7,8], способный узнавать опухолевые антигены и связываться с ними. При В-клеточных лимфопро-лиферативных новообразованиях CAR могут быть нацелены на связывание с маркером нормальных и трансформированных B-клеток -поверхностным антигеном CD19 [9].…”

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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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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“…Furthermore, the success of CD19 CAR-T cell treatment depends on its functionality and persistence. However, current T cell therapies had a limited clinical response in solid tumors [83]. Therefore, there are emerging challenges in the field of T cell-based immunotherapy for solid tumors: (1) how can we expand less-differentiated engineered T cell subsets in vitro; and (2) [84].…”

Section: Integrating Mirnas Into the Design Of Future Immunotherapeutmentioning

confidence: 99%

Regulation of Memory CD8+ T Cell Differentiation by MicroRNAs

Zhang

et al. 2018

Cell Physiol Biochem

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MicroRNAs (miRNAs) have emerged as crucial regulators of T lymphocyte survival, differentiation and function, all of which are key factors impacting the outcome of adoptive T cell-based immunotherapy. It has become increasingly clear that the adoptive transfer of memory CD8⁺ T cell subsets is highly correlated with objective clinical responses for patients with advanced cancer. However, it is unclear how to improve the long-term persistence of transferred CD8⁺ T cells using miRNAs. Here, we highlight the current advances in our understanding of the role of miRNAs in regulating the differentiation of memory CD8⁺ T cells. We specifically discuss the effect of miRNAs on key transcription factors, immune checkpoints and signal pathways, which contribute to the differentiation of effector and memory T cell subsets. Ultimately, miRNAs may be easily integrated into existing T cell receptor (TCR) and chimeric antigen receptor (CAR) platforms to promote adoptive T cell therapy with multiple advantages. Thus, combining T cell-based therapy with miRNAs could be considered a promising and robust strategy for cancer treatment.

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The Principles of Engineering Immune Cells to Treat Cancer

Cited by 904 publications

References 149 publications

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics

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

Regulation of Memory CD8+ T Cell Differentiation by MicroRNAs

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