Prospects for chimeric antigen receptor-modified T cell therapy for solid tumors

Zhang, Erhao; Gu, Jieyi; Xu, Hong‐Xi

doi:10.1186/s12943-018-0759-3

Cited by 69 publications

(58 citation statements)

References 141 publications

(124 reference statements)

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“…Moreover, MDSCs have the ability to release important cytokines, to name a few, the TGF-β and IL10, among others, inside solid tumors, acting as immunosuppressants and promoting tumor growth. In this sense, inhibiting MDSCs function has been shown to promote antitumor immune responses ( Zhang et al, 2018 ).…”

Section: Microglia and Astrocytes’ Role In Glioblastoma Malignancymentioning

confidence: 99%

Microglia/Astrocytes–Glioblastoma Crosstalk: Crucial Molecular Mechanisms and Microenvironmental Factors

Matias

Balça-Silva

Graça

et al. 2018

Front. Cell. Neurosci.

130

120

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In recent years, the functions of glial cells, namely, astrocytes and microglia, have gained prominence in several diseases of the central nervous system, especially in glioblastoma (GB), the most malignant primary brain tumor that leads to poor clinical outcomes. Studies showed that microglial cells or astrocytes play a critical role in promoting GB growth. Based on the recent findings, the complex network of the interaction between microglial/astrocytes cells and GB may constitute a potential therapeutic target to overcome tumor malignancy. In the present review, we summarize the most important mechanisms and functions of the molecular factors involved in the microglia or astrocytes–GB interactions, which is particularly the alterations that occur in the cell’s extracellular matrix and the cytoskeleton. We overview the cytokines, chemokines, neurotrophic, morphogenic, metabolic factors, and non-coding RNAs actions crucial to these interactions. We have also discussed the most recent studies regarding the mechanisms of transportation and communication between microglial/astrocytes – GB cells, namely through the ABC transporters or by extracellular vesicles. Lastly, we highlight the therapeutic challenges and improvements regarding the crosstalk between these glial cells and GB.

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Section: Microglia and Astrocytes’ Role In Glioblastoma Malignancymentioning

confidence: 99%

Microglia/Astrocytes–Glioblastoma Crosstalk: Crucial Molecular Mechanisms and Microenvironmental Factors

Matias

Balça-Silva

Graça

et al. 2018

Front. Cell. Neurosci.

130

120

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“…We envision that our sdCAR structure combined with a bifunctional molecule can achieve positive responses against solid tumors in spite of the blunt immune-surveillance, including some immune suppressor cells, cytokines, and physical barriers around tumor tissues [ 32 – 34 ]. In our opinion, the bifunctional molecule containing both a targeted part specific for sdCAR-T cells and an active part with the ability to improve the tumor microenvironment serves as a “switch” to control the state of sdCAR-T cells and a “scavenger” that clears immunosuppressive factors or physical barriers around tumor tissues (Fig.…”

Section: Discussionmentioning

confidence: 99%

Accurate control of dual-receptor-engineered T cell activity through a bifunctional anti-angiogenic peptide

Zhang

Xue

et al. 2018

J Hematol Oncol

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BackgroundChimeric antigen receptors (CARs) presented on T cell surfaces enable redirection of T cell specificity, which has enormous promise in antitumor therapy. However, excessive activity and poor control over such engineered T cells cause significant safety challenges, such as cytokine release syndrome and organ toxicities. To enhance the specificity and controllable activity of CAR-T cells, we report a novel switchable dual-receptor CAR-engineered T (sdCAR-T) cell and a new switch molecule of FITC-HM-3 bifunctional molecule (FHBM) in this study.MethodsWe designed a fusion molecule comprising FITC and HM-3. HM-3, an antitumor peptide including an Arg-Gly-Asp sequence, can specifically target integrin αvβ3 that is presented on some tumor cells. Moreover, to improve the specificity of CAR-T cells, we also generated the sdCAR-T cell line against cognate tumor cells expressing human mesothelin (MSLN) and integrin αvβ3. Finally, the activity of sdCAR-T cell and FHBM is verified via in vitro and in vivo experiments.ResultsIn the presence of FHBM, the designed sdCAR-T cells exerted high activity including activation and proliferation and had specific cytotoxicity in a time- and dose-dependent manner in vitro. Furthermore, using a combination of FHBM in nude mice, sdCAR-T cells significantly inhibited the growth of MSLN+ K562 cells and released lower levels of the cytokines (e.g., interleukin-2, interferon γ, interleukin-6, and tumor necrosis factor α) relative to conventional CAR-T cells, obtaining specific, controllable, and enhanced cytotoxicity.ConclusionsOur data indicate that FHBM can accurately control timing and dose of injected CAR-T cells, and sdCAR-T cells exert significant antitumor activity while releasing lower levels of cytokines for the cognate tumor cells expressing both MSLN and integrin αvβ3. Therefore, combination therapies using sdCAR-T cells and the switch molecule FHBM have significant potential to treat malignancies.Electronic supplementary materialThe online version of this article (10.1186/s13045-018-0591-7) contains supplementary material, which is available to authorized users.

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“…Mesothelin-targeted CAR-T cells have been reported in mesothelioma, lung cancer, breast cancer, gastric cancer and pancreatic cancer [77,78]. EGFR, HER2, and claudin18.2 are favorite targets for solid tumor immunotherapy including CAR-T and MoAbs [79][80][81][82]. T cell receptorengineered T cells against AFP and MAGE-A1 have been reported for immunotherapy of solid tumors [83][84][85][86][87][88].…”

Section: B Cell Maturation Antigen (Bcma) -Targeted Multiple Myelomamentioning

confidence: 99%

Cancer biomarkers for targeted therapy

Liu

2019

Biomark Res

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Tumor-associated antigens (TAA) or cancer biomarkers are major targets for cancer therapies. Antibody-based agents targeting the cancer biomarkers include monoclonal antibodies (MoAbs), radiolabeled MoAbs, bispecific T cell engagers, and antibody-drug conjugates. Antibodies targeting CD19, CD20, CD22, CD30, CD33, CD38, CD79B and SLAMF7 are in clinical applications for hematological malignancies. CD123, CLL-1, B cell maturation antigen, and CD138 are targets for cancer immunotherapeutic agents, including the chimeric antigen receptor-engineered T cells. Immune checkpoint inhibitors (ICIs) against PD-1, PD-L1, and CTLA-4 have led to the revolution of cancer immunotherapy. More ICIs targeting IDO, LAG3, TIM-3, TIGIT, SIGLECs, VISTA and CD47 are being explored. Small molecule inhibitors (SMIs) against tyrosine kinase oncoproteins such as BCR-ABL, JAK2, Bruton tyrosine kinase, FLT3, EGFR, ALK, HER2, VEGFR, FGFR, MEK, and MET have fundamentally changed the landscape of cancer therapy. SMIs against BCL-2, IDHs, BRAF, PI3 kinase, mTOR, PARP, and CDKs have become the mainstay in the treatment of a variety of cancer types. To reduce and avoid off-tumor toxicities, cancer-specific TAAs such as CD33 are being manufactured through systems biology approach. Search for novel biomarkers and new designs as well as delivery methods of targeted agents are fueling the next wave of advances in cancer therapy.

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Prospects for chimeric antigen receptor-modified T cell therapy for solid tumors

Cited by 69 publications

References 141 publications

Microglia/Astrocytes–Glioblastoma Crosstalk: Crucial Molecular Mechanisms and Microenvironmental Factors

Microglia/Astrocytes–Glioblastoma Crosstalk: Crucial Molecular Mechanisms and Microenvironmental Factors

Accurate control of dual-receptor-engineered T cell activity through a bifunctional anti-angiogenic peptide

Cancer biomarkers for targeted therapy

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