krn-7000 and Carcinoma--Squamous-Cell

The intravenous administration of α-Galactosylceramide (α-GalCer)-pulsed antigen presenting cells (APCs) is well tolerated and the increased IFN-γ producing cells in the peripheral blood after the treatment appeared to be associated with prolonged survival. An exploratory study protocol was designed with the preoperative administration of α-GalCer-pulsed APCs to clarify the mechanisms of these findings, while especially focusing on the precise tumor site.. Patients with operable advanced lung cancer received an intravenous injection of α-GalCer-pulsed APCs before surgery. The resected lung and tumor infiltrating lymphocytes (TILs) as well as peripheral blood mononuclear cells were collected and the invariant NKT (iNKT) cell-specific immune responses were analyzed.. Four patients completed the study protocol. We observed a significant increase in iNKT cell numbers in the TILs and augmented IFN-γ production by the α-GalCer-stimulated TILs.. The administration of α-GalCer-pulsed APCs successfully induced the dramatic infiltration and activation of iNKT cells in the tumor microenvironment.

Topics: Adenocarcinoma; Aged; Antigen-Presenting Cells; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Galactosylceramides; Humans; Immunotherapy; Lung Neoplasms; Lymph Nodes; Male; Natural Killer T-Cells; Receptors, Antigen, T-Cell; Tumor Microenvironment

Antigen-presenting cells (APCs) play a crucial role in the induction of immune responses. However, the optimal administration route of tumor-specific APCs for inducing effective immunological responses via cancer immunotherapy remains to be elucidated. Human NKT cells are known to have strong anti-tumor activities and are activated by the specific ligand, namely, α-galactosylceramide (αGalCer).. Seventeen patients with head and neck squamous cell carcinoma (HNSCC) were enrolled in this study. Patients received an injection of αGalCer-pulsed APCs into the nasal, or the oral floor submucosa. Then total body image and single photon emission computed tomography (SPECT) images were examined. The immunological responses including the number of peripheral blood NKT cells, anti-tumor activities and the CD4(+) CD25(high) Foxp3(+) T cells (Tregs) induced following APCs were also compared.. APCs injected into the nasal submucosa quickly migrated to the lateral lymph nodes and those injected into the oral floor submucosa dominantly migrated to the submandibular nodes rather than the lateral lymph nodes. An increase in the absolute number of NKT cells and the IFN-γ producing cells was observed in peripheral blood after injection of the APCs into the nasal submucosa, however, these anti-tumor activities were not detected and the increased frequency of Treg cells were observed after administration into oral floor.. These results indicate that a different administration route of APCs has the potential to bring a different immunological reaction. The submucosal administration of αGalCer into the oral submucosa tends to induce immunological suppression.

Topics: Administration, Mucosal; Administration, Oral; Adult; Aged; Aged, 80 and over; Antigen-Presenting Cells; Carcinoma, Squamous Cell; CD4 Antigens; Cell Movement; Female; Galactosylceramides; Head and Neck Neoplasms; Humans; Ligands; Male; Middle Aged; Mouth Mucosa; Nasal Mucosa; Staining and Labeling; Treatment Outcome

Invariant natural killer T (iNKT) cells are glycolipid-reactive T lymphocytes that share receptors and function with natural killer (NK) cells and reportedly play a pivotal role in various immune responses. However, iNKT cells are not well characterized in patients with oral squamous cell carcinoma (OSCC). We investigated the populations and functions of circulating iNKT (CD3(+) 6B11(+) ) cells from thirty-eight patients with OSCC and twenty-eight healthy donors by flow cytometry. Circulating iNKT cells were significantly lower (P < 0.01) in patients as compared to those in healthy controls. Further, iNKT subsets revealed a marked decrease in CD4(-) CD8(-) (double negative, DN) subset with concomitant increase in CD8(+) subset in patients as compared to healthy controls (P = 0.03 and P < 0.01, respectively), whereas CD4(+) subset was similarly distributed in both groups. The functional analysis demonstrated that residual iNKT cells from patients had impaired proliferative response to α-galactosylceramide (α-GalCer)-pulsed dendritic cells (DCs) and Th2-like cytokine profile. However, in vitro activation with α-GalCer-pulsed DCs restores IFN-γ expression and enhances antitumour activity to human cancer cells lines (SCC-4, KB and MCF7). It appears that the selectively enriched iNKT subsets and modulation of their function by specific ligand/agonist may be useful for cellular therapy in patients with OSCC. Further, reduced levels of iNKT cells and its DN subset may be used as potential prognostic factors for patients with OSCC.

Topics: Adult; Aged; Carcinoma, Squamous Cell; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Cell Proliferation; Dendritic Cells; Female; Flow Cytometry; Galactosylceramides; Humans; Interferon-gamma; Lymphocyte Activation; Male; Middle Aged; Mouth Neoplasms; Natural Killer T-Cells; Prognosis; T-Lymphocyte Subsets; Young Adult

Our previous report indicated that carbon ion beam irradiation upregulated membrane-associated immunogenic molecules, underlining the potential clinical application of radioimmunotherapy. The antimetastatic efficacy of local combination therapy of carbon ion radiotherapy and immunotherapy was examined by use of an in vivo murine model.. Tumors of mouse squamous cell carcinoma (NR-S1) cells inoculated in the legs of C3H/HeSlc mice were locally irradiated with a single 6-Gy dose of carbon ions (290 MeV/nucleon, 6-cm spread-out Bragg peak). Thirty-six hours after irradiation, α-galactosylceramide-pulsed dendritic cells (DCs) were injected into the leg tumor. We investigated the effects on distant lung metastases by counting the numbers of lung tumor colonies, making pathologic observations, and assessing immunohistochemistry.. The mice with no treatment (control) presented with 168 ± 53.8 metastatic nodules in the lungs, whereas the mice that received the combination therapy of carbon ion irradiation and DCs presented with 2.6 ± 1.9 (P = 0.009) at 2 weeks after irradiation. Immunohistochemistry showed that intracellular adhesion molecule 1, which activates DCs, increased from 6 h to 36 h after irradiation in the local tumors of the carbon ion-irradiated group. The expression of S100A8 in lung tissue, a marker of the lung pre-metastatic phase, was decreased only in the group with a combination of carbon ions and DCs.. The combination of carbon ion radiotherapy with the injection of α-galactosylceramide-pulsed DCs into the primary tumor effectively inhibited distant lung metastases.

Topics: Animals; Calgranulin A; Carbon Radioisotopes; Carcinoma, Squamous Cell; Combined Modality Therapy; Dendritic Cells; Galactosylceramides; Intercellular Adhesion Molecule-1; Lung Neoplasms; Mice; Mice, Inbred C3H; Models, Animal; Neoplasm Proteins; Radioimmunotherapy; Radiotherapy Dosage; Xenograft Model Antitumor Assays