CAR-T cells secreting BiTEs circumvent antigen escape without detectable toxicity

Choi, Bryan D.; Yu, Xiaoling; Castaño, Ana P.; Bouffard, Amanda A.; Schmidts, Andrea; Larson, Rebecca C.; Bailey, Stefanie R.; Boroughs, Angela C.; Frigault, Matthew J.; Leick, Mark B.; Scarfò, Irene; Cetrulo, Curtis L.; Demehri, Shadmehr; Nahed, Brian V.; Cahill, Daniel P.; Wakimoto, Hiroaki; Curry, William T.; Carter, Bob S.; Maus, Marcela V.

doi:10.1038/s41587-019-0192-1

Cited by 418 publications

(311 citation statements)

References 33 publications

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“…It has been previously reported that the RTCA system utilizes cellular impedance readouts to monitor real-time changes in cell number, cell size, and cell-substrate attachment strength, which are together represented by a parameter called the cell index (CI) that reflects the cell number of target cancer cells. Importantly, the RTCA data have been found to be comparable with the data from cytotoxicity assays including the Cr 51 -release assay [34][35][36][37]. U-251MG and Ev-DKMG cells were seeded and cultured for 1 day, and then, T cells, EvCAR-T cells, and PD-1-disrupted EvCAR-T cells cultured for 14 days were added to the wells at an effector-to-target ratio of 0.3:1.…”

Section: Expression Of Pd-1 In Pd-1-disrupted Evcar-t Cells and Theirmentioning

confidence: 63%

Effect of CRISPR/Cas9-Mediated PD-1-Disrupted Primary Human Third-Generation CAR-T Cells Targeting EGFRvIII on In Vitro Human Glioblastoma Cell Growth

Nakazawa

Natsume

Nishimura

et al. 2020

Cells

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Glioblastoma (GBM), which is the most common malignant brain tumor, is resistant to standard treatments. Immunotherapy might be a promising alternative for the treatment of this cancer. Chimeric antigen receptor (CAR) is an artificially modified fusion protein that can be engineered to direct the specificity and function of T cells against tumor antigens. However, the antitumor effects of EGFRvIII-targeting CAR-T (EvCAR-T) cells in GBM are limited. The inhibitory effect is induced by the interaction between programmed cell death protein 1 (PD-1) on activated EvCAR-T cells and its ligands on GBM cells. In the present study, PD-1-disrupted EvCAR-T cells were established using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9). The sgRNA/Cas9 expression vectors designed precisely disrupted the target region of PD-1 and inhibited the expression of PD-1 in EvCAR-T cells. The PD-1-disrupted EvCAR-T cells had an in vitro growth inhibitory effect on EGFRvIII-expressing GBM cells without altering the T-cell phenotype and the expression of other checkpoint receptors. In the future, the in vivo antitumor effect of this vector should be evaluated in order to determine if it could be applied clinically for improving the efficacy of EvCAR-T cell-based adoptive immunotherapy for GBM.

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Section: Expression Of Pd-1 In Pd-1-disrupted Evcar-t Cells and Theirmentioning

confidence: 63%

Effect of CRISPR/Cas9-Mediated PD-1-Disrupted Primary Human Third-Generation CAR-T Cells Targeting EGFRvIII on In Vitro Human Glioblastoma Cell Growth

Nakazawa

Natsume

Nishimura

et al. 2020

Cells

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“…The fact that activated T cells are capable of entering the brain across the BBB [ 145 ] has originated several approaches related to T-cell function including the use of vaccines, adoptive cell transfer (ACT), and immune checkpoint inhibitors [ 144 ]. Chimeric antigen receptor (CAR)-T-cell (CART) therapy is the most recent immune-based strategy to treat cancer, and it has presented promising results in malignant glioma models [ 146 , 147 ] and in patients with recurrent GBM [ 148 ]. However, most studies show that, despite being well tolerated, immunotherapy failed to prolong GBM patient survival [ 149 ], perhaps because it focused on T-cells, which are sparse in GBM [ 150 , 151 , 152 ].…”

Section: Malignant Gliomas a Therapeutic Challengementioning

confidence: 99%

Take Advantage of Glutamine Anaplerosis, the Kernel of the Metabolic Rewiring in Malignant Gliomas

et al. 2020

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Glutamine is a non-essential amino acid that plays a key role in the metabolism of proliferating cells including neoplastic cells. In the central nervous system (CNS), glutamine metabolism is particularly relevant, because the glutamine-glutamate cycle is a way of controlling the production of glutamate-derived neurotransmitters by tightly regulating the bioavailability of the amino acids in a neuron-astrocyte metabolic symbiosis-dependent manner. Glutamine-related metabolic adjustments have been reported in several CNS malignancies including malignant gliomas that are considered ‘glutamine addicted’. In these tumors, glutamine becomes an essential amino acid preferentially used in energy and biomass production including glutathione (GSH) generation, which is crucial in oxidative stress control. Therefore, in this review, we will highlight the metabolic remodeling that gliomas undergo, focusing on glutamine metabolism. We will address some therapeutic regimens including novel research attempts to target glutamine metabolism and a brief update of diagnosis strategies that take advantage of this altered profile. A better understanding of malignant glioma cell metabolism will help in the identification of new molecular targets and the design of new therapies.

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“…Co-expression of the IL-8 receptor, CXCR1/CXCR2, was found to enhance CAR-T cells trafficking and persistence in the tumor in a glioma mouse model ( 83 ). Engineering EGFRvIII-CAR-T cells to co-express a bispecific T-cell engager (BiTE) against wild-type EGFR was demonstrated to ameliorate this therapy by countering the heterogeneity of EGFRvIII expression ( 84 ). A CAR-engineered NK cell targeting both WT EGFR and EGFRvIII mutant, NK-92-EGFR-CAR, was similarly efficient in targeting and killing GBM cells in mice engrafted with patients' mesenchymal GBM stem cells ( 85 ).…”

Section: The Future Of Immunotherapies In Gbmmentioning

confidence: 99%

Glioblastoma Immune Landscape and the Potential of New Immunotherapies

et al. 2020

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Glioblastoma (GBM) are the most common tumors of the central nervous system and among the deadliest cancers in adults. GBM overall survival has not improved over the last decade despite optimization of therapeutic standard-of-care. While immune checkpoint inhibitors (ICI) have revolutionized cancer care, they unfortunately have little therapeutic success in GBM. Here, we elaborate on normal brain and GBM-associated immune landscapes. We describe the role of microglia and tumor-associated macrophages (TAMs) in immune suppression and highlight the impact of energy metabolism in immune evasion. We also describe the challenges and opportunities of immunotherapies in GBM and discuss new avenues based on harnessing the anti-tumor activity of myeloid cells, vaccines, chimeric antigen receptors (CAR)-T and -NK cells, oncolytic viruses, nanocarriers, and combination therapies.

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CAR-T cells secreting BiTEs circumvent antigen escape without detectable toxicity

Cited by 418 publications

References 33 publications

Effect of CRISPR/Cas9-Mediated PD-1-Disrupted Primary Human Third-Generation CAR-T Cells Targeting EGFRvIII on In Vitro Human Glioblastoma Cell Growth

Effect of CRISPR/Cas9-Mediated PD-1-Disrupted Primary Human Third-Generation CAR-T Cells Targeting EGFRvIII on In Vitro Human Glioblastoma Cell Growth

Take Advantage of Glutamine Anaplerosis, the Kernel of the Metabolic Rewiring in Malignant Gliomas

Glioblastoma Immune Landscape and the Potential of New Immunotherapies

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