Specificity redirection by CAR with human VEGFR-1 affinity endows T lymphocytes with tumor-killing ability and anti-angiogenic potency

Wang, W; Ma, Yupo; Li, Jian; Hs, Shi; Lq, Wang; Fc, Guo; Zhang, J; D, Li; Bh, Mo; Fang, Wen; T, Liu; Yt, Liu; Ys, Wang; Yq, Wei

doi:10.1038/gt.2013.19

Cited by 77 publications

(39 citation statements)

References 52 publications

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“…We successfully developed and characterized 64 Cu-NOTA-RamAb for PET imaging of VEGFR-2 expression in NSCLC xenograft tumors. Although the selectively of RamAb for VEGFR-2 was previously reported in vitro (29), we used A549 (VEGFR-2–negative/VEGFR-1–positive) and HCC4006 (VEGFR-2–positive/VEGFR-1–negative) cell lines to further show the selectivity of RamAb for VEGFR-2 (30,31). VEGFR-2 specificity of 64 Cu-NOTA-RamAb was demonstrated by experiments in vitro, in vivo, and ex vivo, proving it as a promising PET tracer with high clinical potential for diagnosing and monitoring VEGFR-2 expression in tumors.…”

Section: Discussionmentioning

confidence: 98%

PET Imaging of VEGFR-2 Expression in Lung Cancer with ⁶⁴Cu-Labeled Ramucirumab

et al. 2015

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Lung cancer accounts for 17% of cancer-related deaths worldwide, and most patients present with locally advanced or metastatic disease. Novel PET imaging agents for assessing vascular endothelial growth factor receptor-2 (VEGFR-2) expression can be used for detecting VEGFR-2–positive malignancies and subsequent monitoring of therapeutic response to VEGFR-2–targeted therapies. Here, we report the synthesis and characterization of the antibody-based imaging agent for PET imaging of VEGFR-2 expression in vivo. Methods Ramucirumab (named RamAb), a fully humanized IgG1 monoclonal antibody, was conjugated to 2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) and labeled with 64Cu. Flow cytometry analysis and microscopy studies were performed to compare the VEGFR-2 binding affinity of RamAb and NOTA-RamAb. PET imaging and biodistribution studies were performed in nude mice bearing HCC4006 and A549 xenograft tumors. Ex vivo histopathology was performed to elucidate the expression patterns of VEGFR-2 in different tissues and organs to validate in vivo results. Results Flow cytometry examination revealed the specific binding capacity of FITC-RamAb to VEGFR-2, and no difference in VEGFR-2 binding affinity was seen between RamAb and NOTA-RamAb. After being labeled with 64Cu, PET imaging revealed specific and prominent uptake of 64Cu-NOTA-RamAb in VEGFR-2–positive HCC4006 tumors (9.4 ± 0.5 percentage injected dose per gram at 48 h after injection; n = 4) and significantly lower uptake in VEGFR-2–negative A549 tumors (4.3 ± 0.2 percentage injected dose per gram at 48 h after injection; n = 3). Blocking experiments revealed significantly lower uptake in HCC4006 tumors, along with histology analysis, further confirming the VEGFR-2 specificity of 64Cu-NOTA-RamAb. Conclusion This study provides initial evidence that 64Cu-NOTA-RamAb can function as a PET imaging agent for visualizing VEGFR-2 expression in vivo, which may also find potential applications in monitoring the treatment response of VEGFR-2 targeted cancer therapy.

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Section: Discussionmentioning

confidence: 98%

PET Imaging of VEGFR-2 Expression in Lung Cancer with ⁶⁴Cu-Labeled Ramucirumab

et al. 2015

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“…While positive pre-clinical 91,92 , including suppression of metastasis 92 were reported for CAR-T VEGF-1, the trials using CAR-T anti-VEGFR2 (NCT01218867) failed to show significant clinical activity.…”

Section: Future Perspectives Of Car-t Approachmentioning

confidence: 99%

The biological basis and clinical symptoms of CAR-T therapy-associated toxicites

et al. 2018

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Currently, immunotherapy is attracting a lot of attention and may potentially become a leading approach in the treatment of cancer. One emerging therapeutic, the chimeric-antigen receptor T-cell adoptive immunotherapy (CAR-T) is showing remarkable efficacy in the treatment of several B-cell malignancies. The popularity of CAR-T has been founded on two CAR T-cell products recently approved by FDA (during 2017) in the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia and B-cell lymphoma. However, their toxicities observed in clinical trials were extremely significant and in some cases even fatal with no approved algorithms for toxicity prediction being available to date. A deeper understanding of the biological basis of such complications is the key to prompt and comprehensive clinical management. Here we review the wide spectrum of effects associated with CAR T cell therapy with a major focus on the pathogenesis of cytokine release syndrome and neurotoxicity as the most common, potentially life-threatening effects of this treatment. We discuss the basis of clinical management and the existing models that predict the severity of toxicity, as well as the key factors that modulate this event. Finally, we will summarize the literature detailing universal allogenic CAR T-cells and their toxicity profile.

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“…The expression pattern in the "Rationale" column was retrieved from the literature or from the Protein Atlas database. formation in vitro and delay A549 cell line-mediated tumor growth and pulmonary metastasis in mice, especially if CAR+ T cells are modified to co-express IL-15 [109].…”

Section: Targeting the Most Relevant Cell Populationmentioning

confidence: 99%

Moving Receptor Redirected Adoptive Cell Therapy Toward Fine Tuning of Antitumor Responses

Chicaybam

Bonamino

2014

International Reviews of Immunology

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Adoptive cell transfer (ACT) is emerging as a powerful modality of cancer treatment. While ACT has proved able to induce massive clinical responses, genetic modification of T lymphocytes further improved clinical responses obtained. One of the major current limitations of ACT is the inability to discern healthy from malignant cells, leading to on target/off tumor responses that can limit its application. We here discuss some of the approaches currently under development and potential solutions to circumvent these limitations and extend this potentially curative therapy to different tumors by targeting a variety of antigens.

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Specificity redirection by CAR with human VEGFR-1 affinity endows T lymphocytes with tumor-killing ability and anti-angiogenic potency

Cited by 77 publications

References 52 publications

PET Imaging of VEGFR-2 Expression in Lung Cancer with ⁶⁴Cu-Labeled Ramucirumab

PET Imaging of VEGFR-2 Expression in Lung Cancer with ⁶⁴Cu-Labeled Ramucirumab

The biological basis and clinical symptoms of CAR-T therapy-associated toxicites

Moving Receptor Redirected Adoptive Cell Therapy Toward Fine Tuning of Antitumor Responses

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Specificity redirection by CAR with human VEGFR-1 affinity endows T lymphocytes with tumor-killing ability and anti-angiogenic potency

Cited by 77 publications

References 52 publications

PET Imaging of VEGFR-2 Expression in Lung Cancer with 64Cu-Labeled Ramucirumab

PET Imaging of VEGFR-2 Expression in Lung Cancer with 64Cu-Labeled Ramucirumab

The biological basis and clinical symptoms of CAR-T therapy-associated toxicites

Moving Receptor Redirected Adoptive Cell Therapy Toward Fine Tuning of Antitumor Responses

Contact Info

Product

Resources

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PET Imaging of VEGFR-2 Expression in Lung Cancer with ⁶⁴Cu-Labeled Ramucirumab

PET Imaging of VEGFR-2 Expression in Lung Cancer with ⁶⁴Cu-Labeled Ramucirumab