Development of Engineered CAR T Cells Targeting Tumor-Associated Glycoforms of MUC1 for the Treatment of Intrahepatic Cholangiocarcinoma

Mao, Li; Su, Shih Bin; Li, Jia; Yu, Song-Yang; Gong, Yu; Chen, Changzhou; Hu, Zhiqiang; Huang, Xiaowu

doi:10.1097/cji.0000000000000460

Cited by 11 publications

(7 citation statements)

References 27 publications

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“…Notably, although the functional mechanisms of mucin-positive cells may not be directly facilitated by mucins, mucin-directed immune therapy or chemotherapy still shows strong clinical application potential. Recently, MUC1 -directed chimeric antigen receptor (CAR) T cell therapies have shown promising killing effects both in-vitro and in-vivo [ 47 , 48 ]. Our data reveal attractive targets for immunotherapy, suggesting that anti- MUC4 , anti- MUC5AC , anti- MUC5B , anti- MUC13 or anti- MUC16 CAR T cells may also show promising treatment effects in the future.…”

Section: Discussionmentioning

confidence: 99%

Establishment of a cholangiocarcinoma risk evaluation model based on mucin expression levels

Yang,

Guo,

et al. 2024

World J Gastrointest Oncol

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BACKGROUND Cholangiocarcinoma (CCA) is a highly malignant cancer, characterized by frequent mucin overexpression. MUC1 has been identified as a critical oncogene in the progression of CCA. However, the comprehensive understanding of how the mucin family influences CCA progression and prognosis is still incomplete. AIM To investigate the functions of mucins on the progression of CCA and to establish a risk evaluation formula for stratifying CCA patients. METHODS Single-cell RNA sequencing data from 14 CCA samples were employed for elucidating the roles of mucins, complemented by bioinformatic analyses. Subsequent validations were conducted through spatial transcriptomics and immunohistochemistry. The construction of a risk evaluation model utilized the least absolute shrinkage and selection operator regression algorithm, which was further confirmed by independent cohorts and diverse data types. RESULTS CCA tumor cells with elevated levels of MUC1 and MUC4 showed activated nucleotide metabolic pathways and increased invasiveness. MUC5AC -high cells were found to promote CCA progression through WNT signaling. MUC5B -high cells exhibited robust cellular oxidation activities, leading to resistance against antitumoral treatments. MUC13 -high cells were observed to secret chemokines, recruiting and transforming macrophages into the M2-polarized state, thereby suppressing antitumor immunity. MUC16 -high cells were found to promote tumor progression through interleukin-1/nuclear factor kappa-light-chain-enhancer of activated B cells signaling upon interaction with neutrophils. Utilizing the expression levels of these mucins, a risk factor evaluation formula for CCA was developed and validated across multiple cohorts. CCA samples with higher risk factors exhibited stronger metastatic potential, chemotherapy resistance, and poorer prognosis. CONCLUSION Our study elucidates the functional mechanisms through which mucins contribute to CCA development, and provides tools for risk stratification in CCA.

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Section: Discussionmentioning

confidence: 99%

Establishment of a cholangiocarcinoma risk evaluation model based on mucin expression levels

Yang,

Guo,

et al. 2024

World J Gastrointest Oncol

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“…Both first and third-generation CAR T cells targeting MUC1 have been developed, which are able to specifically eliminate HCC cells with high MUC1 expression, while causing minimal damage to normal hepatic cells with low MUC1 expression levels [ 139 ]. A recent study has reported the use of Tn-MUC1-targeted CAR T cells in intrahepatic cholangiocarcinoma (ICC) [ 140 ]. Tn-MUC1 expression was associated with poor ICC prognosis [ 140 ].…”

Section: Car T Cell Therapy Targets For Hccmentioning

confidence: 99%

“…A recent study has reported the use of Tn-MUC1-targeted CAR T cells in intrahepatic cholangiocarcinoma (ICC) [ 140 ]. Tn-MUC1 expression was associated with poor ICC prognosis [ 140 ]. Moreover, Tn-MUC1-targeted CAR T cells could selectively eliminate Tn-MUC1-positive ICC cells, both in vitro and in vivo, while there was no effect in Tn-MUC1-negative ICC cells [ 140 ].…”

Section: Car T Cell Therapy Targets For Hccmentioning

confidence: 99%

“…Tn-MUC1 expression was associated with poor ICC prognosis [ 140 ]. Moreover, Tn-MUC1-targeted CAR T cells could selectively eliminate Tn-MUC1-positive ICC cells, both in vitro and in vivo, while there was no effect in Tn-MUC1-negative ICC cells [ 140 ]. Currently, a clinical trial involving MUC1 CAR T cells for HCC is actively underway (NCT02587689).…”

Section: Car T Cell Therapy Targets For Hccmentioning

confidence: 99%

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Chimeric Antigen Receptor T Cell Therapy for Hepatocellular Carcinoma: Where Do We Stand?

Aggeletopoulou,

Kalafateli,

Triantos

2024

IJMS

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Hepatocellular carcinoma (HCC) remains a global health challenge that urgently calls for innovative therapeutic strategies. Chimeric antigen receptor T cell (CAR T) therapy has emerged as a promising avenue for HCC treatment. However, the therapeutic efficacy of CAR T immunotherapy in HCC patients is significantly compromised by some major issues including the immunosuppressive environment within the tumor, antigen heterogeneity, CAR T cell exhaustion, and the advanced risk for on-target/off-tumor toxicity. To overcome these challenges, many ongoing preclinical and clinical trials are underway focusing on the identification of optimal target antigens and the decryption of the immunosuppressive milieu of HCC. Moreover, limited tumor infiltration constitutes a significant obstacle of CAR T cell therapy that should be addressed. The continuous effort to design molecular targets for CAR cells highlights the importance for a more practical approach for CAR-modified cell manufacturing. This review critically examines the current landscape of CAR T cell therapy for HCC, shedding light on the changes in innate and adaptive immune responses in the context of HCC, identifying potential CAR T cell targets, and exploring approaches to overcome inherent challenges. Ongoing advancements in scientific research and convergence of diverse treatment modalities offer the potential to greatly enhance HCC patients’ care in the future.

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“…The study successfully demonstrated the specific cytotoxic activity of these CAR T against CCA cells [ 95 ]. Another study on antitumor efficacy in ICCA revealed the toxicity of Tn-MUC1 CAR T targeting glycosylated MUC1, both in vitro and in vivo [ 97 ]. In a recent study, fourth-generation A20-4G CAR T exhibited remarkable cytotoxicity against CCA cells expressing integrin integrin alphavbeta6/8 (αvβ6) [ 98 ].…”

Section: Current State Recent Advances and Challenges Of Immunotherap...mentioning

confidence: 99%

Therapeutic significance of tumor microenvironment in cholangiocarcinoma: focus on tumor-infiltrating T lymphocytes

Li,

Bie,

Chen

et al. 2023

Exploration of Targeted Anti-Tumor Therapy

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Cholangiocarcinoma (CCA) is a highly aggressive type of adenocarcinoma distinguished by its invasiveness. Depending on specific anatomical positioning within the biliary tree, CCA can be categorized into intrahepatic CCA (ICCA), perihilar CCA (pCCA) and distal CCA (dCCA). In recent years, there has been a significant increase in the global prevalence of CCA. Unfortunately, many CCA patients are diagnosed at an advanced stage, which makes surgical resection impossible. Although systemic chemotherapy is frequently used as the primary treatment for advanced or recurrent CCA, its effectiveness is relatively low. Therefore, immunotherapy has emerged as a promising avenue for advancing cancer treatment research. CCA exhibits a complex immune environment within the stromal tumor microenvironment (TME), comprising a multifaceted immune landscape and a tumor-reactive stroma. A deeper understanding of this complex TME is indispensable for identifying potential therapeutic targets. Thus, targeting tumor immune microenvironment holds promise as an effective therapeutic strategy.

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Development of Engineered CAR T Cells Targeting Tumor-Associated Glycoforms of MUC1 for the Treatment of Intrahepatic Cholangiocarcinoma

Cited by 11 publications

References 27 publications

Establishment of a cholangiocarcinoma risk evaluation model based on mucin expression levels

Establishment of a cholangiocarcinoma risk evaluation model based on mucin expression levels

Chimeric Antigen Receptor T Cell Therapy for Hepatocellular Carcinoma: Where Do We Stand?

Therapeutic significance of tumor microenvironment in cholangiocarcinoma: focus on tumor-infiltrating T lymphocytes

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