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Updated: Sep 29, 2025
Analysis of Human T Cell Activity in an Allogeneic Co-Culture Setting of Pre-Treated Tumor Cells
Published on: March 7, 2025
Human induced-T-to-natural killer cells have potent anti-tumour activities
Zhiwu Jiang1, Le Qin1, Yuou Tang2
1China-New Zealand Joint Laboratory of Biomedine and Health, State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Chinese Academy of Sciences Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
Background:
Adoptive cell therapy (ACT) is a particularly promising area of cancer immunotherapy, engineered T and NK cells that express chimeric antigen receptors (CAR) are being explored for treating hematopoietic malignancies but exhibit limited clinical benefits for solid tumour patients, successful cellular immunotherapy of solid tumors demands new strategies.
Methods:
Inactivation of BCL11B were performed by CRISPR/Cas9 in human T cells. Immunophenotypic and transcriptional profiles of sgBCL11B T cells were characterized by cytometer and transcriptomics, respectively. sgBCL11B T cells are further engineered with chimeric antigen receptor. Anti-tumor activity of ITNK or CAR-ITNK cells were evaluated in preclinical and clinical studies.
Results:
We report that inactivation of BCL11B in human CD8+ and CD4+ T cells induced their reprogramming into induced T-to-natural killer cells (ITNKs). ITNKs contained a diverse TCR repertoire; downregulated T cell-associated genes such as TCF7 and LEF1; and expressed high levels of NK cell lineage-associated genes. ITNKs and chimeric antigen receptor (CAR)-transduced ITNKs selectively lysed a variety of cancer cells in culture and suppressed the growth of solid tumors in xenograft models. In a preliminary clinical study, autologous administration of ITNKs in patients with advanced solid tumors was well tolerated, and tumor stabilization was seen in six out nine patients, with one partial remission.
Conclusions:
The novel ITNKs thus may be a promising novel cell source for cancer immunotherapy.
Trial Registration:
ClinicalTrials.gov, NCT03882840 . Registered 20 March 2019-Retrospectively registered.
Insights
Researchers reprogrammed T cells into induced T-to-natural killer cells (ITNKs) by inactivating BCL11B. These novel ITNKs show promise for treating solid tumors in preclinical and early clinical studies, offering a new avenue for cancer immunotherapy.
Area of Science:
- Immunology
- Cell Biology
- Oncology
Background:
- Adoptive cell therapy (ACT) shows promise in cancer immunotherapy but has limited success in solid tumors.
- Engineered T and NK cells with chimeric antigen receptors (CAR) are being explored for hematologic malignancies.
- New strategies are needed for effective cellular immunotherapy of solid tumors.
Purpose of the Study:
- To investigate the reprogramming of human T cells into induced T-to-natural killer cells (ITNKs) by inactivating BCL11B.
- To evaluate the anti-tumor activity and safety of ITNKs and CAR-engineered ITNKs.
- To explore ITNKs as a potential cell source for solid tumor immunotherapy.
Main Methods:
- BCL11B was inactivated in human T cells using CRISPR/Cas9 gene editing.
- Immunophenotypic and transcriptional profiles of BCL11B-inactivated T cells were analyzed.
- ITNKs were engineered with CARs and tested in preclinical solid tumor models and a preliminary clinical trial.
Main Results:
- BCL11B inactivation reprogrammed T cells into ITNKs, which expressed NK cell markers and downregulated T cell genes.
- ITNKs and CAR-ITNKs demonstrated selective lysis of cancer cells in vitro and suppressed solid tumor growth in vivo.
- In a Phase I trial, autologous ITNK administration was well-tolerated in patients with advanced solid tumors, showing tumor stabilization in 6/9 patients and one partial remission.
Conclusions:
- Novel induced T-to-natural killer cells (ITNKs) represent a promising new cell source for cancer immunotherapy.
- BCL11B inactivation offers a viable strategy for generating potent anti-tumor immune cells.
- ITNKs demonstrate potential for treating solid tumors, warranting further clinical investigation.
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