Author of

• 18502

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  P3.02c - Poster Session with Presenters Present (ID 472)

  • Event: WCLC 2016
  • Type: Poster Presenters Present
  • Track: Advanced NSCLC
  • Presentations: 1
  • Moderators:
  • Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)

  • 18564

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    P3.02c-062 - Anti-Lung Cancer Effect of CD8+ T Cells Transduced Retroviral Vector Encoding WT1-Specific TCRs and siRNAs Targeting Endogenous TCRs (ID 4333)

    14:30 - 14:30  |  Author(s): J. An
    • Abstract

    Background:
    Using of genetically engineered T lymphocytes with tumor antigen-specific T-cell receptor for treatment of cancer has clinically proved promise, however, this approach is complicated by several potential problems: (1) on-target adverse events directed against normal tissues, especially when affinity-enhanced TCRs are used; (2) issues related to chain mispairing between the introduced and endogenous TCR genes; (3) off-target adverse events because of inherent cross-reactivity of the introduced TCR. In this study, we examined in detail the efficacy and safety of normal CD8[+] T lymphocytes transduced retroviral vector encoding siRNAs which specifically down-regulate endogenous TCR expression, and a siRNA-resistant WT1-specific TCR construct for adoptive immunotherapy against human lung cancer cells.
    
    Methods:
    A novel TCR vector system which simultaneously delivers shRNAs for endogenous TCR α/β genes and WT1-specific TCRs genes were transduced into normal peripheral CD8+ T cells. The safety and effectiveness of these transfectant against lung cancer cells was evaluated both in vitro and in vivo.
    
    Results:
    First, we confirmed the augmented and inhibitory efficacies of the WT1-specific TCRs with siRNAs targeting endogenous TCRs (WT1-siTCR) vector for expression of the respectively introduced and endogenous TCRs. The result indicating that sufficient functional suppression of endogenous TCR and enhanced expression of the introduced TCR are achievable using the WT1-siTCR vector. Secondly, The WT1-specific TCRs with siRNAs targeting endogenous TCRs double gene modified T cells were augmented cytotoxic activities compared with only WT1-TCR–transduced T cells against lung cancer cells by standard 5-hour 51Cr-release assays at various effector/target (E/T) ratios.
    
    Conclusion:
    These data revealed that WT1-siTCR vector system shows safety resulting from stronger expression of the introduced WT1-specific TCR with inhibition of endogenous TCRs. Results from this study also demonstrate that significant enhancement of anti-lung cancer cells reactivity of these WT1-siTCR gene-modified T cells. In summary, the present study shows considerable promise in terms of safety and efficacy for adoptive immunotherapy against lung cancer cells using WT1-specific TCRs with siRNAs targeting endogenous TCRs gene-engineered T cells.