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

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

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 8

Cryopreserved PSCA CAR_sIL-15 iNKT cells exhibit anti-tumor functions comparable to conventional PSCA CAR T cells but do not cause GvHD.

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Cryopreserved PSCA CAR_sIL-15 iNKT cells exhibit anti-tumor functions co...
(A) Schematic diagram of treatment with PSCA CAR_sIL-15 iNKT cells or PSCA CAR_sIL-15 T cells in a Capan-1–transplanted metastatic PDAC humanized mouse model to investigate the risk of GvHD. (B) Fourteen days after transplantation, the percentage of repopulated human CD3+CD4+ T cells, CD3+CD8+ T cells, CD19+ B cells, and CD56+ NK cells were assessed in the peripheral blood of the mice. (C) The burden of tumor was monitored by BLI on days 24 and day 31. (D) Clinical GvHD scores were observed on day 42. ***P < 0.001. n = 3 per group. (E) Splenic dimensions of tumor-bearing mice treated with PSCA CAR_sIL-15 T cells (left) or PSCA CAR_sIL-15 iNKT cells (right) measured on day 42. (F) SGM3 mice engrafted with PBMCs were injected with 2 × 106 Capan-1-luc cells. Seven days later, mice were injected either PBS (n = 3) or off-the-shelf cryopreserved iNKT cells (4 × 106 cells/mouse i.p. plus 2 × 106 cells/mouse i.v., n = 6). Sera were harvested 1 (day 1) and 3 days (day 3) after the iNKT cell injection to assess for CRS-associated cytokines. The sera from the PBS group were collected 1 day after injection (Day 1). Data are displayed as the mean ± SD. Statistical analyses were conducted using a 2-sided t test.