Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia

BACKGROUND: In a single-center phase 1-2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). METHODS: We conducted a phase 2, single-cohort, 25-center, global study of tisagenlecleucel in pediatric and young adult patients with CD19+ relapsed or refractory B-cell ALL. The primary end point was the overall remission rate (the rate of complete remission or complete remission with incomplete hematologic recovery) within 3 months. RESULTS: For this planned analysis, 75 patients received an infusion of tisagenlecleucel and could be evaluated for efficacy. The overall remission rate within 3 months was 81%, with all patients who had a response to treatment found to be negative for minimal residual disease, as assessed by means of flow cytometry. The rates of event-free survival and overall survival were 73% (95% confidence interval [CI], 60 to 82) and 90% (95% CI, 81 to 95), respectively, at 6 months and 50% (95% CI, 35 to 64) and 76% (95% CI, 63 to 86) at 12 months. The median duration of remission was not reached. Persistence of tisagenlecleucel in the blood was observed for as long as 20 months. Grade 3 or 4 adverse events that were suspected to be related to tisagenlecleucel occurred in 73% of patients. The cytokine release syndrome occurred in 77% of patients, 48% of whom received tocilizumab. Neurologic events occurred in 40% of patients and were managed with supportive care, and no cerebral edema was reported. CONCLUSIONS: In this global study of CAR T-cell therapy, a single infusion of tisagenlecleucel provided durable remission with long-term persistence in pediatric and young adult patients with relapsed or refractory B-cell ALL, with transient high-grade toxic effects. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02435849.

Relative nutritional quality of C 3 and C 4 grasses for a graminivorous lepidopteran, Paratrytone melane (Hesperiidae)

We tested the hypothesis that C 4 grasses are inferior to C 3 grasses as host plants for herbivorous insects by measuring the relative performance of larvae of a graminivorous lepidopteran, Paratrytone melane (Hesperiidae), fed C 3 and C 4 grasses. Relative growth rates and final weights were higher in larvae fed a C 3 grass in Experiment I. However, in two additional experiments, relative growth rates and final weights were not significantly different in larvae fed C 3 and C 4 grasses. We examined two factors which are believed to cause C 4 grasses to be of lower nutritional value than C 3 grasses: foliar nutrient levels and nutrient digestibility. In general, foliar nutrient levels were higher in C 3 grasses. In Experiment I, protein and soluble carbohydrates were digested from a C 3 and a C 4 grass with equivalent efficiencies. Therefore, differences in larval performance are best explained by higher nutrient levels in the C 3 grass in this experiment. In Experiment II, soluble carbohydrates were digested with similar efficiencies from C 3 and C 4 grasses but protein was digested with greater efficiency from the C 3 grasses. We conclude (1) that the bundle sheath anatomy of C 4 grasses is not a barrier to soluble carbohydrate digestion and does not have a nutritionally significant effect on protein digestion and (2) that P. melane may consume C 4 grasses at compensatory rates.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47798/1/442_2004_Article_BF00317268.pd

EGF Receptor and mTORC1 are Novel Therapeutic Targets in Nonseminomatous Germ Cell Tumors

Abstract Germ cell tumors (GCT) are malignant tumors that arise from pluripotent embryonic germ cells and occur in children and young adults. GCTs are treated with cisplatin-based regimens which, while overall effective, fail to cure all patients and cause significant adverse late effects. The seminoma and nonseminoma forms of GCT exhibit distinct differentiation states, clinical behavior, and response to treatment; however, the molecular mechanisms of GCT differentiation are not fully understood. We tested whether the activity of the mTORC1 and MAPK pathways were differentially active in the two classes of GCT. Here we show that nonseminomatous germ cell tumors (NSGCT, including embryonal carcinoma, yolk sac tumor, and choriocarcinoma) from both children and adults display activation of the mTORC1 pathway, while seminomas do not. In seminomas, high levels of REDD1 may negatively regulate mTORC1 activity. In NSGCTs, on the other hand, EGF and FGF2 ligands can stimulate mTORC1 and MAPK signaling, and members of the EGF and FGF receptor families are more highly expressed. Finally, proliferation of NSGCT cells in vitro and in vivo is significantly inhibited by combined treatment with the clinically available agents erlotinib and rapamycin, which target EGFR and mTORC1 signaling, respectively. These results provide an understanding of the signaling network that drives GCT growth and a rationale for therapeutic targeting of GCTs with agents that antagonize the EGFR and mTORC1 pathways. Mol Cancer Ther; 17(5); 1079–89. ©2018 AACR.</jats:p