Adoptive Transfer of Autologous Invariant Natural Killer T Cells as Immunotherapy for Advanced Hepatocellular Carcinoma: A Phase I Clinical Trial

Gao, Yao; Guo, Jianhua; Bao, Xuli; Xiong, Fang; Ma, Yonggang; Tan, Bi-Bo; Yu, Lele; Zhao, Yong; Lu, Jun Q.

doi:10.1002/onco.13899

Cited by 24 publications

(12 citation statements)

References 36 publications

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“…DC-mediated αGC presentation transiently expanded peripheral iNKT cell levels, leading to rapid iNKT tumor infiltration, proinflammatory cytokine profile in the serum, and the adjuvant stimulation of natural killer (NK) cells and cytotoxic lymphocytes (CTLs) [ 30 , 31 ]. These results suggest the powerful anti-tumor potential of iNKT cell activation; however, variability in endogenous iNKT cell quality, especially in immune-exhausted cancer patients, has elicited a transition towards therapies engrafting PBMC-iNKT cells activated using in vitro αGC stimulation [ 32 ]. The adoptive transfer of PBMC-iNKT cells displayed similar immunostimulatory effects as the in vivo modulation of mature iNKT cells but with a greater efficacy for late stage cancer patients [ 33 , 34 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

Tumor-Localized Administration of α-GalCer to Recruit Invariant Natural Killer T Cells and Enhance Their Antitumor Activity against Solid Tumors

Zhou

Wilson

et al. 2022

IJMS

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Invariant natural killer T (iNKT) cells have the capacity to mount potent anti-tumor reactivity and have therefore become a focus in the development of cell-based immunotherapy. iNKT cells attack tumor cells using multiple mechanisms with a high efficacy; however, their clinical application has been limited because of their low numbers in cancer patients and difficulties in infiltrating solid tumors. In this study, we aimed to overcome these critical limitations by using α-GalCer, a synthetic glycolipid ligand specifically activating iNKT cells, to recruit iNKT to solid tumors. By adoptively transferring human iNKT cells into tumor-bearing humanized NSG mice and administering a single dose of tumor-localized α-GalCer, we demonstrated the rapid recruitment of human iNKT cells into solid tumors in as little as one day and a significantly enhanced tumor killing ability. Using firefly luciferase-labeled iNKT cells, we monitored the tissue biodistribution and pharmacokinetics/pharmacodynamics (PK/PD) of human iNKT cells in tumor-bearing NSG mice. Collectively, these preclinical studies demonstrate the promise of an αGC-driven iNKT cell-based immunotherapy to target solid tumors with higher efficacy and precision.

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Section: Discussionmentioning

confidence: 99%

Tumor-Localized Administration of α-GalCer to Recruit Invariant Natural Killer T Cells and Enhance Their Antitumor Activity against Solid Tumors

Zhou

Wilson

et al. 2022

IJMS

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“…Invariant NKT is a type of natural killer T cell that can produce large quantities of cytokines, such as the Th1-type cytokine interferon-γ (IFN-γ) and the Th2-type cytokine interleukin-4 (IL-4), to promote dendritic cell maturation, enhance their capacity for antigen presentation, and subsequently reinforce CD8 + T cell responses ( 16 ). The results of our phase 1 trial indicated that autologous iNKT cell therapy is well-tolerated by hepatocellular carcinoma (HCC) patients ( 17 ), suggesting its potential to improve outcomes in other cancers. In addition, elevated PD-1 levels were found to be associated with iNKT cell deficiency ( 18 ), indicating that iNKT cells likely contribute to overcoming poor immune cell response in tumors.…”

Section: Discussionmentioning

confidence: 99%

SOX chemotherapy with anti-PD-1 and iNKT cell immunotherapies for stage IV gastric adenocarcinoma with liver metastases: A case report

Liu

Wang

et al. 2022

Front. Immunol.

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Gastric cancer (GC) is the fourth most common cancer worldwide, with overall 5-year survival rate of approximate 20%. Although multimodal treatments that combine surgery with chemotherapy and immunotherapy have been shown to improve survival, pathological complete response (pCR) is rare in advanced GC patients with liver metastases. Pre-clinical studies and clinical trials have demonstrated the antitumor efficacy of invariant natural killer T (iNKT) cells in various malignancies, including GC. While multimodal therapy comprised of chemotherapy, anti-programmed cell death-1 (PD-1) therapy, and iNKT cell immunotherapy have not been reported in GC patients. This case report describes the treatment of an early 60s patient diagnosed with advanced stage IVB (T1N1M1) adenocarcinomas of gastric cardia with liver metastases who received multimodal therapy comprised of SOX chemotherapy, anti-programmed cell death-1 (PD-1) therapy, and iNKT cell immunotherapy followed by surgical resection. Dramatic decreases in tumor area were observed in both the primary tumor and metastatic lesions following six cycles of SOX chemotherapy and iNKT cell immunotherapy, and four cycles of anti-PD-1 therapy. This combined treatment resulted in the transformation of a remarkably large, unresectable liver metastases into a resectable tumor, and the patient received total gastrectomy with D2 lymph node dissection and liver metastasectomy. Subsequent pathological examination detected no cancer cells in either the primary site or liver metastatic lesions, supporting the likelihood that this treatment achieved pCR. To our knowledge, this report represents the first case of a metastatic gastric cancer patient displaying pCR after six months of multimodal therapy, thus supporting that a SOX chemotherapy, anti-PD-1 therapy, and iNKT cell immunotherapy combination strategy may be effective for treating, and potentially curing, patients with advanced gastric adenocarcinoma.

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“…All procedures used for the preparation of iNKT cells were detailed in our previous phase 1 trial. 24 Approximately 6~9×10 7 cells/m 2 of iNKT cells were infused in each patient, with > 95% purity and viability. Extensive details of iNKT cell preparation are provided in Supplement ( Supplementary Method 1 in Supplement ).…”

Section: Methodsmentioning

confidence: 99%

Efficacy of Invariant Natural Killer T Cell Infusion Plus Transarterial Embolization vs Transarterial Embolization Alone for Hepatocellular Carcinoma Patients: A Phase 2 Randomized Clinical Trial

Guo,

Bao,

Liu

et al. 2023

JHC

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Purpose Invariant NKT cells (iNKT) are CD1d-restricted T cells with the capacity of antitumor immunity. The safety of autologous iNKT cell treatment in hepatocellular carcinoma (HCC) has been verified. This study aimed to investigate its efficacy in advanced HCC after transarterial chemoembolization (TACE) failure. Patients and methods This open-label, randomized, controlled, trial enrolled 60 patients with unresectable HCC after TACE failure at three centers. Transarterial embolization (TAE) was used instead of TACE to protect iNKT cell function. Patients were randomly assigned (1:1) to receive TAE therapy with (TAE–iNKT) or without (TAE) biweekly iNKT cell infusion. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), quality of life (QoL), peripheral blood cell count, and safety. Results Fifty-four patients completed the study. Median PFS was significantly higher in TAE–iNKT patients (5.7 months [95% CI, 4.3–7.0 months]) compared with TAE patients (2.7 months [95% CI, 2.3–3.2 months]; hazard ratio 0.32 [95% CI, 0.16–0.63]; P <0.001). Higher ORR and DCR were observed in TAE–iNKT patients (52% and 85%, respectively) compared with TAE patients (11% and 33%; respectively). Five TAE–iNKT patients and 1 TAE patient achieved completed response. The median time to deterioration in QoL was longer in TAE–iNKT patients (9.2 months [95% CI, 6.0–13.3 months]) compared with TAE patients (3.0 months [95% CI, 2.9–3.0 months]). The mean lymphocytes were higher in the TAE-iNKT group than in the TAE group at 8 (1.48 vs 0.95×10 9 /L, P = 0.007) and 12 (1.49 vs 0.89×10 9 /L, P = 0.001) weeks. Grade 3 adverse events occurred in 1 TAE-iNKT patient (4%) and 5 TAE patients (19%). All the other adverse events were grade 1–2. Conclusion iNKT cell infusion significantly improved PFS, ORR, DCR, and QoL with manageable toxicity during TAE therapy in patients with HCC. Trial Registration ClinicalTrials.gov Identifier: NCT04011033.

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Adoptive Transfer of Autologous Invariant Natural Killer T Cells as Immunotherapy for Advanced Hepatocellular Carcinoma: A Phase I Clinical Trial

Cited by 24 publications

References 36 publications

Tumor-Localized Administration of α-GalCer to Recruit Invariant Natural Killer T Cells and Enhance Their Antitumor Activity against Solid Tumors

Tumor-Localized Administration of α-GalCer to Recruit Invariant Natural Killer T Cells and Enhance Their Antitumor Activity against Solid Tumors

SOX chemotherapy with anti-PD-1 and iNKT cell immunotherapies for stage IV gastric adenocarcinoma with liver metastases: A case report

Efficacy of Invariant Natural Killer T Cell Infusion Plus Transarterial Embolization vs Transarterial Embolization Alone for Hepatocellular Carcinoma Patients: A Phase 2 Randomized Clinical Trial

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