Dual-function chimeric antigen receptor T cells targeting c-Met and PD-1 exhibit potent anti-tumor efficacy in solid tumors

Yuan, Xingxing; Sun, Zujun; Yuan, Qingqing; Hou, Weihua; Liang, Qiaoyan; Wang, Yu-Xiong; Mo, Wei; Wang, Huijie; Yu, Min

doi:10.1007/s10637-020-00978-3

Cited by 25 publications

(18 citation statements)

References 49 publications

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“…Researchers have tried to target PD-1 or PD-L1 to increase the sensitivity of CAR-T and weaken the inhibition tendency caused by the tumor microenvironment. Several studies have confirmed this idea [ 125 , 126 , 127 , 128 ].…”

Section: Prospects Of Car-t For the Treatment Of Prostate Cancermentioning

confidence: 87%

Prospect of Prostate Cancer Treatment: Armed CAR-T or Combination Therapy

Jiang

Wen

et al. 2022

Cancers

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The incidence rate of prostate cancer is higher in male cancers. With a hidden initiation of disease and long duration, prostate cancer seriously affects men’s physical and mental health. Prostate cancer is initially androgen-dependent, and endocrine therapy can achieve good results. However, after 18–24 months of endocrine therapy, most patients eventually develop castration-resistant prostate cancer (CRPC), which becomes metastatic castration resistant prostate cancer (mCRPC) that is difficult to treat. Chimeric Antigen Receptor T cell (CAR-T) therapy is an emerging immune cell therapy that brings hope to cancer patients. CAR-T has shown considerable advantages in the treatment of hematologic tumors. However, there are still obstacles to CAR-T treatment of solid tumors because the physical barrier and the tumor microenvironment inhibit the function of CAR-T cells. In this article, we review the progress of CAR-T therapy in the treatment of prostate cancer and discuss the prospects and challenges of armed CAR-T and combined treatment strategies. At present, there are still many obstacles in the treatment of prostate cancer with CAR-T, but when these obstacles are solved, CAR-T cells can become a favorable weapon for the treatment of prostate cancer.

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Section: Prospects Of Car-t For the Treatment Of Prostate Cancermentioning

confidence: 87%

Prospect of Prostate Cancer Treatment: Armed CAR-T or Combination Therapy

Jiang

Wen

et al. 2022

Cancers

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“…60 Yuan et al constructed a dual-function CAR-T targeting c-Met and PD-1 and found that it not only blocked PD-L1 but decreased the expression of LAG-3 and TIM-3. 61 Similarly, CD19 CAR-T containing anti-PD-1 scFv can also limit the up-regulation of PD-1 in CAR-T cells after antigen stimulation and enhance the proliferation ability of CAR-T. 62 In addition, Rafiq et al found that the PD-1 antibody-secreting CAR-T could survive longer, and because the secreted PD-1 antibody is localized near the tumor, it could avoid the related toxicity caused by systemic application of ICI. 63 However, the design of adding the PD-1/PD-L1 antibody gene sequence to the CAR plasmid greatly increases the length of CAR plasmid which will improve the difficulty of CAR-T cell infection.…”

Section: Discussionmentioning

confidence: 99%

Construction of PD1/CD28 chimeric-switch receptor enhances anti-tumor ability of c-Met CAR-T in gastric cancer

Chen

Zhang

et al. 2021

OncoImmunology

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Chimeric antigen receptor (CAR) T cell is a promising method in cancer immunotherapy but faces many challenges in solid tumors. One of the major problems was immunosuppression caused by PD-1. In our study, the expression of c-Met in GC was analyzed from TCGA datasets, GC tissues, and cell lines. The c-Met CAR was a second-generation CAR with 4-1BB, cMet-PD1/CD28 CAR was c-Met CAR adding PD1/CD28 chimeric-switch receptor (CSR). In vitro, we measured the changes of different subgroups, phenotypes and PD-1 expression in CAR-T cells. We detected the secretion levels of different cytokines and the killing ability of CAR-Ts. In vivo, we established a xenograft GC model and observed the anti-tumor effect and offtarget toxicity of different CAR-Ts. We find that the expression of c-Met was increased in GC. CD3 + CD8 + T cells and CD62L + CCR7 + central memory T cells (T CM ) were increased in two CAR-Ts. The stimulation of target cells could promote the expression of PD-1 in c-Met CAR-T. Compared with Mock T, the secretion of cytokines as IFN-γ, TNF-α, IL-6, IL-10 secreted by two CAR-Ts was increased, and the killing ability to c-Met positive GC cells was enhanced. The PD1/CD28 CSR could further enhance the killing ability, especially the long-term anti-tumor effect of c-Met CAR-T, and reduce the release level of IL-6. CAR-Ts target c-Met had no obvious off-target toxicity to normal organs. Thus, the PD1/CD28 CSR could further enhance the antitumor ability of c-Met CAR-T, and provides a promising design strategy to improve the efficacy of CAR-T in GC.

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“…[47][48][49] Moreover, dual-functioning CAR T cells targeting both MET and programmed death-1 (PD-1) has also been described as a strategy for therapy of solid tumors. 50 The communication presented here focuses on pathogenic mechanism-based validation of METtargeting therapeutics for clinical trials. Based on complex mechanisms of MET dysregulation in different types of cancer, our objective is to summarize the latest development of strategies in pharmaceutical validation of MET-targeting therapeutics.…”

Section: Acɵvaɵon Of Major Intracellular Signaling Pathwaysmentioning

confidence: 99%

“…1,6,[47][48][49][50]72,[86][87][88][89] Because the fusion partner sequences often contain a coiled-coil domain that facilitates protein dimerization, almost all of MET fusions exhibit ligandindependent MET activation. 8,[46][47][48][49][50]55,72,73,[86][87][88][89] The frequency of MET fusions in cancer such as those from lung, gastric, hepatic, kidney, and pancreatic tissues is relatively low, ranging from 0.1 to 2%. [86][87][88][89] The only exception is glioma, in which MET fusion has been found in ~12% cases.…”

Section: Met Dysregulation and Underlying Mechanismmentioning

confidence: 99%

“…1 Mechanistically, MET fusion occurs through either intrachromosomal or interchromosomal rearrangements. 1,6,47–50,72,86–89 Because the fusion partner sequences often contain a coiled-coil domain that facilitates protein dimerization, almost all of MET fusions exhibit ligand-independent MET activation. 8,46–50,55,72,73,86–89 The frequency of MET fusions in cancer such as those from lung, gastric, hepatic, kidney, and pancreatic tissues is relatively low, ranging from 0.1 to 2%.…”

Section: Met Dysregulation and Underlying Mechanismmentioning

confidence: 99%

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Oncogenic mechanism-based pharmaceutical validation of therapeutics targeting MET receptor tyrosine kinase

2021

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Aberrant expression and/or activation of the MET receptor tyrosine kinase is characterized by genomic recombination, gene amplification, activating mutation, alternative exon-splicing, increased transcription, and their different combinations. These dysregulations serve as oncogenic determinants contributing to cancerous initiation, progression, malignancy, and stemness. Moreover, integration of the MET pathway into the cellular signaling network as an addiction mechanism for survival has made this receptor an attractive pharmaceutical target for oncological intervention. For the last 20 years, MET-targeting small-molecule kinase inhibitors (SMKIs), conventional therapeutic monoclonal antibodies (TMABs), and antibody-based biotherapeutics such as bispecific antibodies, antibody–drug conjugates (ADC), and dual-targeting ADCs have been under intensive investigation. Outcomes from preclinical studies and clinical trials are mixed with certain successes but also various setbacks. Due to the complex nature of MET dysregulation with multiple facets and underlying mechanisms, mechanism-based validation of MET-targeting therapeutics is crucial for the selection and validation of lead candidates for clinical trials. In this review, we discuss the importance of various types of mechanism-based pharmaceutical models in evaluation of different types of MET-targeting therapeutics. The advantages and disadvantages of these mechanism-based strategies for SMKIs, conventional TMABs, and antibody-based biotherapeutics are analyzed. The demand for establishing new strategies suitable for validating novel biotherapeutics is also discussed. The information summarized should provide a pharmaceutical guideline for selection and validation of MET-targeting therapeutics for clinical application in the future.

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Dual-function chimeric antigen receptor T cells targeting c-Met and PD-1 exhibit potent anti-tumor efficacy in solid tumors

Cited by 25 publications

References 49 publications

Prospect of Prostate Cancer Treatment: Armed CAR-T or Combination Therapy

Prospect of Prostate Cancer Treatment: Armed CAR-T or Combination Therapy

Construction of PD1/CD28 chimeric-switch receptor enhances anti-tumor ability of c-Met CAR-T in gastric cancer

Oncogenic mechanism-based pharmaceutical validation of therapeutics targeting MET receptor tyrosine kinase

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