Abstract
Invariant natural killer T (iNKT) cells produce copious amounts of cytokines in response to T-cell receptor (TCR) stimulation by recognizing antigens such as α-galactosylceramide (α-GalCer) presented on CD1d; thus, orchestrating other immune cells to fight against pathogen infection and tumors. Because of their ability to induce strong anti-tumor responses and the convenience of their invariant TCR activated by a synthetic ligand, α-GalCer, iNKT cells have been intensively studied for application in immunotherapeutic approaches to treat cancer patients in the clinic. Here, we summarize the clinical trials of iNKT cell based immunotherapy for non-small cell lung cancer, and head and neck cancer. Although solid tumors are thought to be refractory to immunotherapeutic approaches, our clinical trials showed that the intravenous injection of α-GalCer-pulsed antigen presenting cells (APCs) activated endogenous iNKT cells and iNKT cell dependent responses. Moreover, an increase in the number of IFN-γ producing cells in PBMCs was associated with prolonged survival. The marked infiltration of iNKT cells and the accumulation of conventional T cells in the tumor microenvironment were also observed after the administration of α-GalCer-pulsed APCs and/or ex vivo activated iNKT cells. In cases of advanced head and neck squamous cell carcinoma, the increased accumulation of iNKT cells in the tumor microenvironment was correlated with objective clinical responses. We will also discuss potential combination therapies of iNKT cell based immunotherapy to achieve enhanced anti-tumor activity and provide better treatment options for these patients.
Highlights
Invariant natural killer T cells comprise 1–2% of the mouse spleen and less than 0.1% in human peripheral tissues [1]
Whereas conventional T cells express diverse T cell receptors (TCR) after TCR rearrangement and recognize their cognate peptide presented on MHC, Invariant natural killer T (iNKT) cells express monoclonal TCRs composed of a Vα24-Jα18 chain and Vβ11 chain in humans, and a Vα14-Jα18 chain and Vβ8.2 chain in mice that recognize glycolipid antigens presented on CD1d, a MHC class I like molecule [2, 3]
These results suggested that the administration of α-GalCer-pulsed antigen presenting cells (APCs) was a more effective treatment compared with the administration of ex vivo expanded iNKT cells
Summary
Invariant natural killer T (iNKT) cells comprise 1–2% of the mouse spleen and less than 0.1% in human peripheral tissues [1]. Even established metastatic tumors were rejected by the administration of α-GalCer loaded DCs. iNKT cells produce large amounts of cytokines including IFN-γ and IL-4 upon TCR stimulation by recognizing α-GalCer presented on CD1d These events lead to the activation of NK cells and CD8+ T cells and the conversion of immature DCs to mature DCs; enhancing other immune cell responses to indirectly eradicate tumors [7]. Because a large number of APCs can present α-GalCer and activate iNKT cells more effectively compared with monocyte derived DCs, and can be generated from PBMCs by culturing with GM-CSF and IL-2, we designed a phase I clinical trial for NSCLC patients using α-GalCer-pulsed APCs [10]. The level 3 dose (1 × 109 cells/m2) was considered the most effective and safe dose of α-GalCer-pulsed APCs to treat advanced NSCLC patients
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