GD2-CART01 for Relapsed or Refractory High-Risk Neuroblastoma.

BACKGROUND: Immunotherapy with chimeric antigen receptor (CAR)-expressing T cells that target the disialoganglioside GD2 expressed on tumor cells may be a therapeutic option for patients with high-risk neuroblastoma. METHODS: In an academic, phase 1-2 clinical trial, we enrolled patients (1 to 25 years of age) with relapsed or refractory, high-risk neuroblastoma in order to test autologous, third-generation GD2-CAR T cells expressing the inducible caspase 9 suicide gene (GD2-CART01). RESULTS: A total of 27 children with heavily pretreated neuroblastoma (12 with refractory disease, 14 with relapsed disease, and 1 with a complete response at the end of first-line therapy) were enrolled and received GD2-CART01. No failure to generate GD2-CART01 was observed. Three dose levels were tested (3-, 6-, and 10×106 CAR-positive T cells per kilogram of body weight) in the phase 1 portion of the trial, and no dose-limiting toxic effects were recorded; the recommended dose for the phase 2 portion of the trial was 10×106 CAR-positive T cells per kilogram. Cytokine release syndrome occurred in 20 of 27 patients (74%) and was mild in 19 of 20 (95%). In 1 patient, the suicide gene was activated, with rapid elimination of GD2-CART01. GD2-targeted CAR T cells expanded in vivo and were detectable in peripheral blood in 26 of 27 patients up to 30 months after infusion (median persistence, 3 months; range, 1 to 30). Seventeen children had a response to the treatment (overall response, 63%); 9 patients had a complete response, and 8 had a partial response. Among the patients who received the recommended dose, the 3-year overall survival and event-free survival were 60% and 36%, respectively. CONCLUSIONS: The use of GD2-CART01 was feasible and safe in treating high-risk neuroblastoma. Treatment-related toxic effects developed, and the activation of the suicide gene controlled side effects. GD2-CART01 may have a sustained antitumor effect. (Funded by the Italian Medicines Agency and others; ClinicalTrials.gov number, NCT03373097.).

Antitumor activity of delimotecan against human metastatic melanoma: pharmacokinetics and molecular determinants.

Delimotecan (MEN 4901/T-0128) is a new cytotoxic prodrug constituted by a camptothecin analog (T-2513) bound to carboxymethyl dextran through a triglycine linker. A significant antitumor activity of delimotecan against human metastatic melanoma xenograft model Me15392 is reported. Dacarbazine, the drug approved for the treatment of metastatic melanoma, was ineffective in this melanoma model. Pharmacokinetic studies, together with the expression analysis of mRNA for enzymes involved in delimotecan metabolism, showed that T-2513 and other cytotoxic metabolites of delimotecan (SN 38 and T-0055) are generated in greater quantities in the tumor tissue than in toxicity target tissues, such as liver, thus accounting for the antitumoral activity. Moreover, we demonstrated that human metastatic melanoma cells are able to phagocytose delimotecan and cleave it to release the cytotoxic moieties T-2513 in the tumoral environment. Further flow cytometric analysis showed a higher recruitment of macrophages in xenografted human metastatic melanoma, when compared with other human tumors. Thus, the antitumoral activity of delimotecan exerted on metastatic melanoma is due to several factors: (i) the ability of melanoma cells to phagocytose and metabolise delimotecan; (ii) the accumulation of delimotecan in tumoral mass; (iii) the recruitment of macrophage cells to the melanoma nodule and (iv) the expression in melanoma cells of a pattern of enzymes that converts delimotecan into cytotoxic metabolites. Based on these results, delimotecan might be exploited as a new anticancer agent for the therapy of metastatic melanoma because of its high efficacy and good selectivity, and therefore clinical trials for this indication are warranted.

MEN1309/OBT076, a First-In-Class Antibody-Drug Conjugate Targeting CD205 in Solid Tumors.

CD205 is a type I transmembrane glycoprotein and is a member of the C-type lectin receptor family. Analysis by mass spectrometry revealed that CD205 was robustly expressed and highly prevalent in a variety of solid malignancies from different histotypes. IHC confirmed the increased expression of CD205 in pancreatic, bladder, and triple-negative breast cancer (TNBC) compared with that in the corresponding normal tissues. Using immunofluorescence microscopy, rapid internalization of the CD205 antigen was observed. These results supported the development of MEN1309/OBT076, a fully humanized CD205-targeting mAb conjugated to DM4, a potent maytansinoid derivate, via a cleavable N-succinimidyl-4-(2-pyridyldithio) butanoate linker. MEN1309/OBT076 was characterized in vitro for target binding affinity, mechanism of action, and cytotoxic activity against a panel of cancer cell lines. MEN1309/OBT076 displayed selective and potent cytotoxic effects against tumor cells exhibiting strong and low to moderate CD205 expression. In vivo, MEN1309/OBT076 showed potent antitumor activity resulting in durable responses and complete tumor regressions in many TNBC, pancreatic, and bladder cancer cell line-derived and patient-derived xenograft models, independent of antigen expression levels. Finally, the pharmacokinetics and pharmacodynamic profile of MEN1309/OBT076 was characterized in pancreatic tumor-bearing mice, demonstrating that the serum level of antibody-drug conjugate (ADC) achieved through dosing was consistent with the kinetics of its antitumor activity. Overall, our data demonstrate that MEN1309/OBT076 is a novel and selective ADC with potent activity against CD205-positive tumors. These data supported the clinical development of MEN1309/OBT076, and further evaluation of this ADC is currently ongoing in the first-in-human SHUTTLE clinical trial.

Nutritional value of cherry tomatoes (Lycopersicon esculentum Cv. Naomi F1) harvested at different ripening stages.

The average content of some classes of antioxidants is generally higher in cherry tomatoes than in normal-sized berries. The aim of this work was to assess the nutritional value of cherry tomato (cv. Naomi F1) by investigating the compositional pattern of berries harvested at different ripening stages and evaluating, in particular, all of the main antioxidants (carotenoids, ascorbic acid, phenolic compounds, and alpha-tocopherol) and the antioxidant activity of the water-soluble and water-insoluble fractions. Results confirmed the relatively high level of carotenoids in cherry tomato but showed that not all biologically active compounds necessarily increase in tomatoes picked at later stages of ripeness. Cherry tomatoes harvested at full ripeness exhibited the highest level of carotenoids and antioxidant activity in the water-insoluble fraction. On the other hand, no significant differences in ascorbic acid content were observed at different ripening stages, whereas the main phenolics content and the antioxidant activity of water-soluble fraction showed slight, but significant, decreases at later stages of ripeness.

Effect of acute ingestion of fresh and stored lettuce (Lactuca sativa) on plasma total antioxidant capacity and antioxidant levels in human subjects.

The present study investigated whether storage under modified-atmosphere packaging (MAP) affected the antioxidant properties of fresh lettuce (Lactuca sativa). Eleven healthy volunteers (six men, five women) consumed 250 g fresh lettuce, and blood was sampled before (0 h) and 2, 3 and 6 h after consumption. The protocol was repeated 3 d later with the same lettuce stored at 5 degrees C under MAP conditions (O2-N2 (5:95, v/v)). Results showed that after ingestion of fresh lettuce, plasma total radical-trapping antioxidant potential (TRAP), measured as area under the curve, was significantly higher (1.3 (sem 0.3) mmol/l per 6 h; P<0.05) than the value obtained with MAP-stored lettuce (0.1 (sem 0.2) mmol/l per 6 h). Plasma TRAP, quercetin and p-coumaric acid were significantly different from baseline values (P

Naringenin from cooked tomato paste is bioavailable in men.

Naringenin has been shown to exert antiestrogenic, cholesterol-lowering and antioxidant activities, as well as an indirect modulation on the metabolism of many xenobiotics. It is one of the most abundant polyphenols in tomato. Given the widespread consumption of tomato (Lycopersicum esculentum) and tomato-based products, this study was designed to determine whether plasma levels of naringenin were detectable in five men after consumption of a test meal containing 150 mg of cooked tomato paste. Naringenin intake with the test meal was 3.8 mg. Blood was drawn from fasting subjects and 2, 4, 6, 8 and 24 h after the meal. To compare the results with a control, the same meal without tomato paste (control meal) was administered to the same subjects 2 wk later. Analyses were performed using high-performance liquid chromatography coupled with a CoulArray electrochemical detector. The peak plasma concentration was 0.12 +/- 0.03 micro mol/L 2 h after the meal. Unconjugated naringenin was not detected. Naringenin was not detected in plasma at any time after consumption of the control meal. In addition to naringenin, we detected rutin and chlorogenic acid in tomato paste, but these polyphenols and their derivatives (quercetin and caffeic acid) were not detected in plasma at any time. To the best of our knowledge, this is the first study demonstrating naringenin bioavailability in humans after consumption of a meal containing cooked tomato paste.