Related Experiment Video
Updated: Jul 30, 2025
A Real-time Potency Assay for Chimeric Antigen Receptor T Cells Targeting Solid and Hematological Cancer Cells
Published on: November 12, 2019
A chimeric antigen receptor uniquely recognizing MICA/B stress proteins provides an effective approach to target
John Goulding1, Wen-I Yeh1, Bryan Hancock1
1Fate Therapeutics Inc., San Diego, CA 92131, USA.
Background:
The advent of chimeric antigen receptor (CAR) T cell therapies has transformed the treatment of hematological malignancies; however, broader therapeutic success of CAR T cells has been limited in solid tumors because of their frequently heterogeneous composition. Stress proteins in the MICA and MICB (MICA/B) family are broadly expressed by tumor cells following DNA damage but are rapidly shed to evade immune detection.
Methods:
We have developed a novel CAR targeting the conserved α3 domain of MICA/B (3MICA/B CAR) and incorporated it into a multiplexed-engineered induced pluripotent stem cell (iPSC)-derived natural killer (NK) cell (3MICA/B CAR iNK) that expressed a shedding-resistant form of the CD16 Fc receptor to enable tumor recognition through two major targeting receptors.
Findings:
We demonstrated that 3MICA/B CAR mitigates MICA/B shedding and inhibition via soluble MICA/B while simultaneously exhibiting antigen-specific anti-tumor reactivity across an expansive library of human cancer cell lines. Pre-clinical assessment of 3MICA/B CAR iNK cells demonstrated potent antigen-specific in vivo cytolytic activity against both solid and hematological xenograft models, which was further enhanced in combination with tumor-targeted therapeutic antibodies that activate the CD16 Fc receptor.
Conclusions:
Our work demonstrated 3MICA/B CAR iNK cells to be a promising multi-antigen-targeting cancer immunotherapy approach intended for solid tumors.
Funding:
Funded by Fate Therapeutics and NIH (R01CA238039).
Insights
Engineered natural killer (NK) cells targeting MICA/B stress proteins show promise for solid tumor immunotherapy by overcoming immune evasion mechanisms. This novel approach demonstrates potent anti-tumor activity in preclinical models.
Area of Science:
- Immunology
- Oncology
- Cell Therapy
Background:
- Chimeric antigen receptor (CAR) T-cell therapy has revolutionized hematological cancer treatment but faces challenges in solid tumors due to tumor heterogeneity.
- Stress proteins MICA/B, expressed by tumor cells after DNA damage, are often shed to evade immune detection.
Purpose of the Study:
- To develop a novel CAR targeting the MICA/B stress proteins for enhanced cancer immunotherapy.
- To engineer induced pluripotent stem cell (iPSC)-derived natural killer (NK) cells with a MICA/B-targeting CAR and a shedding-resistant CD16 receptor for improved tumor recognition and activity.
Main Methods:
- Development of a novel CAR (3MICA/B CAR) targeting the conserved α3 domain of MICA/B.
- Engineering of multiplexed iPSC-derived NK cells (3MICA/B CAR iNK) with the 3MICA/B CAR and a shedding-resistant CD16 Fc receptor.
- Evaluation of anti-tumor reactivity against a library of human cancer cell lines and in vivo xenograft models.
Main Results:
- The 3MICA/B CAR effectively mitigates MICA/B shedding and soluble MICA/B-mediated inhibition.
- 3MICA/B CAR iNK cells exhibited antigen-specific anti-tumor reactivity against diverse human cancer cell lines.
- Preclinical studies showed potent in vivo cytolytic activity against solid and hematological tumors, enhanced by combination with CD16-activating antibodies.
Conclusions:
- 3MICA/B CAR iNK cells represent a promising multi-antigen-targeting immunotherapy strategy for solid tumors.
- This approach addresses immune evasion by targeting broadly expressed stress proteins and enhancing NK cell effector functions.
More Related Videos
11:02Induction of Invasive Transitional Cell Bladder Carcinoma in Immune Intact Human MUC1 Transgenic Mice: A Model for Immunotherapy Development
Published on: October 30, 2013
![Dynamic Imaging of Chimeric Antigen Receptor T Cells with [18F]Tetrafluoroborate Positron Emission Tomography/Computed Tomography](/_next/image?url=https%3A%2F%2Fcloudfront.jove.com%2FCDNSource%2Fteasers%2F62334.jpg&w=3840&q=50)
09:34Dynamic Imaging of Chimeric Antigen Receptor T Cells with [18F]Tetrafluoroborate Positron Emission Tomography/Computed Tomography
Published on: February 17, 2022
