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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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Genome editing technologies allow scientists to modify an organism’s DNA via the addition, removal, or rearrangement of genetic material at specific genomic locations. These types of techniques could potentially be used to cure genetic disorders such as hemophilia and sickle cell anemia. One popular and widely used DNA-editing research tool that could lead to safe and effective cures for genetic disorders is the CRISPR-Cas9 system. CRISPR-Cas9 stands for Clustered Regularly Interspaced...
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Bacteria and archaea are susceptible to viral infections just like eukaryotes; therefore, they have developed a unique adaptive immune system to protect themselves. Clustered regularly interspaced short palindromic repeats and CRISPR-associated proteins (CRISPR-Cas) are present in more than 45% of known bacteria and 90% of known archaea.
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Engineering CRISPR System-Based Bacterial Outer Membrane Vesicle Potentiates T Cell Immunity for Enhanced Cancer

Hongjin Wang1, Hengji Zhan1, Bolin Pan1

  • 1Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, 510120, China.

Advanced Materials (Deerfield Beach, Fla.)
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Engineered bacterial outer membrane vesicles (OMVs) deliver genes to enhance T-cell responses against cancer. This novel immunotherapy approach improves tumor inhibition and synergizes with existing treatments, overcoming resistance to immune checkpoint blockade.

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Area of Science:

  • Biotechnology and Nanomedicine
  • Cancer Immunotherapy
  • Molecular Biology

Background:

  • Immune checkpoint blockade (ICB) therapy shows promise in cancer treatment but has limited efficacy due to poor T-cell infiltration and activity.
  • Bacterial outer membrane vesicles (OMVs) are explored for immunotherapy due to their immune-activating properties and potential for therapeutic delivery.
  • Challenges exist in efficiently targeting and loading therapeutic molecules into OMVs for enhanced cancer treatment.

Purpose of the Study:

  • To engineer bacterial outer membrane vesicles (OMVs) for efficient gene packaging and delivery in cancer immunotherapy.
  • To evaluate the therapeutic potential of engineered OMVs encoding CXCL9 and IL12 (OMV-C9I12) in enhancing anti-tumor immunity.
  • To investigate the synergistic effects of OMV-C9I12 with anti-PD-1/PD-L1 therapy in preclinical cancer models.

Main Methods:

  • Engineered E. coli BL21-derived OMVs for enhanced DNA enrichment and gene silencing capabilities.
  • Constructed OMV-C9I12 by packaging genes for CXCL9 and IL12 to promote T-cell recruitment and activation.
  • Assessed tumor inhibition, survival rates, and immune responses in murine MB49 and B16F10 tumor models, including single-cell RNA sequencing (scRNA-seq) and humanized mouse models.

Main Results:

  • Engineered OMVs demonstrated a 7-fold increase in DNA enrichment efficiency and effective gene silencing in vitro.
  • OMV-C9I12 treatment reprogrammed tumor cells to secrete CXCL9 and IL12, significantly enhancing T-cell chemotaxis and activation.
  • OMV-C9I12 markedly inhibited tumor growth, extended survival, and synergized with anti-PD-1/PD-L1 therapy in preclinical models, including bladder and breast cancer in humanized mice.

Conclusions:

  • Engineered OMVs provide a potent platform for cancer gene therapy, overcoming limitations of current immunotherapies.
  • The OMV-C9I12 system effectively enhances T-cell mediated anti-tumor immunity and overcomes resistance to immune checkpoint blockade.
  • This engineered OMV platform offers a promising strategy for developing novel cancer treatments and improving therapeutic outcomes.