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In Vitro Tumor Cell Rechallenge For Predictive Evaluation of Chimeric Antigen Receptor T Cell Antitumor Function
Published on: February 27, 2019
DR5 CAR-NK cells demonstrate superior scalability and potent antitumor activity with favorable safety
Qian Chen1, Meng Xia2, Mengyan Tang2
1Department of Biochemistry and Molecular Biology, Shenzhen University Medical School, Shenzhen 518055, China; Guangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Shenzhen BinDeBio Tech Company, Shenzhen 518000, China.
Abstract:
CAR-NK cells are promising off-the-shelf tumor therapies, yet a scarcity of suitable targets hinders their development. Death receptor 5 (DR5) is an attractive target due to its selective overexpression on tumors and ability to trigger apoptosis. A central challenge, however, is that many tumors exhibit inherent resistance to DR5-mediated cell death, which has stymied the efficacy of existing therapies. Here, we developed a novel DR5-specific chimeric antigen receptor (CAR) from the monoclonal antibody 3E7, which binds human and murine DR5 without cross-reacting to DR4. Primary natural killer (NK) cells transduced with baboon envelope-pseudotyped lentiviral vectors showed stable CAR expression and robust expansion. Remarkably, the culture self-enriched to near 100% CAR positivity, a phenomenon we attribute to the selective elimination of DR5-expressing senescent NK cells that acted as inadvertent feeder cells. In vitro, the engineered NK cells potently killed DR5+ tumor cells through direct cytolysis and DR5-mediated apoptosis, even under exhaustion-like conditions. In vivo, they suppressed tumor growth in xenograft models without observable toxicity to normal tissues, despite their recognition of murine DR5. Furthermore, they exhibited negligible cytotoxicity against human liver organoids, underscoring a favorable safety profile. These results position DR5 CAR-NK cells as a potent, scalable, and safe therapeutic strategy for DR5+ tumors, including those resistant to conventional apoptosis-based therapies.
Insights
Engineered natural killer (NK) cells targeting Death Receptor 5 (DR5) show potent anti-tumor activity. These DR5 CAR-NK cells effectively eliminate tumors, including resistant types, with a favorable safety profile.
Area of Science:
- Immunology
- Oncology
- Cell Therapy
Background:
- Chimeric antigen receptor (CAR)-NK cells offer off-the-shelf cancer therapy potential.
- Targeting Death Receptor 5 (DR5) is promising due to tumor-specific expression, but tumor resistance limits efficacy.
Purpose of the Study:
- To develop novel DR5-specific CAR-NK cells for enhanced cancer therapy.
- To evaluate the efficacy and safety of these engineered NK cells.
Main Methods:
- Developed a novel DR5-specific CAR using the 3E7 antibody.
- Transduced primary NK cells with lentiviral vectors.
- Assessed in vitro killing of DR5+ tumor cells and in vivo tumor suppression in xenograft models.
- Evaluated safety using normal tissues and human liver organoids.
Main Results:
- Engineered NK cells demonstrated stable CAR expression and robust expansion, with near 100% CAR positivity achieved through self-enrichment.
- In vitro, CAR-NK cells potently killed DR5+ tumor cells, even under exhaustion.
- In vivo, CAR-NK cells suppressed tumor growth without observable toxicity to normal tissues.
- Negligible cytotoxicity against human liver organoids indicated a favorable safety profile.
Conclusions:
- DR5 CAR-NK cells are a potent, scalable, and safe therapeutic strategy for DR5+ tumors.
- This approach shows promise for treating tumors resistant to conventional apoptosis-based therapies.
