Phase II study of α-galactosylceramide-pulsed antigen-presenting cells in patients with advanced or recurrent non-small cell lung cancer

Abstract

BackgroundInvariant natural killer T (iNKT) cells produce copious amounts of cytokines in response to specific glycolipid antigens such as α-galactosylceramide (αGalCer) presented by CD1d-expressing antigen-presenting cells (APCs), thus orchestrating other immune cells to fight tumors. Because of their ability to induce strong antitumor responses activated by αGalCer, iNKT cells have been studied for their application in cancer immunotherapy. In our previous phase I/II trial in non-small cell lung cancer (NSCLC) patients who had completed the standard treatment, we showed a relatively long median survival time without severe treatment-related adverse events. Based on these results, we performed a phase II trial to evaluate clinical responses, safety profiles and immune responses as a second-line treatment for advanced NSCLC.MethodsPatients with advanced or recurrent NSCLC refractory to first-line chemotherapy were eligible. αGalCer-pulsed APCs were intravenously administered four times. Overall survival time was evaluated as the primary endpoint. The safety profile and immune responses after APC injection were also monitored. This study was an open label, single-arm, phase II clinical trial performed at Chiba University Hospital, Japan.ResultsThirty-five patients were enrolled in this study, of which 32 (91.4%) completed the trial. No severe adverse events related to the treatment were observed. The estimated median survival time of the 35 cases was 21.9 months (95% CI, 14.8 to 26.0). One case (2.9%) showed a partial response, 14 cases (40.0%) remained as stable disease, and 19 cases (54.3%) were evaluated as progressive disease. The geometric mean number of iNKT cells in all cases was significantly decreased and the mean numbers of natural killer (NK) cells, interferon-γ-producing cells in response to αGalCer, and effector CD8+ T cells were significantly increased after the administration of αGalCer-pulsed APCs.ConclusionsThe intravenous administration of αGalCer-pulsed APCs was well-tolerated and was accompanied by prolonged overall survival. These results are encouraging and warrant further evaluation in a randomized phase III trial to demonstrate the survival benefit of this immunotherapy.Trial registration numberUMIN000007321.

The Current Landscape of NKT Cell Immunotherapy and the Hills Ahead

“…The increased immune response led to a median survival time of 31.9 months, compared with the median survival time of all patients being 18.6 months [142]. A follow-up study by Toyoda et al [105], examined overall survival time two years post-treatment and found a median overall survival of 21.9 months. Both studies demonstrate that α-GalCer-loaded-DCs can be an effective treatment option for NSCLC.…”

CCR7 as a therapeutic target in Cancer

“…Similarly embryonic stem cell-derived DCs transfected in vitro to express an antigen as well as CCL21 and loaded with α-galactosylceramide, an antigen specific for invariant NK T cells [84], was able to mobilise both conventional and NK T cells and showed an increased anti-tumour effect [85]. The clinical potential of this approach was assessed in a phase II study in patients with advanced non-small cell lung carcinoma (NSCLC) [86]. Intra-tumoural administration of autologous dendritic cells (DC) transduced with an adenoviral (Ad) vector to express CCL21, resulted in enhanced tumour CD8 + T-cell infiltration as well as increased tumour PD-L1 expression [87].…”

Prognostic significance and immune infiltration of microenvironment-related signatures in pancreatic cancer

“…CD1D, a member of the CD1 family, is a class of non-polypeptide transmembrane glycoprotein molecules, which is widely expressed in thymocyte B cells, epidermal Langham cells, dendritic cells, and intestinal epithelial cells [40] . With function of antigen presentation similar to MHC I, CD1D can speci cally present antigens to NKT cells, make them activate and secrete a variety of cytokines, and directly or indirectly participate in the body's immune response [41] .Recently, a research about CD1d-binding glycolipid for iNKT-cell-based therapy showed a potent and effective treatment against human breast cancer [42] .Another clinical phase II study showed that intravenous administration of α-GalCer-pulsed antigen-presenting cells (APCs) prolonged overall survival for patients with advanced or recurrent non-small cell lung cancer [43] . (α-GalCer an exogenous glycolipid antigen extracted from sponges speci cally binding to CD1D molecule can activate NKT cells to exert immune effects [44] . )…”