Therapeutic activation of Vα24+Vβ11+ NKT cells in human subjects results in highly coordinated secondary activation of acquired and innate immunity

Abstract

IntroductionHuman V␣24 ϩ V␤11 ϩ natural killer T (NKT) cells are a distinct CD1d-restricted lymphoid subset specifically activated and induced to proliferate by ␣-galactosylceramide (␣-GalCer) (KRN7000) presented by CD1d on antigen-presenting cells (APCs), including dendritic cells (DCs) and monocyte-derived DCs (MoDCs). [1][2][3][4][5] Preclinical murine in vivo and human in vitro data suggest NKT cell activation may be therapeutic for human malignancy. 6,7 NKT cells have direct antitumor cytotoxicity, dependent on and independent of target CD1d expression, 8 and antiproliferative actions 9 that may contribute to clinical antitumor activity.Potentially critical for successful human tumor eradication are secondary immune effects, including cytokine release 9,10 and activation of conventional T cells 11 and NK cells [12][13][14][15][16][17] resulting from the hypothesized pivotal role of NKT cells in bridging, coordinating, and activating innate and acquired immunity. 11 A human clinical study showed that direct intravenous administration of ␣-GalCer results in disappearance of peripheral blood (PB) NKT cells within 24 hours, and with multiple administrations at weekly intervals, NKT cell numbers remain below pretreatment levels. 18 Furthermore, it has been demonstrated in murine models that administration of ␣-GalCer-pulsed DCs has more potent antitumour activities than direct administration of ␣-GalCer alone. 19 In addition to their essential role in NKT cell activation, DCs may have a crucial intermediary role in secondary immune effects of activated NKT cells as the latter alter DC functions, including cytokine production. 20,21 In view of these earlier murine and clinical studies and to confirm the proposed key immune-activating activities of NKT cells, we have undertaken a clinical phase 1 study to determine the effects of ␣-GalCer-pulsed DCs in human subjects. We evaluated clinical and immunologic effects of ␣-GalCer-pulsed MoDCs administered at 2-week intervals to 12 human subjects with metastatic malignancy. Materials and methods Overview of study designThe study was a phase 1, open-labeled clinical study involving 12 patients with metastatic malignancy (Table 1). Subjects received a median of 5 ϫ 10 6 CD1d-expressing immature MoDCs generated from plastic adherent monocytes cultured with interleukin 4 (IL-4) and granulocytemacrophage colony-stimulating factor (GM-CSF). Subjects involved in another of our studies with metastatic malignancy (n ϭ 3) receiving therapy with MoDCs prepared with the use of identical protocols, but with addition of tumor lysate or tumor-specific peptides rather than ␣-GalCer, were used as controls but had less extensive immunologic evaluations than for the study described here. One subject (KS103) received 2 series of treatments with KRN7000-pulsed MoDCs, several months apart, and subsequently (6 months later) a series of treatments with tumor lysate-pulsed MoDCs. Protocols were based on those previously described 22 with our minor modifications, 23 except that 100 ng/mL ␣-GalCe...

Modulation of human Vα24+Vβ11+ NKT cells by age, malignancy and conventional anticancer therapies

“…With the development of therapeutic approaches with the potential to activate NKT cells in vivo (Nieda et al, 2003) and expand NKT cells in vitro (Nieda et al, 1999;Nicol et al, 2000a;Takahashi et al, 2000), it is important to more clearly define their applicability in the clinical setting. Previous data indicate that NKT cells may be decreased in some cancer patients (Kawano et al, 1999a;Tahir et al, 2001;Motohashi et al, 2002).…”

Activation of invariant natural killer T cells by α-galactosylceramide ameliorates myocardial ischemia/reperfusion injury in mice

“…In addition, based on our previous study of postinfarct heart failure [17], αGC administration may attenuate also LV remodeling and reduce mortality after MI. To date, several clinical trials (Phase I/II) using activated iNKT cells by αGC have been conducted in patients with cancer [45][46][47][48][49]. No severe adverse events were observed in these trials.…”

Dendritic cell maturation by CD11c− T cells and Vα24+ natural killer T‐cell activation by α‐Galactosylceramide

“…18 The results of a clinical study using IL-4 and GM-CSF-cultured DCs loaded with aGalCer suggested the feasibility of the procedure. 23,24 Thus, inducing the activation and expansion of endogenous Va24 1 NKT cells by aGalCer-loaded DCs would be a promising strategy for cancer immunotherapy.…”