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In vivo proof of concept of adoptive immunotherapy for hepatocellular carcinoma using allogeneic suicide gene-modified killer cells.

ABSTRACT: Cell therapy based on alloreactivity has completed clinical proof of concept against hematological malignancies. However, the efficacy of alloreactivity as a therapeutic approach to treat solid tumors is unknown. Using cell culture and animal models, we aimed to investigate the efficacy and safety of allogeneic suicide gene-modified killer cells as a cell-based therapy for hepatocellular carcinoma (HCC), for which treatment options are limited. Allogeneic killer cells from healthy donors were isolated, expanded, and phenotypically characterized. Antitumor cytotoxic activity and safety were studied using a panel of human or murine HCC cell lines engrafted in immunodeficient or immunocompetent mouse models. Human allogeneic suicide gene-modified killer cells (aSGMKCs) exhibit a high, rapid, interleukin-2-dependent, and non-major histocompatibility complex class I-restricted in vitro cytotoxicity toward human hepatoma cells, mainly mediated by natural killer (NK) and NK-like T cells. In vivo evaluation of this cell therapy product demonstrates a marked, rapid, and sustained regression of HCC. Preferential liver homing of effector cells contributed to its marked efficacy. Calcineurin inhibitors allowed preventing rejection of allogeneic lymphocytes by the host immune system without impairing their antitumor activity. Our results demonstrate proof of concept for aSGMKCs as immunotherapy for HCC and open perspectives for the clinical development of this approach.

SUBMITTER: Leboeuf C

PROVIDER: S-EPMC3944343 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Lessons learnedAdministration of autologous invariant natural killer T (iNKT) cells was safe and well-tolerated in patients with hepatocellular carcinoma (Barcelona Clinic Liver Cancer stage B/C). Expanded iNKT cells produced T-helper 1-like responses with possible antitumor activity. No severe adverse events were observed in any of the enrolled patients, including one patient who received 1010 in vitro-expanded autologous iNKT cells as a single infusion.BackgroundInvariant natural killer T cells co-express T-cell antigen receptor and natural killer (NK) cell receptors. Invariant natural killer T (iNKT) cells exhibit antitumor activity, but their numbers and functions are impaired in patients with hepatocellular carcinoma (HCC). The adoptive transfer of iNKT cells might treat advanced HCC.MethodsThis phase I study (NCT03175679) enrolled 10 patients with HCC (Barcelona Clinic Liver Cancer [BCLC] stage B/C) at Beijing YouAn Hospital (April 2017 to May 2018). iNKT cells isolated from peripheral blood mononuclear cells (PBMCs) were expanded and alpha-galactosylceramide (α-GalCer)-pulsed. Dosage escalated from 3 × 107 to 6 × 107 to 9 × 107 cells/m2 (3+3 design). An exploratory dose trial (1 × 1010 cells/m2 ) was conducted in one patient.ResultsExpanded iNKT cells produced greater quantities of T-helper 1 (Th1) cytokines (e.g., interferon-gamma, perforin, and granzyme B) but less interleukin-4 than nonexpanded iNKT cells. Circulating numbers of iNKT cells and activated NK cells were increased after iNKT cell infusion. Most treatment-related adverse events were grade 1-2, and three grade 3 adverse events were reported; all resolved without treatment. Four patients were progression-free at 5.5, 6, 7, and 11 months after therapy, and one patient was alive and without tumor recurrence at the last follow-up. Five patients died at 1.5 to 11 months after treatment.ConclusionAutologous iNKT cell treatment is safe and well-tolerated. Expanded iNKT cells produce Th1-like responses with possible antitumor activity. The antitumor effects of iNKT cell infusion in patients with advanced HCC merit further investigation.

Project description:BackgroundAdoptive transfer of virus-specific T cells (VSTs) represents a prophylactic and curative approach for opportunistic viral infections and reactivations after transplantation. However, inadequate frequencies of circulating memory VSTs in the T-cell donor's peripheral blood often result in insufficient enrichment efficiency and purity of the final T-cell product, limiting the effectiveness of this approach.MethodsThis pilot study was designed as a cross-over trial and compared the effect of a single bout (30 min) of high-intensity interval training (HIT) with that of 30 min of continuous exercise (CONT) on the frequency and function of circulating donor VSTs. To this end, we used established immunoassays to examine the donors' cellular immune status, in particular, with respect to the frequency and specific characteristics of VSTs restricted against Cytomegalovirus (CMV)-, Epstein-Barr-Virus (EBV)- and Adenovirus (AdV)-derived antigens. T-cell function, phenotype, activation and proliferation were examined at different time points before and after exercise to identify the most suitable time for T-cell donation. The clinical applicability was determined by small-scale T-cell enrichment using interferon- (IFN-) γ cytokine secretion assay and virus-derived overlapping peptide pools.ResultsHIT proved to be the most effective exercise program with up to fivefold higher VST response. In general, donors with a moderate fitness level had higher starting and post-exercise frequencies of VSTs than highly fit donors, who showed significantly lower post-exercise increases in VST frequencies. Both exercise programs boosted the number of VSTs against less immunodominant antigens, specifically CMV (IE-1), EBV (EBNA-1) and AdV (Hexon, Penton), compared to VSTs against immunodominant antigens with higher memory T-cell frequencies.ConclusionThis study demonstrates that exercise before T-cell donation has a beneficial effect on the donor's cellular immunity with respect to the proportion of circulating functionally active VSTs. We conclude that a single bout of HIT exercise 24 h before T-cell donation can significantly improve manufacturing of clinically applicable VSTs. This simple and economical adjuvant treatment proved to be especially efficient in enhancing virus-specific memory T cells with low precursor frequencies.

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In vivo proof of concept of adoptive immunotherapy for hepatocellular carcinoma using allogeneic suicide gene-modified killer cells.

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