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Off-the-shelf invariant NKT cells expressing anti-PSCA CAR and IL-15 promote pancreatic cancer regression in mice
Zhenyu Dai, … , Michael A. Caligiuri, Jianhua Yu
Zhenyu Dai, … , Michael A. Caligiuri, Jianhua Yu
Published April 15, 2025
Citation Information: J Clin Invest. 2025;135(8):e179014. https://doi.org/10.1172/JCI179014.
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Research Article Immunology Oncology Article has an altmetric score of 17

Off-the-shelf invariant NKT cells expressing anti-PSCA CAR and IL-15 promote pancreatic cancer regression in mice

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Abstract

Pancreatic ductal adenocarcinoma cancer (PDAC) continues to pose a significant health burden, with a 5-year survival rate of only 10%. Prostate stem cell antigen (PSCA) is highly expressed on the surface of tumor cells of most PDAC patients, with minimum expression in most normal tissues. Here, we generated cryopreserved, off-the-shelf, allogeneic PSCA chimeric antigen receptor (CAR) invariant NKT (iNKT) cells using human peripheral blood mononuclear cells as a cell source. In multiple in vitro and in vivo PDAC models, freshly manufactured PSCA CAR_sIL-15 iNKT cells and frozen-thawed, off-the-shelf PSCA CAR_sIL-15 iNKT cells demonstrate comparable efficacies, and both show remarkable suppression of PSCA-positive and gemcitabine-resistant PDAC. Importantly, off-the-shelf cryopreserved PSCA CAR_sIL-15 iNKT cells show equivalent efficacy when compared with PSCA CAR T cells using the same PSCA CAR and in the same PDAC model; however, PSCA CAR_sIL-15 iNKT cells do not appear to induce systemic toxicity or graft-versus-host disease, thus allowing for multiple infusions to control recurrent disease. Collectively, our study suggests that PSCA CAR_sIL-15 iNKT cells merit clinical investigation for PDAC patients exhibiting positive PSCA expression. The therapy could be given as a single agent or in combination with established therapeutic modalities for PDAC.

Authors

Zhenyu Dai, Zheng Zhu, Zhiyao Li, Lei Tian, Kun-Yu Teng, Hanyu Chen, Li-Shu Wang, Jianying Zhang, Laleh Melstrom, Michael A. Caligiuri, Jianhua Yu

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Figure 5

PSCA CAR_sIL-15 iNKT cells eliminate human PDAC cells in an orthotopic tumor model and maintain long-term tumor-free survival.

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PSCA CAR_sIL-15 iNKT cells eliminate human PDAC cells in an orthotopic t...
(A) Schematic diagram of treatment with PSCA CAR_sIL-15 iNKT cells in a human orthotopic PDAC model established by i.p. injection of MIA PaCa-2_luc cells into NSG mice. The image was created in BioRender. (B) Representative images of the pancreas and the liver of each group in the MIA PaCa-2-transplanting PDAC mouse model at the endpoint of the in vivo experiments. Red arrows mark metastatic tumors in the liver. In this orthotopic PDAC model, PSCA CAR_sIL-15 iNKT cells efficiently eliminated carcinoma in situ within the pancreas and decreased metastatic lesion formation in the liver. (C) Summary statistical data of mouse tumor burden changes of each treatment group. The results are displayed as mean ± SD. **P < 0.01; ****P < 0.0001 (2-way ANOVA). n = 7 for the untreated and PSCA CAR_sIL-15 groups. n = 6 for the sIL-15 group. (D) The growth of the tumor was monitored by BLI imaging until week 8. (E) Overall Kaplan-Meier survival curve. ***P < 0.001 (log-rank test). n = 7 for the untreated and PSCA CAR_sIL-15 groups. n = 6 for the sIL-15 group. Treatment with PSCA CAR_sIL-15 iNKT cells resulted in complete clearance of orthotopic tumors and reached 100% survival. (F) Assessment of blood cell populations on day 15 after PDAC cell transplantation (12 days after iNKT cell treatment). Peripheral blood counts and HGB in the PSCA CAR_sIL-15 iNKT group were not changed compared with the untreated group and sIL-15 iNKT cell treatment group. Values represent mean ± SD (n = 7 for the untreated and PSCA CAR_sIL-15 groups. n = 4 for the sIL-15 group.). 2-way ANOVA.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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