Incorporation of functional elements enhances the antitumor capacity of CAR T cells

Qin, Le; Zhao, Ruocong; Li, Peng

doi:10.1186/s40164-017-0088-z

Cited by 24 publications

(17 citation statements)

References 27 publications

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“…Notably, 1928zT2 T cells used in this study were incorporated with TLR2 domain, which showed improved anti-leukemia efficacy of CARs [ 12 , 22 ]. These 1928zT2 T cells not only could eradicate the CD19-expressing NALM6 cells and K562 cells specifically and potently in vitro, they could significantly promote the remission of NALM-6 subcutaneous tumors ex vivo, indicating the TLR2 incorporation enhanced the anti-leukemia effects of CAR T cells.…”

Section: Discussionmentioning

confidence: 99%

A novel generation 1928zT2 CAR T cells induce remission in extramedullary relapse of acute lymphoblastic leukemia

et al. 2018

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BackgroundAnti-CD19 chimeric antigen receptor (CAR) T cells have shown promise in the treatment of B cell acute lymphocytic leukemia (B-ALL). However, its efficacy in B-ALL patients with extramedullary involvement is limited due to poor responses and neurotoxicity. Here, we utilized a third generation of CAR T cell vector, which contains the Toll/interleukin-1 receptor (ITR) domain of Toll-like receptor 2 (TLR2), to generate 1928zT2 T cells targeting CD19, and evaluated the efficacy of 1928zT2 T cells in relapse or refractory B-ALL patients with extramedullary involvement.Methods1928zT2 T cells were generated by 19-28z-TLR2 lentiviral vector transfection into primary human T lymphocytes. The anti-leukemia effect of 1928zT2 T cells were determined by killing assays and in xenografts. Three patients diagnosed as relapse or refractory ALL with extramedullary involvement were infused with 1928zT2 T cells, and the clinical responses were evaluated by BM smear, B-ultrasonography, PET/CT, histology, flow cytometry, qPCR, ELISA, and luminex assay.Results1928zT2 T cells exhibited enhanced effector function against CD19+ leukemic cells in vitro and in a xenograft model of human extramedullary leukemia. Notably, the 1928zT2 T cells eradicated extramedullary leukemia and induced complete remission in the three relapse and refractory ALL patients without serious adverse effects. 1928zT2 T cells expanded robustly in the circulation of these three patients and were detected in the cerebrospinal fluid of patient 3. These three patients experienced cytokine release syndrome (CRS) with grade 2 or 3, which remitted spontaneously or after tocilizumab treatment. None of the three patients suffered neurotoxicity or needed further intensive care.ConclusionsOur results demonstrate that 1928zT2 T cells with TLR2 incorporation augment anti-leukemic effects, particularly for eradicating extramedullary leukemia cells, and suggest that the infusion of 1928zT2 T cells is an encouraging treatment for relapsed/refractory ALL patients with extramedullary involvement.Trial registrationClinicalTrials.gov identifier NCT02822326. Date of registration: July 4, 2016.

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Section: Discussionmentioning

confidence: 99%

A novel generation 1928zT2 CAR T cells induce remission in extramedullary relapse of acute lymphoblastic leukemia

et al. 2018

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“…CAR-T and TCR-T cell therapy makes use of functionally active T cells isolated from patients. These T cells are reconstructed and expanded ex vivo to recognize specific antigens on target cells and are now widely trialed to treat leukemia, lymphoma, and several solid tumors [ 52 – 58 ]. However, there are functional challenges of engineered T cell therapy in regard to T cell senescence and exhaustion.…”

Section: Introductionmentioning

confidence: 99%

T cell senescence and CAR-T cell exhaustion in hematological malignancies

2018

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T cell senescence has been recognized to play an immunosuppressive role in the aging population and cancer patients. Strategies dedicated to preventing or reversing replicative and premature T cell senescence are required to increase the lifespan of human beings and to reduce the morbidity from cancer. In addition, overcoming the T cell terminal differentiation or senescence from lymphoma and leukemia patients is a promising approach to enhance the effectiveness of adoptive cellular immunotherapy (ACT). Chimeric antigen receptor T (CAR-T) cell and T cell receptor-engineered T (TCR-T) cell therapy highly rely on functionally active T cells. However, the mechanisms which drive T cell senescence remain unclear and controversial. In this review, we describe recent progress for restoration of T cell homeostasis from age-related senescence as well as recovery of T cell activation in hematological malignancies.

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“…CAR T cells are produced by inserting specific CAR genes via viral vectors into autologous or allogeneic T cells [ 42 ]. New-generation CARs have two or more co-stimulatory domains (e.g., 4-1BB, OX 40) that boost the stimulatory signal [ 43 , 44 ]. Anti-CD19 CAR T cells were recently FDA-approved for B-ALL in pediatric and young adult population [ 45 ].…”

Section: Chimeric Antigen Receptor (Car) T Cellsmentioning

confidence: 99%

Cancer immunotherapy beyond immune checkpoint inhibitors

et al. 2018

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Malignant cells have the capacity to rapidly grow exponentially and spread in part by suppressing, evading, and exploiting the host immune system. Immunotherapy is a form of oncologic treatment directed towards enhancing the host immune system against cancer. In recent years, manipulation of immune checkpoints or pathways has emerged as an important and effective form of immunotherapy. Agents that target cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1 (PD-L1) are the most widely studied and recognized. Immunotherapy, however, extends beyond immune checkpoint therapy by using new molecules such as chimeric monoclonal antibodies and antibody drug conjugates that target malignant cells and promote their destruction. Genetically modified T cells expressing chimeric antigen receptors are able to recognize specific antigens on cancer cells and subsequently activate the immune system. Native or genetically modified viruses with oncolytic activity are of great interest as, besides destroying malignant cells, they can increase anti-tumor activity in response to the release of new antigens and danger signals as a result of infection and tumor cell lysis. Vaccines are also being explored, either in the form of autologous or allogenic tumor peptide antigens, genetically modified dendritic cells that express tumor peptides, or even in the use of RNA, DNA, bacteria, or virus as vectors of specific tumor markers. Most of these agents are yet under development, but they promise to be important options to boost the host immune system to control and eliminate malignancy. In this review, we have provided detailed discussion of different forms of immunotherapy agents other than checkpoint-modifying drugs. The specific focus of this manuscript is to include first-in-human phase I and phase I/II clinical trials intended to allow the identification of those drugs that most likely will continue to develop and possibly join the immunotherapeutic arsenal in a near future.

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Incorporation of functional elements enhances the antitumor capacity of CAR T cells

Cited by 24 publications

References 27 publications

A novel generation 1928zT2 CAR T cells induce remission in extramedullary relapse of acute lymphoblastic leukemia

A novel generation 1928zT2 CAR T cells induce remission in extramedullary relapse of acute lymphoblastic leukemia

T cell senescence and CAR-T cell exhaustion in hematological malignancies

Cancer immunotherapy beyond immune checkpoint inhibitors

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