Engineered triple inhibitory receptor resistance improves anti-tumor CAR-T cell performance via CD56

Zou, Fan; Lu, Lijuan; Li, Jun; Xia, Baijin; Zhang, Wanying; Hu, Qifei; Liu, Weiwei; Zhang, Yiwen; Lin, Yingtong; Jing, Shuliang; Huang, Mei; Huang, Bifen; Liu, Bingfeng; Zhang, Hui

doi:10.1038/s41467-019-11893-4

Cited by 90 publications

(82 citation statements)

References 61 publications

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“…They were able to show that knock down of all three inhibitory receptors led to the highest cytotoxicity and IFNγ production compared to CAR-T cells with knockdown of one of the receptors or no knockdown. Furthermore, they were able to show that the triple knockdown CAR-T cells up-regulated CD56, which correlated with enhanced infiltration of the CAR-T cells into the tumor tissue [99].…”

Section: Inhibiting Checkpoint Signaling In the Car-t Cellmentioning

confidence: 94%

Combination Strategies for Immune-Checkpoint Blockade and Response Prediction by Artificial Intelligence

Huemer

Leisch

Geisberger³

et al. 2020

IJMS

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The therapeutic concept of unleashing a pre-existing immune response against the tumor by the application of immune-checkpoint inhibitors (ICI) has resulted in long-term survival in advanced cancer patient subgroups. However, the majority of patients do not benefit from single-agent ICI and therefore new combination strategies are eagerly necessitated. In addition to conventional chemotherapy, kinase inhibitors as well as tumor-specific vaccinations are extensively investigated in combination with ICI to augment therapy responses. An unprecedented clinical outcome with chimeric antigen receptor (CAR-)T cell therapy has led to the approval for relapsed/refractory diffuse large B cell lymphoma and B cell acute lymphoblastic leukemia whereas response rates in solid tumors are unsatisfactory. Immune-checkpoints negatively impact CAR-T cell therapy in hematologic and solid malignancies and as a consequence provide a therapeutic target to overcome resistance. Established biomarkers such as programmed death ligand 1 (PD-L1) and tumor mutational burden (TMB) help to select patients who will benefit most from ICI, however, biomarker negativity does not exclude responses. Investigating alterations in the antigen presenting pathway as well as radiomics have the potential to determine tumor immunogenicity and response to ICI. Within this review we summarize the literature about specific combination partners for ICI and the applicability of artificial intelligence to predict ICI therapy responses.

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Section: Inhibiting Checkpoint Signaling In the Car-t Cellmentioning

confidence: 94%

Combination Strategies for Immune-Checkpoint Blockade and Response Prediction by Artificial Intelligence

Huemer

Leisch

Geisberger³

et al. 2020

IJMS

View full text Add to dashboard Cite

show abstract

“…Blockade of PD-1 in combination with other immune checkpoint receptors, including TIM-3 and LAG-3, has strong synergistic effects, and boosts effector functions of CAR T cells [35,36]. The high efficacy of this combinatorial approach suggests that TIM-3 and LAG-3 pathways have non-redundant effects that synergize with PD-1 signaling to dampen antitumor responses in dysfunctional CAR T cells.…”

Section: Tim-3 and Lag-3mentioning

confidence: 99%

Counteracting CAR T cell dysfunction

et al. 2021

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In spite of high rates of complete remission following chimeric antigen receptor (CAR) T cell therapy, the efficacy of this approach is limited by generation of dysfunctional CAR T cells in vivo, conceivably induced by immunosuppressive tumor microenvironment (TME) and excessive antigen exposure. Exhaustion and senescence are two critical dysfunctional states that impose a pivotal hurdle for successful CAR T cell therapies. Recently, modified CAR T cells with an “exhaustion-resistant” phenotype have shown superior antitumor functions and prolonged lifespan. In addition, several studies have indicated the feasibility of senescence delay in CAR T cells. Here, we review the latest reports regarding blockade of CAR T cell exhaustion and senescence with a particular focus on the exhaustion-inducing pathways. Subsequently, we describe what potential these latest insights offer for boosting the potency of adoptive cell transfer (ACT) therapies involving CAR T cells. Furthermore, we discuss how induction of costimulation, cytokine exposure, and TME modulation can impact on CAR T cell efficacy and persistence, while potential safety issues associated with reinvigorated CAR T cells will also be addressed.

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“…Hamieh et al ( 71 ) found that the CD19 antigen is transferred to CAR T-cells from malignant cells by trogocytosis, which not only leads to escape of the CD19 antigen, but also causes CAR T cells to kill each other and accelerates the depletion of T cells. To weaken mutual killing, CAR T cells gradually express and activate T cell-inhibiting molecules such as programmed cell death protein-1, lymphocyte activation gene-3, and T-cell immunoglobulin and mucin domain 3, leading to the immune escape of tumors ( 71 – 73 ). Similar experiments performed on CD22-CAR T cells, co-cultured with various cell lines such as SUP-B15 and Raji, and primary tumor cells from patients, also showed similar results that is CAR-induced trogocytosis was observed ( 71 , 74 , 75 ).…”

Section: Recurrence After Car T-cell Therapymentioning

confidence: 99%

Cluster of differentiation 19 chimeric antigen receptor T‑cell therapy in pediatric acute lymphoblastic leukemia (Review)

Zhou

Chen

et al. 2020

Oncol Lett

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Chimeric antigen receptor (CAR) T cells have an unprecedented positive curative effect for hematological malignances. Most notably, cluster of differentiation 19 (CD19) CAR T-cell therapy for pediatric acute lymphoblastic leukemia is associated with a high complete remission rate and has aroused considerable attention in the medical field. However, it also causes a series of adverse reactions and increases the risk of recurrence. The present review examines the results of CD19 CAR T-cell therapy and lists its adverse effects. In addition, some of the mechanisms of recurrence are characterized and applicable strategies to address this challenging problem are proposed.

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Engineered triple inhibitory receptor resistance improves anti-tumor CAR-T cell performance via CD56

Cited by 90 publications

References 61 publications

Combination Strategies for Immune-Checkpoint Blockade and Response Prediction by Artificial Intelligence

Combination Strategies for Immune-Checkpoint Blockade and Response Prediction by Artificial Intelligence

Counteracting CAR T cell dysfunction

Cluster of differentiation 19 chimeric antigen receptor T‑cell therapy in pediatric acute lymphoblastic leukemia (Review)

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