Dual-targeting CAR-T cells with optimal co-stimulation and metabolic fitness enhance antitumor activity and prevent escape in solid tumors

Hirabayashi, Koichi; Du, Hongwei; Xu, Yingxin; Shou, Peishun; Zhou, Xin; Fucà, Giovanni; Landoni, Elisa; Sun, Chuang; Chen, Yuhui; Savoldo, Barbara; Dotti, Gianpietro

doi:10.1038/s43018-021-00244-2

Cited by 79 publications

(72 citation statements)

References 48 publications

(66 reference statements)

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“…Furthermore, we recently reported in a model of neuroblastoma that tumor escape can occur when tumor cells express low levels of GD2. 36 Recent efforts have been directed into exploring pharmaceutical strategies to increase antigen expression. 37 For example, in neuroblastoma GD2, although uniformly expressed, can be further upregulated in vitro in the presence of the HDAC inhibitor vorinostat.…”

Section: Discussionmentioning

confidence: 99%

Targeting disialoganglioside GD2 with chimeric antigen receptor-redirected T cells in lung cancer

Reppel

Tsahouridis

Akulian

et al. 2022

J Immunother Cancer

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BackgroundWe explored whether the disialoganglioside GD2 (GD2) is expressed in small cell lung cancer (SCLC) and non-SCLC (NSCLC) and can be targeted by GD2-specific chimeric antigen receptor (CAR) T cells.MethodsGD2 expression was evaluated in tumor cell lines and tumor biopsies by flow cytometry and immunohistochemistry. We used a GD2.CAR that coexpress the IL-15 to promote T-cell proliferation and persistence, and the inducible caspase 9 gene safety switch to ablate GD2.CAR-T cells in case of unforeseen toxicity. The antitumor activity of GD2.CAR-T cells was evaluated using in vitro cocultures and in xenograft models of orthotopic and metastatic tumors. The modulation of the GD2 expression in tumor cell lines in response to an epigenetic drug was also evaluated.ResultsGD2 was expressed on the cell surface of four of fifteen SCLC and NSCLC cell lines (26.7%) tested by flow cytometry, and in 39% of SCLC, 72% of lung adenocarcinoma and 56% of squamous cell carcinoma analyzed by immunohistochemistry. GD2 expression by flow cytometry was also found on the cell surface of tumor cells freshly isolated from tumor biopsies. GD2.CAR-T cells exhibited antigen-dependent cytotoxicity in vitro and in vivo in xenograft models of GD2-expressing lung tumors. Finally, to explore the applicability of this approach to antigen low expressing tumors, we showed that pretreatment of GD2low/neg lung cancer cell lines with the Enhancer of zeste homolog 2 inhibitor tazemetostat upregulated GD2 expression at sufficient levels to trigger GD2.CAR-T cell cytotoxic activity.ConclusionsGD2 is a promising target for CAR-T cell therapy in lung cancer. Tazemetostat treatment could be used to upregulate GD2 expression in tumor cells, enhancing their susceptibility to CAR-T cell targeting.

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Section: Discussionmentioning

confidence: 99%

Targeting disialoganglioside GD2 with chimeric antigen receptor-redirected T cells in lung cancer

Reppel

Tsahouridis

Akulian

et al. 2022

J Immunother Cancer

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“…In addition, ECAR measures the rate of extracellular acidification, which mainly comes from the accumulation of lactic acid in the medium (glycolytic pathway) [64]. Among the studies reported, some used the Seahorse technology to explore the influence of CAR signaling tails (4-1BB vs. CD28) [49,65], while others focused on comparing CARs with either different designs or targets [52,[66][67][68][69], the additional secretory functions [53,70], the combination with PD-1/PD-L1 blockage [71], the polarization of the T cells [53,72], or the influence of co-expressing enzymes alongside the CARs in T cells [73,74]. The second injection of Oligomycin, an ATP synthase inhibitor, permits, through the measurement of ECAR, assessment of the maximum glycolytic capacity.…”

Section: Study Of Metabolism In Car T Cellsmentioning

confidence: 99%

How CAR T Cells Breathe

Forcados

Joaquina

Casey

et al. 2022

Cells

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The manufacture of efficacious CAR T cells represents a major challenge in cellular therapy. An important aspect of their quality concerns energy production and consumption, known as metabolism. T cells tend to adopt diverse metabolic profiles depending on their differentiation state and their stimulation level. It is therefore expected that the introduction of a synthetic molecule such as CAR, activating endogenous signaling pathways, will affect metabolism. In addition, upon patient treatment, the tumor microenvironment might influence the CAR T cell metabolism by compromising the energy resources. The access to novel technology with higher throughput and reduced cost has led to an increased interest in studying metabolism. Indeed, methods to quantify glycolysis and mitochondrial respiration have been available for decades but were rarely applied in the context of CAR T cell therapy before the release of the Seahorse XF apparatus. The present review will focus on the use of this instrument in the context of studies describing the impact of CAR on T cell metabolism and the strategies to render of CAR T cells more metabolically fit.

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“…The balance between the anti-tumor functions of CAR-engineering cells and safety is under active study ( 56 ). Of note, our results have distinguished that B7-H3, also known as CD276, might be a promising therapeutic target for CAR-based therapy, and there is evidence that it carries no risk of on-target off-tumor toxicity ( 57 , 58 ). Recently, our research team also found that SAHA, a pan histone deacetylase inhibitor, could enhance B7-H3.CAR-T cells in solid tumors ( 59 ).…”

Section: Discussionmentioning

confidence: 66%

Bibliometric Analysis of Chimeric Antigen Receptor-Based Immunotherapy in Cancers From 2001 to 2021

Qiu

Rong

et al. 2022

Front. Immunol.

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BackgroundChimeric antigen receptor (CAR)-based immunotherapy has shown great potential for the treatment of both hematopoietic malignancies and solid tumors. Nevertheless, multiple obstacles still block the development of CAR-based immunotherapy in the clinical setting. In this study, we aimed to summarize the research landscape and highlight the front lines and trends of this field.MethodsLiterature published from 2001 to 2021 was searched in the Web of Science Core Collection database. Full records and cited references of all the documents were extracted and screened. Bibliometric analysis and visualization were conducted using CiteSpace, Microsoft Excel 2019, VOSviewer and R software.ResultsA total of 5981 articles and reviews were included. The publication and citation results exhibited increasing trends in the last 20 years. Frontiers in Immunology and Blood were the most productive and most co-cited journals, respectively. The United States was the country with the most productive organizations and publications in the comprehensive worldwide cooperation network, followed by China and Germany. June, C.H. published the most papers with the most citations, while Maude, S.L. ranked first among the co-cited authors. The hotspots in CAR-based therapy research were multiple myeloma, safety and toxicity, solid tumors, CAR-engineered immune cells beyond T cells, and gene editing.ConclusionCAR-based immunotherapy is a promising treatment for cancer patients, and there is an emerging movement toward using advanced gene modification technologies to overcome therapeutic challenges, especially in solid tumors, and to generate safer and more effective universal CAR-engineered cell products.

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Dual-targeting CAR-T cells with optimal co-stimulation and metabolic fitness enhance antitumor activity and prevent escape in solid tumors

Cited by 79 publications

References 48 publications

Targeting disialoganglioside GD2 with chimeric antigen receptor-redirected T cells in lung cancer

Targeting disialoganglioside GD2 with chimeric antigen receptor-redirected T cells in lung cancer

How CAR T Cells Breathe

Bibliometric Analysis of Chimeric Antigen Receptor-Based Immunotherapy in Cancers From 2001 to 2021

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