Off-the-shelf invariant NKT cells expressing anti-PSCA CAR and IL-15 promote pancreatic cancer regression in mice
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
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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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 4

In vivo assessment of PSCA CAR_sIL-15 iNKT cells.

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In vivo assessment of PSCA CAR_sIL-15 iNKT cells. (A) Treatment schema f...
(A) Treatment schema for i.p. plus i.v. injection of PSCA CAR_sIL-15 iNKT cells in a human metastatic PDAC model established by i.p. injection of PSCA+ Capan-1_luc cells into NSG mice. The image was created in BioRender. (B) Tumor growth, directly correlated with color intensity, was monitored by BLI until week 9. (C) Graphical depiction of BLI from B up to day 32. The results are displayed as mean ± SD (n = 4). *P < 0.05; **P < 0.01 (2-way ANOVA). (D) Overall Kaplan–Meier survival curve. **P < 0.01 (log-rank test, n = 5). Compared with the 2 control groups, PSCA CAR_sIL-15 iNKT cells significantly inhibited the progression of metastatic PDAC and prolonged the survival of the tumor-bearing mice. (E) Schematic diagram as in A but with MIA PaCa-2_luc PDAC tumor cells. (F) Representative images of the pancreas and liver from each treatment group at the endpoint of the in vivo experiment. Red arrows mark metastatic tumors in the liver. PSCA CAR_sIL-15 iNKT cells demonstrated strong therapeutic effects, as evidenced by their ability to kill MIA PaCa-2 cells in the pancreas and the liver. (G) Summary of relative fold change in BLI over 15 days as shown in H. The results are displayed as mean ± SD (n = 5). **P < 0.01; ***P < 0.001 (2-way ANOVA). (H) The growth of the tumor was monitored by BLI imaging until week 6. (I) Overall Kaplan-Meier survival curve. ***P < 0.001 (log-rank test, n = 5). PSCA CAR_sIL-15 iNKT cells completely eradicated PDAC in vivo. sIL-15 iNKT cells were inferior to PSCA CAR_sIL-15 iNKT cells but also exhibited some degree of efficacy in delaying tumor progression in mice bearing MIA PaCa-2 cells. (J) Assessment of blood cells and HGB on day 15 after PDAC cell transplantation (12 days after treatment with PBS, sIL-15 iNKT cells, or PSCA CAR_sIL-15 iNKT cells). Values represent mean ± SD (n = 5). Not significant (2-way ANOVA).