Immune activation by combination human lymphokine-activated killer and dendritic cell therapy

Abstract

Background:Optimal cellular immunotherapy for cancer should ideally harness both the innate and adaptive arms of the immune response. Lymphokine-activated killer cells (LAKs) can trigger early innate killing of tumour targets, whereas long-term adaptive-specific tumour control requires priming of CD8+ cytotoxic lymphocytes (CTLs) following acquisition of tumour-associated antigens (TAAs) by antigen-presenting cells such as dendritic cells (DCs). As DCs stimulate both innate and adaptive effectors, combination cell therapy using LAKs and DCs has the potential to maximise anti-tumour immune priming.Methods:Reciprocal activation between human clinical grade LAKs and DCs on co-culture, and its immune consequences, was monitored by cell phenotype, cytokine release and priming of both innate and adaptive cytotoxicity against melanoma targets.Results:Co-culture of DCs and LAKs led to phenotypic activation of natural killer (NK) cells within the LAK population, which was associated with increased production of inflammatory cytokines and enhanced innate cytotoxicity against tumour cell targets. The LAKs reciprocally matured DCs, and the combination of LAKs and DCs, on addition of melanoma cells, supported priming of specific anti-tumour CTLs better than DCs alone.Conclusion:Clinical-grade LAKs/DCs represents a practical, effective combination cell immunotherapy for stimulation of both innate and adaptive anti-tumour immunity in cancer patients.

Lymphokine‐activated killer and dendritic cell carriage enhances oncolytic reovirus therapy for ovarian cancer by overcoming antibody neutralization in ascites

“…We have not used murine models because there are significant differences between the effects of reovirus in mouse and human systems; for example, human DC protect reovirus from NAb by internalizing the virus without cell toxicity or viral replication, whilst murine DC support reovirus replication and die after infection . Moreover, human data are more directly relevant to clinical application, and we have previously shown LAKDC represent a practical immunogenic mixed cell population, which can readily be prepared to clinical grade from patient blood …”

“…Previous studies have demonstrated the ability of both LAK cells and reovirus to mature iDC, an essential step for generation of antigen-specific adaptive T cell antitumor immunity. 25,28 However, whether this applies in the context of malignant ascites, which may contain immunosuppressive factors that might impede DC maturation, has not been addressed. The ability of LAK cells and reovirus to phenotypically mature iDC in the presence of ascites was investigated by flow cytometry.…”

“…However, whilst LAK cells alone were well tolerated (up to 10 cells per infusion), concomitant systemic delivery of IL‐2 to patients resulted in significant toxicities, including vascular leakage and hypotension. Coculture of LAK cells with DC (LAKDC) has been reported to eliminate the need for coadministration of IL‐2, due to bi‐directional signaling supporting LAK cell activation and viability, as well as inducing DC maturation and the production of proinflammatory cytokines . In vivo studies have shown that the combination of LAKDC can effectively eradicate subcutaneous tumors, leading to the generation of antitumor immunity, whereas treatment with either cell type alone was ineffective .…”

“…Coculture of LAK cells with DC (LAKDC) has been reported to eliminate the need for coadministration of IL-2, due to bi-directional signaling supporting LAK cell activation and viability, as well as inducing DC maturation and the production of proinflammatory cytokines. [24][25][26] In vivo studies have shown that the combination of LAKDC can effectively eradicate subcutaneous tumors, leading to the generation of antitumor immunity, whereas treatment with either cell type alone was ineffective. 27 Previous studies have also highlighted DC as effective cell carriers for reovirus in the presence of neutralizing serum for the treatment of melanoma.…”

Efficacy and safety of cord blood–derived cytokine-induced killer cells in treatment of patients with malignancies

“…LAK cells demonstrated potent in vitro cytotoxicity against tumor cells and led to the regression of established tumors in animal models [3,4]. In clinical studies, LAK cells had demonstrated modest efficacy against metastatic cancer such as renal cell carcinoma and melanoma [5]. Many patients with cancer were ineligible for TIL-based therapy because their TILs did not expand sufficiently.…”