Dataset Information

Efficacy of the induced pluripotent stem cell derived and engineered CD276-targeted CAR-NK cells against human esophageal squamous cell carcinoma.

ABSTRACT:

Introduction

Chimeric antigen receptor natural killer (CAR-NK) cells have been found to be successful in treating hematologic malignancies and present potential for usage in solid tumors.

Methods

In this study, we created CD276-targeted CAR-expressing NK cells from pluripotent stem cells (iPSC CD276-targeted CAR-NK cells) and evaluated their cytotoxicity against esophageal squamous cell carcinoma (ESCC) using patient-specific organoid (PSO) models comprising of both CD276-positive and CD276-negative adjacent epithelium PSO models (normal control PSO, NC PSO) as well as primary culture of ESCC cell models. In addition, in vitro and in vivo models such as KYSE-150 were also examined. iPSC NK cells and NK-free media were used as the CAR-free and NK-free controls, respectively.

Results

The positive CD276 staining was specifically detected on the ESCC membrane in 51.43% (54/105) of the patients of all stages, and in 51.35% (38/74) of stages III and IV. The iPS CD276-targeted CAR-NK cells, comparing with the iPS NK cells and the NK-free medium, exhibited specific and significant cytotoxic activity against CD276-positive ESCC PSO rather than CD276-negative NC PSO, and exhibited significant cytotoxicity against CD276-expressing cultured ESCC cells, as well as against CD276-expressing KYSE-150 in vitro and in BNDG mouse xenograft.

Discussion

The efficacy of the iPSC CD276-targeted CAR-NK cells demonstrated by their successful treatment of CD276-expressing ESCC in a multitude of pre-clinical models implied that they hold tremendous therapeutic potential for treating patients with CD276-expressing ESCC.

SUBMITTER: Lin X

PROVIDER: S-EPMC10985341 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature

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Publications

Efficacy of the induced pluripotent stem cell derived and engineered CD276-targeted CAR-NK cells against human esophageal squamous cell carcinoma.

Lin Xiaolan X Guan Tian T Xu Yien Y Li Yun Y Lin Yanchun Y Chen Shaobin S Chen Yuping Y Wei Xiaolong X Li Dongsheng D Cui Yukun Y Lin Yan Y Sun Pingnan P Guo Jianmin J Li Congzhu C Gu Jiang J Yang Wei W Zeng Haoyu H Ma Changchun C

Frontiers in immunology 20240319

<h4>Introduction</h4>Chimeric antigen receptor natural killer (CAR-NK) cells have been found to be successful in treating hematologic malignancies and present potential for usage in solid tumors.<h4>Methods</h4>In this study, we created CD276-targeted CAR-expressing NK cells from pluripotent stem cells (iPSC CD276-targeted CAR-NK cells) and evaluated their cytotoxicity against esophageal squamous cell carcinoma (ESCC) using patient-specific organoid (PSO) models comprising of both CD276-positive ...[more]

PMID: 38566988

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Project description:BackgroundChimeric antigen receptor NK (CAR-NK) cell therapy is one of the most promising immunotherapies. Although it has shown a significant therapeutic effect in hematologic malignancies, few successes have been obtained in solid tumors including esophageal squamous cell carcinoma (ESCC). The major reasons are lack of specific cell surface antigens and complex tumor microenvironment. Here we identify CD22, a well-known tumor surface marker in hematologic malignancies, is expressed in ESCC, possibly serving as a potential target of CAR-NK cell therapy.MethodsThe expression of 13 tumor cell surface antigens used clinically was analyzed in patients from The Cancer Genome Atlas (TCGA) database. Also, mRNA expression were detected in 2 ESCC cell lines and 2 patients samples by qCPR. Then according to Venn diagram, CD22 was selected for further investigation. Following this, the expression of CD22 by immunofluorescence (IF) in ESCC cell lines and by immunohistochemistry (IHC) in 87 cases of human ESCC samples was detected respectively. On the basis of H-score results, the correlation between CD22 expression and clinical parameters was analyzed. As a proof, the efficacy of CD22-targeted CAR-NK cells against ESCC cell lines was performed by a real-time cell analyzer (RTCA) platform.ResultsKYSE-140 and KYSE-150 cell lines displayed surface expression of CD22. IHC showed an 80.46% (70/87) positive rate in ESCC patient samples. Among these, cell membranous expression of CD22 was observed in 27.59% (24/87) patient samples. Through chi-square test, expression of CD22 in ESCC was associated with lymph node metastasis while it was no related to the depth of tumor invasion and clinical stage. Engineered CD22-targeted CAR-NK cells exhibited inhibitory growth capability against ESCC cell lines (p < 0.0001).ConclusionsCD22 is a potential tumor surface antigen capable of being targeted by CAR-NK cells in ESCC. And potential therapeutics for ESCC may be developed based on immune cells expressing anti-CD22 CAR. The study also indicates that CD22 CAR-NK cells could be used in other cancers and more in vivo experiments are needed.

Project description:BackgroundDue to the lack of effective treatment options, the prognosis of patients with relapsed/refractory acute myeloid leukemia (R/R AML) remains poor. Although chimeric antigen receptor (CAR)-T-cell therapy has shown promising effects in acute lymphoblastic leukemia (ALL) and lymphoma, its application in R/R AML is limited by "off-target" effects, which lead to severe bone marrow suppression and limit its clinical application. CAR-natural killer (NK) cells not only exhibit antitumor effects but also demonstrate increased safety and universality. We have developed a new CAR construct that targets CD33 and modified NK cells, specifically eliminating AML cells while reducing severe side effects on stem cells.MethodsThe CD33-targeting domain was selected by CAR-T cells, and this optimized CAR construct was subsequently transduced into umbilical cord-derived NK cells via a retroviral vector. Preclinical efficacy and safety studies were conducted both in vitro and in vivo. Ten eligible patients with R/R AML aged 18-65 years who received one or more infusions of anti-CD33 CAR-NK cells following the preconditioning regimen were enrolled. We assessed the response rates and treatment-related side effects post-infusion, while also documenting the long-term efficacy of the therapy.ResultsThe CD33 sequence was selected on the basis of its antitumor efficacy and safety in CAR-T-cell studies conducted both in vitro and in vivo. CD33 CAR-NK cells demonstrated efficacy comparable to that of CD33 CAR-T cells but showed limited toxicity to hematopoietic stem cells (HSCs). Ten patients, with a median of five prior lines of treatment, completed the efficacy evaluation (range, 3-8). No grade 3-4 adverse events were observed, except bone marrow suppression, which was relieved within one month. No cases of immune effector cell-associated neurotoxicity syndrome (ICANS) or graft-versus-host disease (GVHD) were reported following CAR-NK cell infusion. Only one patient experienced grade 2 cytokine release syndrome (CRS) and presented with persistent fever. By day 28, six of ten patients had achieved minimal residual disease (MRD)-negative complete remission.ConclusionsOur preclinical and clinical data demonstrated the primary efficacy and safety of CD33 CAR-NK cells for patients with R/R AML. Expanded samples and longer follow-up periods are needed to provide further efficacy data.Trial registrationNCT05008575 ( https://clinicaltrials.gov/study/NCT05008575 ).

Dataset Information

Efficacy of the induced pluripotent stem cell derived and engineered CD276-targeted CAR-NK cells against human esophageal squamous cell carcinoma.

Introduction

Methods

Results

Discussion

Publications

Efficacy of the induced pluripotent stem cell derived and engineered CD276-targeted CAR-NK cells against human esophageal squamous cell carcinoma.

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