Effects of local injection of ex vivo expanded autologous tumor-specific T lymphocytes in cases with recurrent malignant gliomas.

PURPOSE: The aim of this report was to indicate both the advantages and disadvantages of local cell transfer therapy using ex vivo expanded autologous tumor-specific T lymphocytes (ATTLs) for recurrent cases of malignant gliomas. EXPERIMENTAL DESIGN: Subjects are 10 cases of malignant gliomas consisting of 7 cases of glioblastoma multiforme, 2 cases of anaplastic astrocytoma, and 1 case of anaplastic oligoastrocytoma. All cases were recurrences. ATTLs were induced by coculturing peripheral blood mononuclear cells with autologous tumor cells in medium containing interleukin-1, -2, -4, and -6 and administered into the local tumor site in total numbers of 3-247 x 10(7) cells. As end points, tumor response and survival time were analyzed observing clinical state. RESULTS: Five cases responded to this therapy (namely, one case showed complete remission, and four cases had a partial response). There were three cases of no change, and two cases of progressive disease. The overall tumor response rate was 50%. No complications were noticed, except for two cases of minor local hemorrhage and eight cases of temporary fever. Nine cases died of further tumor progression, and one case died of aspiration pneumonia, and the cause-specific survival analysis indicates that the median survival time was 5 months from the initial ATTL injection. CONCLUSIONS: The results suggest that local administration of ATTLs is effective in recurrent malignant gliomas in that it demonstrated a high benefit:risk ratio with minor side effects. Although its antitumor effect may be temporary in some advanced cases, it is highly possible that the tumor could be stabilized when conditions are optimal.     

Long-term survival after radical resection of advanced pancreatic cancer

A 65-yr-old man who underwent pancreaticoduodenectomy with portal vein resection for pancreatic cancer is alive 8 yr after surgery. Originally, computed tomography (CT) revealed an 8-cm tumor in the pancreatic head. The tumor had infiltrated the portal vein, but grew expansively, so there was neither biliary obstruction nor jaundice. Pancreaticoduodenectomy with resection of the portal vein was performed for pancreatic cancer. Many tumor-infiltrating lymphocytes were seen within cancer cell nests on routine histopathology. We performed immunostaining for CD8, and found that a large number of the lymphocytes were CD8⁺ T cells. The patient’s prognosis was considered poor because the tumor was large and had infiltrated the portal vein. We suspect that long-term survival may be related to the response of CD8⁺ T cells to the cancer.     

Radioresponse of Thymomas Verified with Histologic Response

Patterns of radiologic response of 10 thymomas treated by preoperative radiotherapy (RT) (18-20 Gy/2 weeks) were determined in conjunction with histologic response. Changes in tumor volume were evaluated with CT scans obtained 5 to 36 days before and 14 to 24 days after the initiation of RT and before surgery. The extent of tumor volume reduction (TR) varied widely (40-78%), while the mean daily volume decrement expressed as a percentage of the pre-RT tumor volume correlated significantly with the pre-RT tumor volume. Histologically, the tumors, all of which were resected 17 to 33 days after RT initiation, generally consisted of predominant fibrous tissues, rare necrotic foci, and few epithelial cells. The TR did not correlate with pre-RT tumor volume, observation period, histologic subtype, or quantity of remaining epithelial cells. The TR of thymomas does not predict RT impact on tumor cells but does reflect the quantity of inherent tumor stroma.     

P-glycoprotein plays a major role in the efflux of fexofenadine in the small intestine and blood-brain barrier, but only a limited role in its biliary excretion.

Fexofenadine is a selective, nonsedating H(1)-receptor antagonist approved for symptoms of allergic conditions, which is mainly excreted into feces via biliary excretion. The purpose of this study is to investigate its pharmacokinetics in mice and rats to determine the role of P-glycoprotein (P-gp) in its biliary excretion. In mice, biliary excretion clearance (17 ml/min/kg) accounted for almost 60% of the total body clearance (30 ml/min/kg). Comparing the pharmacokinetics after intravenous and oral administration indicated that the bioavailability of fexofenadine was at most 2% in mice. Knockout of Mdr1a/1b P-gp did not affect the biliary excretion clearance with regard to both plasma and liver concentrations, whereas the absence of P-gp caused a 6-fold increase in the plasma concentration after oral administration. In addition, the steady-state brain-to-plasma concentration ratio of fexofenadine was approximately 3-fold higher in Mdr1a/1b P-gp knockout mice than in wild-type mice. Together, these results show that P-glycoprotein plays an important role in efflux transport in the brain and small intestine but only a limited role in biliary excretion in mice. In addition, there was no difference in the biliary excretion between normal and hereditarily multidrug resistance-associated protein 2 (Mrp2)-deficient mutant rats (Eisai hyperbilirubinemic rats) and between wild-type and breast cancer resistance protein (Bcrp) knockout mice. These results suggest that the biliary excretion of fexofenadine is mediated by unknown transporters distinct from P-gp, Mrp2, and Bcrp.     

Photodynamic therapy using nanoparticle loaded with indocyanine green for experimental peritoneal dissemination of gastric cancer

Although there have been multiple advances in the development of novel anticancer agents and operative procedures, prognosis of patients with advanced gastric cancer remains poor, especially in patients with peritoneal metastasis. In this study, we established nanoparticles loaded with indocyanine green (ICG) derivatives: ICG loaded lactosomes (ICGm) and investigated the diagnostic and therapeutic value of photodynamic therapy (PDT) using ICGm for experimental peritoneal dissemination of gastric cancer. Experimental peritoneal disseminated xenografts of human gastric cancer were established in nude mice. Three weeks after intraperitoneal injection of the cancer cells, either ICGm (ICGm‐treated mice) or ICG solution (ICG‐treated mice) was injected through the tail vein. Forty‐eight hours after injection of the photosensitizer, in vivo and ex vivo imaging was carried out. For PDT, 48 h after injection of the photosensitizer, other mice were irradiated through the abdominal wall, and the body weight and survival rate were monitored. In vivo imaging revealed that peritoneal tumors were visualized through the abdominal wall in ICGm‐treated mice, whereas only non‐specific fluorescence was observed in ICG‐treated mice. The PDT reduced the total weight of the disseminated nodules and significantly improved weight loss and survival rate in ICGm‐treated mice. In conclusion, ICGm can be used as a novel diagnostic and therapeutic nanodevice in peritoneal dissemination of gastric cancer.     

Potential of a glucagon‐like peptide‐1 receptor/glucose‐dependent insulinotropic polypeptide receptor/glucagon receptor triagonist for the treatment of obesity and type 2 diabetes

Triagonists of GLP‐1R/ GIPR /GCGR, including SAR441255, bind to each receptor and induce specific effects through each receptor signaling pathway, thus result in weight loss and glycemic control in obese T2D animal models.

Type 2 diabetes, which often accompanies obesity, is one of the major health‐threatening diseases worldwide. Incretin‐based therapies, such as dipeptidyl peptidase‐4 inhibitors and glucagon‐like peptide‐1 receptor (GLP‐1R) agonists, are used for the treatment of type 2 diabetes. The GLP‐1R agonists have been shown to improve glycemic control and reduce bodyweight through its various actions, including glucose‐dependent insulin secretion, suppression of glucagon secretion, and inhibition of gastric emptying and food intake ¹ .Recently, dual agonists of GLP‐1R and glucose‐dependent insulinotropic polypeptide receptor (GIPR), and those of GLP‐1R and glucagon receptor (GCGR) have been developed. One of the dual agonists of GLP‐1R and GIPR, named tirzepatide, has been shown to bind and activate both GLP‐1R and GIPR in vitro and in vivo, its efficacy for the treatment of type 2 diabetes has been proven in a phase III trial, and it has recently been approved by the US Food and Drug Administration ^{2 , 3} . In the phase III trial, once‐weekly injection of trizepatide (5, 10 or 15 mg) for 40 weeks reduced glycated hemoglobin (HbA1c) from baseline by 1.87, 1.89 or 2.07%, respectively, and reduced bodyweight from baseline by 7.0, 7.8 or 9.5 kg, respectively, in type 2 diabetes patients. The most frequent adverse events with trizepatide were gastrointestinal events ³ . In the clinical trial that compared trizepatide (5, 10 or 15 mg) with once‐weekly semaglutide (1 mg) in type 2 diabetes patients, trizepatide showed non‐inferior and superior reductions in HbA1c levels and in bodyweight ⁴ . For both treatments, gastrointestinal events were the most common adverse events ⁴ . The possible additional effects of GIP signaling in type 2 diabetes patients might depend on its augmentation of insulin secretion during hyperglycemic states ⁵ .The dual agonists of GLP‐1R and GCGR specific for mice or monkeys have been developed and were investigated their effects in each species. In obese and diabetic cynomolgus monkeys induced by high‐fat diet feeding, the monkey‐specific dual agonist of GLP‐1R and GCGR reduced total energy intake, decreased bodyweight and improved glucose tolerance ⁶ . However, in another study using obese diabetic monkeys, glycemic control was worse when they were co‐administered with both GLP‐1R and GCGR agonists compared with that treated with an GLP‐1R agonist alone ⁷ . Therefore, the significance of the activation of GCGR signaling has not yet been fully clarified.In 2015, Finan et al. ⁸ created a triagonist that activates GLP‐1R, GIPR and GCGR by selecting amino acids from the three peptide hormones, GLP‐1, GIP and glucagon, and reported that the triagonist reduced bodyweight and improved glucose control in rodent models of obesity and diabetes.More recently, Bossart et al. ⁹ developed a novel GLP‐1R, GIPR and GCGR triagonist, SAR441255. SAR441255 was confirmed to efficiently bind to and stimulate all three receptors in in vitro studies. In a diet‐induced obesity mouse model, subcutaneous injection of SAR441255 (0.3, 1, 3, 10 or 30 μg/kg) showed a dose‐dependent effect on bodyweight (+9.7%, +6.9%, +5.8%, −4.8% and −14.1%, respectively) compared with injection of vehicle (+11.5%). Non‐fasted blood glucose levels were significantly lower in mice treated with SAR441255 at doses of ≥1 μg/kg when compared with vehicle‐treated controls. In obese diabetic cynomolgus monkeys, treatment with SAR441255 (11 μg/kg) or a monkey‐specific GLP‐1R/GCGR dual agonist (4 μg/kg) ⁶ significantly reduced the bodyweight by −12.6% or −8.1%, respectively, and decreased the HbA1c levels by −1.37% or −1.85%, respectively. Fasting plasma glucose and alanine aminotransferase levels were significantly reduced with SAR441255, but not with the dual agonist (Figure 1).Open in a separate windowFigure 1Possible mechanisms of glucagon‐like peptide‐1 receptor (GLP‐1R)/glucose dependent insulinotropic polypeptide receptor (GIPR)/glucagon receptor (GCGR) triagonist in weight loss and glycemic control in obese type 2 diabetes animal models. Triagonists of GLP‐1R/GIPR/GCGR, including SAR441255, bind to each receptor and induce specific effects through each receptor signaling pathway, thus resulting in weight loss and glycemic control in obese type 2 diabetes animal models. Potential effects of each receptor signaling that contribute to weight loss and/or better glycemic control are listed below each receptor.To further understand engagement of the different receptors in vivo, receptor occupancy of SAR441255 at the GLP‐1 and the GCG receptors was studied with the use of positron emission tomography imaging after radiotracer administration in lean cynomolgus monkeys. A subcutaneous injection of 11 μg/kg SAR411255 together with radiotracers specific for GLP‐1R and GCGR showed the significant signals of both receptors in the liver and pancreas of monkeys, suggesting the binding of SAR411255 to both receptors existing in these organs. Cardiovascular safety of SAR411255 was further confirmed in lean cynomolgus monkeys.Finally, a phase I study with SAR411255 in lean to overweight healthy participants was carried out to assess the safety, tolerability, pharmacokinetics and pharmacodynamics. After subcutaneous administration, SAR441255 concentration reached the median maximum serum concentration by 3.0–3.5 h, and was eliminated with a mean elimination terminal half‐life of 3.5–6.1 h. After administration of single doses (80 and 150 mg) of SAR441255 in the fasting state, maximal reduction in blood glucose levels were observed at 1 h post‐dose. At this time point, three of six participants who received the 80 mg dose and all six participants who received the 150 mg dose showed hypoglycemia (<70 mg/dL) without any clinical signs or symptoms. No further low blood glucose values were observed in either dose group. Blood glucose levels subsequently returned to baseline levels within 1–2 h. In contrast, fasting insulin and C‐peptide levels were relatively stable, and showed no correlation with the glucose levels. Therefore, the mechanisms of this early phase hypoglycemia have not yet been clarified. After the mixed‐meal test 3 h after the SAR441255 administration (80 and 150 mg), a dose‐dependent reduction in postprandial plasma glucose was observed. Because insulin and C‐peptide levels were also reduced during mixed‐meal test, postprandial plasma glucose reduction was suggested to be due to inhibition of gastric emptying, as observed with GLP‐1R engagement.Gastrointestinal disorders (nausea, vomiting, dry mouth and mouth ulceration) were the most frequent treatment‐emergent adverse events after treatment with SAR441255. All events were mild in severity, and occurred between 3 and 4 h after SAR441255 administration.To clarify the effects of SAR441255 on GIPR and GCGR in humans, specific biomarkers for each receptor were measured. As expected, a biomarker for GIPR activation, C‐telopeptide of cross‐linked type I collagen, which is a marker of bone turnover, was significantly reduced by >50% in participants who received SAR441255 administration (80 and 150 mg). Likely, plasma amino acids levels, which are sensitive biomarkers of GCGR activation, were reduced after SAR441255 administration in these individuals.As aforementioned, the dual agonists of GLP‐1R and GIPR might have comparable or even more stronger effects in reductions of HbA1c and bodyweight in obese type 2 diabetes patients ⁴ ; the significance of the activation of GCGR signaling should be evaluated to confirm the benefits of the triagonists of GLP‐1R, GIPR and GCGR. In this regard, the effects of glucagon to enhance energy expenditure partly through enhancement of fat and glucose oxidation could cover some of the benefits ⁷ , but further investigations should be necessary. In addition, it has recently been reported that GLP‐1R agonists have clinically significant cardiovascular benefits in type 2 diabetes patients ¹ . Therefore, it should be clarified if the dual or triagonists also have comparable cardiovascular benefits, as observed in GLP‐1R agonists in type 2 diabetes patients.Because triagonists have been shown to have better profiles in weight loss and glycemic control in animal models of obese type 2 diabetes compared with GLP‐1R agonists and dual agonists of GLP‐1R and GIPR or GLP‐1R and GCGR ^{8 , 9} , clinical studies that investigate the efficacy in type 2 diabetes patients should be of great interest.     

Genomic determinants impacting the clinical outcome of mogamulizumab treatment for adult T-cell leukemia/lymphoma

In order to identify genomic biomarkers for the outcome of mogamulizumab-containing treatment, an integrated molecular analysis of adult T-cell leukemia/lymphoma (ATL) was conducted on 64 mogamulizumab-naïve patients. Among driver genes, CCR4 and CCR7 alterations were observed in 22% and 11% of the patients, respectively, both consisting of single nucleotide variants (SNV)/insertion-deletions (indels) in the C-terminus. Patients with CCR4 alterations or without CCR7 alterations exhibited a more favorable clinical response (complete response [CR] rate 93%, 13/14; P=0.024, and CR rate 71%, 40/56; P=0.036, respectively). Additionally, TP53, CD28, and CD274 alterations were identified in 35%, 16%, and 10% of the patients, respectively. TP53 alterations included SNV/indels or copy number variations (CNV) such as homozygous deletion; CD28 alterations included SNV, CNV such as amplification, or fusion; CD274 alterations included CNV such as amplification, or structural variants. Univariate analysis revealed that TP53, CD28 or CD274 alterations were associated with worse overall survival (OS) (hazard ratio [HR]: 2.330, 95% confidence interval [CI]: 1.183-4.589; HR: 3.191, 95% CI: 1.287-7.911; HR: 3.301, 95% CI: 1.130-9.641, respectively) but that CCR4 alterations were associated with better OS (HR: 0.286, 95% CI: 0.087-0.933). Multivariate analysis indicated that in addition to performance status, TP53, CCR4 or CD274 alterations (HR: 2.467, 95% CI: 1.197-5.085; HR: 0.155, 95% CI: 0.031-0.778; HR: 14.393, 95% CI: 2.437-85.005, respectively) were independently and significantly associated with OS. The present study contributes to the establishment of precision medicine using mogamulizumab in ATL patients.     

Prognosis Prediction Using Magnetic Resonance Spectroscopy and Oligoclonal Bands in Central Nervous System Methotrexate-associated Lymphoproliferative Disorder

Central nervous system methotrexate-associated lymphoproliferative disorder (CNS-MTX-LPD) is rare, but its spontaneous regression has been observed in some patients after withdrawal of agents. We herein report three cases of primary CNS-MTX-LPD that received oral MTX for rheumatoid arthritis. Epstein-Barr virus and oligoclonal bands (OCBs) were positive, while proton magnetic resonance spectroscopy (¹H-MRS) showed an elevated lipid peak and slightly elevated choline/N-acetylaspartate ratio in common. After MTX withdrawal, brain lesions showed spontaneous regression in all cases. Our patient''s ¹H-MRS findings and OCBs may reflect a non-monoclonal lymphoproliferative histology as benign-type lesions in CNS-MTX-LPD.