Combined antitumor effects of anti-EGFR variant III CAR-T cell therapy and PD-1 checkpoint blockade on glioblastoma in mouse model

Song, Yujie; Liu, Qingtian; Zuo, Tao; Wei, Guo; Jiao, Shunchang

doi:10.1016/j.cellimm.2020.104112

Cited by 39 publications

(41 citation statements)

References 24 publications

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“…Solid tumors are characterized by the immune suppressive microenvironment, with the existence of myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), tumor-associated macrophages (TAM), and cancer-associated fibroblast (CAF), negatively hampering the killing of cytotoxic T cells [41]. However, the application of immune check point inhibitors recuperates tumor inhibition and changes a "cold tumor" into "hot tumor" [42,43]. It is noticeable that oncolytic virus and gene therapies have been widely tested in clinical trials for the treatment of GBM, with significant immune-cell infiltration and tolerance [44,45].…”

Section: Discussionmentioning

confidence: 99%

A Rational Designed Novel Bispecific Antibody for the Treatment of GBM

Sun

Zhou

Han³

et al. 2021

Biomedicines

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Epidermal growth factor receptor variant III (EGFRvIII) is highly and specifically expressed in a subset of lethal glioblastoma (GBM), making the receptor a unique therapeutic target for GBM. Recently, bispecific antibodies (BsAbs) have shown exciting clinical benefits in cancer immunotherapy. Here, we report remarkable results for GBM treatment with a BsAb constructed by the “BAPTS” method. The BsAb was characterized through LC/MS, SEC-HPLC, and SPR. Furthermore, the BsAb was evaluated in vitro for bioactivities through FACS, antigen-dependent T-cell-mediated cytotoxicity, and a cytokine secretion assay, as well as in vivo for antitumor activity and pharmacokinetic (PK) parameters through immunodeficient NOD/SCID and BALB/c mouse models. The results indicated that the EGFRvIII-BsAb eliminated EGFRvIII-positive GBM cells by recruiting and stimulating effector T cells secreting cytotoxic cytokines that killed GBM cells in vitro. The results demonstrated the antitumor potential and long circulation time of EGFRvIII-BsAb in NOD/SCID mice bearing de2–7 subcutaneously heterotopic transplantation tumors and BALB/c mice. In conclusion, our experiments in both in vitro and in vivo have shown the remarkable antitumor activities of EGFRvIII-BsAb, highlighting its potential in clinical applications for the treatment of GBM. Additional merits, including a long circulation time and low immunogenicity, have also made the novel BsAb a promising therapeutic candidate.

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Section: Discussionmentioning

confidence: 99%

A Rational Designed Novel Bispecific Antibody for the Treatment of GBM

Sun

Zhou

Han³

et al. 2021

Biomedicines

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“…The combination of EGFRvIII-CAR-T and PD-1 down-regulation has potent anti-glioma efficacy and prolongs survival in mice. Furthermore, PD-1 knockout significantly enhances lysis of CAR-T cells targeting EGFRvIII for PD-L1 + EGFRvIII + GBM cells ( Song et al, 2020 ; Zhu et al, 2020a ; Zhu et al, 2020b ). Importantly, intratumoral IL-12 administration effectively reshapes the TME (i.e., increased pro-inflammatory CD4 + T cells and decreased Tregs), thus improving CAR-T cell immunotherapy in a preclinical model ( Agliardi et al, 2021 ).…”

Section: Car-t Research Advances In Gbmmentioning

confidence: 99%

Targeting Tumor-Associated Antigen: A Promising CAR-T Therapeutic Strategy for Glioblastoma Treatment

Zhu

Zhang

et al. 2021

Front. Pharmacol.

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Chimeric antigen receptor T cells (CAR-T) therapy is a prospective therapeutic strategy for blood cancers tumor, especially leukemia, but it is not effective for solid tumors. Glioblastoma (GBM) is a highly immunosuppressive and deadly malignant tumor with poor responses to immunotherapies. Although CAR-T therapeutic strategies were used for glioma in preclinical trials, the current proliferation activity of CAR-T is not sufficient, and malignant glioma usually recruit immunosuppressive cells to form a tumor microenvironment that hinders CAR-T infiltration, depletes CAR-T, and impairs their efficacy. Moreover, specific environments such as hypoxia and nutritional deficiency can hinder the killing effect of CAR-T, limiting their therapeutic effect. The normal brain lack lymphocytes, but CAR-T usually can recognize specific antigens and regulate the tumor immune microenvironment to increase and decrease pro- and anti-inflammatory factors, respectively. This increases the number of T cells and ultimately enhances anti-tumor effects. CAR-T therapy has become an indispensable modality for glioma due to the specific tumor-associated antigens (TAAs). This review describes the characteristics of CAR-T specific antigen recognition and changing tumor immune microenvironment, as well as ongoing research into CAR-T therapy targeting TAAs in GBM and their potential clinical application.

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“…It is well known that PD1 antibodies exhibit excellent clinical efficacy against numerous tumors [165]. Combination therapies of PD1 antibodies and CAR T cells have been actively studied in preclinical and clinical studies to achieve a synergistic effect (Figure 4B) [78,[166][167][168][169][170][171][172][173]. Since PD1 expression in CAR T cells is elevated by PDL1 positive tumor cells, PD1 antibody treatment enhanced the antitumor activity of CAR T cells [167].…”

Section: Inhibition Of Pd-1 Signalingmentioning

confidence: 99%

Making Potent CAR T Cells Using Genetic Engineering and Synergistic Agents

Park

2021

Cancers

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Immunotherapies are emerging as powerful weapons for the treatment of malignancies. Chimeric antigen receptor (CAR)-engineered T cells have shown dramatic clinical results in patients with hematological malignancies. However, it is still challenging for CAR T cell therapy to be successful in several types of blood cancer and most solid tumors. Many attempts have been made to enhance the efficacy of CAR T cell therapy by modifying the CAR construct using combination agents, such as compounds, antibodies, or radiation. At present, technology to improve CAR T cell therapy is rapidly developing. In this review, we particularly emphasize the most recent studies utilizing genetic engineering and synergistic agents to improve CAR T cell therapy.

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Combined antitumor effects of anti-EGFR variant III CAR-T cell therapy and PD-1 checkpoint blockade on glioblastoma in mouse model

Cited by 39 publications

References 24 publications

A Rational Designed Novel Bispecific Antibody for the Treatment of GBM

A Rational Designed Novel Bispecific Antibody for the Treatment of GBM

Targeting Tumor-Associated Antigen: A Promising CAR-T Therapeutic Strategy for Glioblastoma Treatment

Making Potent CAR T Cells Using Genetic Engineering and Synergistic Agents

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