Related Experiment Video
Updated: Sep 9, 2025
Advances in Human Induced Pluripotent Stem Cell-Derived Chimeric Antigen Receptor-Expressing Natural Killer Cells
Published on: February 14, 2025
Multimodal targeting of metastatic renal cell carcinoma via CD70-directed allogeneic CAR-NKT cells
Yan-Ruide Li1, Junhui Hu2, Zhe Li1
1Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA.
Abstract:
Renal cell carcinoma (RCC) represents about 90% of kidney cancers, with 30%-40% of patients developing metastatic disease despite current treatments. Conventional chimeric antigen receptor (CAR)-T therapy targeting CD70 shows promise but faces challenges due to its autologous, personalized nature. Here, we develop allogeneic CD70-directed CAR-engineered invariant natural killer T (AlloCAR70-NKT) cells from hematopoietic stem and progenitor cells using a clinically guided culture method. These cells expand robustly with high purity and no fratricide risk. AlloCAR70-NKT cells exhibit potent cytotoxicity against primary and metastatic RCC via CAR- and natural killer (NK) receptor-mediated mechanisms and selectively target the immunosuppressive tumor microenvironment (TME) through T cell receptor (TCR) recognition. Additionally, they eliminate CD70+ host alloreactive T cells, promoting therapeutic persistence. Taken together, our findings support the therapeutic potential of AlloCAR70-NKT cells as a next-generation, off-the-shelf immunotherapy with dual tumor- and TME-targeting functionality and the added capacity to eliminate alloreactive T cells, which offers a compelling strategy for treating metastatic RCC.
Insights
Researchers developed novel allogeneic CAR-NKT cells targeting CD70 for metastatic renal cell carcinoma (RCC). This off-the-shelf immunotherapy offers dual tumor and microenvironment targeting with enhanced persistence for treating kidney cancer.
Area of Science:
- Immunotherapy
- Oncology
- Cell Therapy
Background:
- Renal cell carcinoma (RCC) accounts for 90% of kidney cancers.
- Metastatic disease develops in 30-40% of patients despite current treatments.
- Existing chimeric antigen receptor (CAR)-T therapies face challenges with autologous, personalized approaches.
Purpose of the Study:
- To develop an allogeneic, off-the-shelf immunotherapy for metastatic RCC.
- To engineer CAR-invariant natural killer T (CAR-NKT) cells targeting CD70.
- To evaluate the efficacy and mechanisms of these engineered cells.
Main Methods:
- Hematopoietic stem and progenitor cells were used to generate allogeneic CD70-directed CAR-engineered invariant natural killer T (AlloCAR70-NKT) cells.
- A clinically guided culture method was employed for robust expansion and high purity.
- Cytotoxicity against primary and metastatic RCC, tumor microenvironment (TME) targeting, and alloreactive T cell elimination were assessed.
Main Results:
- AlloCAR70-NKT cells demonstrated robust expansion with high purity and no fratricide.
- These cells exhibited potent cytotoxicity against RCC via CAR- and natural killer (NK) receptor-mediated mechanisms.
- AlloCAR70-NKT cells selectively targeted the immunosuppressive TME via T cell receptor (TCR) recognition and eliminated CD70+ host alloreactive T cells, enhancing persistence.
Conclusions:
- AlloCAR70-NKT cells represent a promising next-generation immunotherapy for metastatic RCC.
- The 'off-the-shelf' nature offers a significant advantage over autologous therapies.
- Dual tumor and TME targeting, along with alloreactive T cell elimination, provides a compelling strategy for treating metastatic kidney cancer.
