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Related Concept Videos

Tumor Immunotherapy01:27

Tumor Immunotherapy

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Immunotherapy is a treatment that boosts or manipulates the immune system to fight diseases, including cancer. For instance, by stimulating an immune response through vaccinations against viruses that cause cancers, like hepatitis B virus and human papillomavirus, these diseases can be prevented. Nonetheless, some cancer cells can avoid the immune system due to their rapid mutation and division. The immune response to many cancers involves three phases: elimination, equilibrium, and escape.
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Masked Chimeric Antigen Receptor for Tumor-Specific Activation.

Xiaolu Han1, Paul D Bryson2, Yifan Zhao3

  • 1Genetic, Molecular & Cellular Biology Program, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.

Molecular Therapy : the Journal of the American Society of Gene Therapy
|January 28, 2017
PubMed
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Engineered T (CAR-T) cells offer potent cancer immunotherapy but can cause toxicities. A novel masked CAR (mCAR) design uses a tumor-specific protease-cleavable shield to enhance safety by enabling CAR-T cell targeting only at the tumor site.

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Area of Science:

  • Oncology
  • Immunology
  • Biotechnology

Background:

  • Adoptive cellular therapy using chimeric antigen receptor (CAR)-engineered T (CAR-T) cells is a significant advancement in cancer immunotherapy.
  • CAR-T cells target tumor-associated antigens (TAAs) for potent antitumor activity.
  • A major limitation is "on-target off-tumor" toxicity due to TAAs expressed on healthy tissues, restricting clinical use.

Purpose of the Study:

  • To develop a safer CAR-T cell therapy by minimizing "on-target off-tumor" toxicities.
  • To design a masked CAR (mCAR) that is selectively activated in the tumor microenvironment.
  • To evaluate the safety and efficacy of the novel mCAR system.

Main Methods:

  • Engineered an epidermal growth factor receptor (EGFR)-specific masked CAR (mCAR) with a protease-sensitive linker and masking peptide.
  • Assessed mCAR binding and activation in vitro with and without tumor-associated proteases.
  • Evaluated the in vivo antitumor efficacy and safety of mCAR-T cells compared to unmasked CAR-T cells.

Main Results:

  • The mCAR demonstrated significantly reduced antigen binding and activation in the absence of specific proteases.
  • Protease treatment restored normal CAR-T cell binding and activity, mimicking tumor microenvironment conditions.
  • mCAR-T cells exhibited comparable antitumor efficacy to conventional CAR-T cells in vivo with an improved safety profile.

Conclusions:

  • The developed masked CAR (mCAR) system effectively enhances the safety of CAR-T cell therapy.
  • Protease-mediated masking and unmasking provides a mechanism for tumor-specific CAR-T cell activation.
  • This strategy holds promise for targeting broadly expressed antigens and improving CAR-T cell therapy applications.