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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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Quantifying Antibody-Dependent Cellular Cytotoxicity in a Tumor Spheroid Model: Application for Drug Discovery
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2B4 co-stimulation and dasatinib modulation enhance anti-CD19 CAR-NK-92 cell cytotoxicity.

Matheus Henrique Dos Santos1, Júlia Teixeira Cottas de Azevedo2, Mara Elisama da Silva Januário1

  • 1Center for Cell-based Therapy (CTC), Regional Blood Center of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.

Frontiers in Immunology
|December 29, 2025
PubMed
Summary

Optimizing Chimeric Antigen Receptor (CAR)-NK cells with NK-specific co-stimulatory domains like 2B4 and DAP12 enhances cytotoxicity. Transient dasatinib treatment reversibly modulates CAR-NK function, improving tumor control in vivo.

Keywords:
2B4B-cell lymphomaCAR-NK-92 cellsDAP12NK-92adoptive cell therapyallogeneic therapydasatinib

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Area of Science:

  • Immunology
  • Cell Biology
  • Oncology

Background:

  • Chimeric Antigen Receptor (CAR)-based therapies have revolutionized cancer treatment, particularly for hematological malignancies.
  • While CAR-T cell co-stimulatory domains are well-understood, optimal signaling modules for CAR-Natural Killer (CAR-NK) cells require further definition.
  • Tailoring co-stimulatory domains is crucial for enhancing CAR-NK cell-mediated cytotoxicity and therapeutic potential.

Purpose of the Study:

  • To engineer and evaluate CAR19 constructs with NK-specific co-stimulatory domains (2B4, DAP12) using the NK-92 cell line.
  • To assess the impact of these domains on CAR-NK cell function, including cytotoxicity and cytokine production.
  • To investigate the pharmacologic modulation of CAR-NK cells using transient dasatinib treatment and its effects on in vivo antitumor activity.

Main Methods:

  • Engineering of CAR19 constructs incorporating 2B4 and DAP12 co-stimulatory domains in the NK-92 cell line.
  • Functional assays (cytotoxicity, cytokine production) and transcriptomic profiling to evaluate CAR-NK cell responses.
  • In vivo studies using a xenograft model to assess antitumor efficacy of engineered CAR-NK cells, with and without dasatinib pretreatment.

Main Results:

  • CAR constructs with 2B4 and 2B4-DAP12 domains significantly enhanced NK cytotoxic programming, confirmed by functional assays and transcriptomic signatures.
  • Short-term dasatinib treatment reversibly suppressed CAR-NK effector function, but led to enhanced activity upon drug withdrawal.
  • In vivo, 2B4-DAP12 CAR19-NK-92 cells pretreated with dasatinib demonstrated superior tumor control compared to conventional 4-1BBζ CAR19-NK-92 cells.

Conclusions:

  • Selection of NK-specific co-stimulatory domains is critical for optimizing CAR-NK cell performance.
  • Reversible inhibition of Src-family kinases via dasatinib offers a strategy to enhance CAR-NK therapy efficacy.
  • The NK-92 cell line serves as a valuable proof-of-concept platform for dissecting CAR signaling mechanisms and informing the development of next-generation CAR-NK therapies for primary NK cells.