EGFR‐targeted CAR‐T cells are potent and specific in suppressing triple‐negative breast cancer both <i>in vitro</i> and <i>in vivo</i>

Lin, Xia; Zheng, Zaozao; Liu, Jun‐yi; Chen, Yu‐jie; Ding, Jian; Xia, Ningshao; Luo, Wenxin; Liu, Wen

doi:10.1002/cti2.1135

Cited by 54 publications

(48 citation statements)

References 93 publications

(105 reference statements)

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“…This capability was exhibited in vitro and in vivo in a xenograft mouse model, with minimal off-tumor cytotoxicity. The activation of the interferon γ, granzyme-perforin-PARP and Fas-FADD-caspase signaling pathways in TNBC cells further confirm that CAR-T as an immunotherapy tool may be used to treat TNBC in the clinical setting 39 .…”

Section: Discussionmentioning

confidence: 61%

Chimeric antigen receptor T-cell immunotherapy in breast cancer: development and challenges

Toulouie¹,

Johanning²,

Shi³

2021

J. Cancer

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Chimeric antigen receptor (CAR) T-cell therapy is an innovative form of immunotherapy wherein autologous T-cells are genetically modified to express chimeric receptors encoding an antigen-specific single-chain variable fragment and costimulatory molecules. Moreover, CAR T-cell therapy can only work successfully in patients who have an intact immune system. Therefore, patients receiving cytotoxic chemotherapy will be immunosuppressed making CART therapy less effective. In adoptive CD8+ T-cell therapy (ACT), numerous tumor-specific, engineered T-cells are sourced from patients, expanded in vitro, and infused back expressing tumor-specific antigen receptors. The most successful ACT, anti-CD19 chimeric antigen receptor T-cell therapy directed against B-cell lymphoma, has proved to be efficacious. However, current efforts to utilize this approach for solid tumors, like breast cancer, have shown only modest improvement. Nevertheless, the potential efficacy of CART therapy is promising in an era of immunological advances. By appropriately manipulating CAR T-cells to combat the immunosuppressive forces of the tumor microenvironment, significant eradication of the solid tumor may occur. This review discusses CAR T-cell therapy and its specificity and safety in adoptive cell transfers in breast cancer. We will highlight novel discoveries in CAR T-cell immunotherapy and the formidable barriers including suppression of T-cell function and localization at tumor sites.

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Section: Discussionmentioning

confidence: 61%

Chimeric antigen receptor T-cell immunotherapy in breast cancer: development and challenges

Toulouie¹,

Johanning²,

Shi³

2021

J. Cancer

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“…We and others have reported that third-generation EGFR CAR-T cells exhibit potent and specific cytotoxicity against TNBC (6,7).…”

Section: Introductionmentioning

confidence: 84%

“…Cytotoxicity assays were performed using the xCELLigence Real-time Cell Analyzer (RTCA) System (ACEA Biosciences, San Diego) as described previously (6). MDA-MB-231 or EMT6 cells were seeded and cultured for 24 hours.…”

Section: Cytotoxicity Assaymentioning

confidence: 99%

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Targeting Triple-Negative Breast Cancer with Combination Therapy of EGFR CAR T Cells and CDK7 Inhibition

Lin

Zheng

Liu

et al. 2021

Cancer Immunology Research

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Epidermal growth factor receptor-targeted chimeric antigen receptor T cells (EGFR CAR-T) are potent and specific in suppressing the growth of triple-negative breast cancer (TNBC) in vitro and in vivo. However, in this study, a subset of mice soon acquired resistance, which limits the potential use of EGFR CAR-T. We aimed to find a way to overcome the observed resistance.Transcriptomic analysis results revealed that EGFR CAR-T treatment induced a set of immunosuppressive genes, presumably through interferon-gamma (IFN signaling, in EGFR CAR-T cell-resistant TNBC tumors. The EGFR CAR-T cell-induced immunosuppressive genes were associated with EGFR CAR-T cell-activated enhancers and were especially sensitive to THZ1, a CDK7 inhibitor we screened out of a panel of small molecules targeting epigenetic modulators. Accordingly, combination therapy with THZ1 and EGFR CAR-T cells suppressed immune resistance, tumor growth, and metastasis in TNBC tumor models, including human MDA-MB-231 cell-and TNBC patient-derived xenografts, and mouse EMT6 cell-derived allografts. Taken together, we demonstrated that transcriptional modulation using epigenetic inhibitors could overcome CAR-T therapy-induced immune resistance, thus providing a therapeutic avenue for treating TNBC in the clinic. Synopsis: CAR T-cell resistance can occur due to multiple factors. EGFR CAR T-cell treatmentinduces expression of an immune-suppressive gene set. Interruption of transcriptional activity using a "unite-and-conquer" strategy sensitizes refractory TNBC to treatment and reduced tumor growth.

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“…Although CAR T-cell therapy has limited use in solid tumors due to the shortage of unique tumor specific antigens, promising results have been reported in several recent in vivo studies [87,88]. Xia et al have successfully used EGFR CAR T with potent and specific antitumor activity against a triple-negative breast cancer model [89]. Likewise, CEA targeted CAR T-cells are also being tested for tumors expressing CEA [90].…”

Section: Genetically Modified T-lymphocytesmentioning

confidence: 99%

Immune gene therapy of cancer

Akbulut

2020

Turk J Med Sci

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Cancer gene therapy emerged as a promising treatment modality 3 decades ago. However, the failure of the first gene therapy trials in cancer treatment has decreased its popularity. Likewise, immunotherapy has followed a similar course. While it was a popular and promising treatment with IL-2 and interferon and cancer vaccines in the 1980s, it later lost its popularity. Immunotherapy became one of the main options for cancer treatment with the successful use of immune checkpoint inhibitors in clinics approximately 10 years ago. The success of immunotherapy has increased even more with the introduction of cancer gene therapy methods in this area. With the identification of the oncolytic herpes simplex virus and Chimeric antigen receptor (CAR) T-cells, immune gene therapy has become an essential modality in cancer treatments such as surgery, radiotherapy, chemotherapy, and targeted therapies.

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EGFR‐targeted CAR‐T cells are potent and specific in suppressing triple‐negative breast cancer both in vitro and in vivo

Abstract: Objectives. Triple-negative breast cancer (TNBC) is well known for its strong invasiveness, rapid recurrence and poor prognosis.

Cited by 54 publications

References 93 publications

Chimeric antigen receptor T-cell immunotherapy in breast cancer: development and challenges

Chimeric antigen receptor T-cell immunotherapy in breast cancer: development and challenges

Targeting Triple-Negative Breast Cancer with Combination Therapy of EGFR CAR T Cells and CDK7 Inhibition

Immune gene therapy of cancer

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