EGFRvIII-CAR-T Cells with PD-1 Knockout Have Improved Anti-Glioma Activity
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ORIGINAL ARTICLE
EGFRvIII-CAR-T Cells with PD-1 Knockout Have Improved Anti-Glioma Activity Haifeng Zhu 1,2 & Yongping You 3 & Zhouming Shen 2 & Lei Shi 4 Received: 29 June 2019 / Accepted: 1 October 2019 # Arányi Lajos Foundation 2020
Abstract Glioblastoma multiforme (GBM) is the most malignant form of the brain tumors. EGFR variant III (EGFRvIII) is expressed in about 30% of GBM specimens, but not expressed in normal brain tissues. Therefore, EGFRvIII protein offers an ideal CAR-T therapeutic target for EGFRvIII-positive GBM patients. PD-L1 is expressed in a variety of cancer cells, including GBM. Tumorassociated PD-L1 can bind to PD-1 on T cells and promote apoptosis of T cells, thus suppressing the anti-cancer immune response. In our current studies, PD-1WT EGFRvIII-CAR-T cells and PD-1KD EGFRvIII-CAR-T cells were generated. Cytokine production and lytic activity of these two CAR-T cells against to PD-L1WT EGFRvIII+ U373 cells or PD-L1KO EGFRvIII+ U373 cells were evaluated. The results showed that PD-1KD EGFRvIII-CAR-T cells and PD-1WT EGFRvIIICAR-T cells showed same levels of interferon-γ (IFN-γ) and interleukin-2 (IL-2) production as well as cytolytic activity against PD-L1KO EGFRvIII+ U373 cells; however, PD-1KD EGFRvIII-CAR-T cells exhibited higher levels of IFN-γ and IL-2 production as well as cytolytic activity against PD-L1+ EGFRvIII+ U373 cells than that of PD-1WT EGFRvIII-CAR-T cells. PD-1KD EGFRvIII-CAR-T cells also exhibited higher anti-glioma activity and longer survival in mice in vivo than that of PD-1WT EGFRvIII-CAR-T cells. Taken together, our findings indicate that PD-1 knockout enhances lytic activity of EGFRvIII-CAR-T cells against PD-L1+ EGFRvIII+ GBM cells. These might provide a new insight into strategy of GBM CAR-T cell therapy. Keywords Glioblastoma multiform . EGFRvIII . CAR-T . PD-1 . PD-L1
Introduction Glioblastoma multiforme (GBM) is the most malignant form of the brain tumors in adults. The different genetic and epigenetic abnormalities are involved in GBM formation. Although various therapeutic approaches including surgery,
* Yongping You [email protected] * Lei Shi [email protected] 1
Department of Neurosurgery, Nanjing Medical University, Nanjing 210029, People’s Republic of China
2
Department of Neurosurgery, Funing People’s Hospital, Funing 224400, People’s Republic of China
3
Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, People’s Republic of China
4
epartment of Neurosurgery, Affiliated Kunshan Hospital of Jiangsu University, Suzhou 215300, People’s Republic of China
radiotherapy and chemotherapy have been applied in clinic, the prognosis of GBM patients remains still poor, with median survival being on average little over a year [1–3]. Chimeric antigen receptors (CARs) on CD8+ cytotoxic T lymphocytes (CTL) directly recognize cell surface antigens independent of MHC, therefore avoids tumor escape caused by MHC downregulation. The majority of GBM exhibits a frequent amplification of epidermal growth facto
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