Abstract
Background: Treatment of high risk neuroblastoma remains challenging; current multimodal treatment regimens achieve long term survival in <50% of patients and are associated with significant ...morbidity. Ganglioside GD2 is abundantly expressed on almost all neuroblastomas whilst expression on normal tissue is highly limited, providing a suitable CAR target. Here, we report the preliminary results of a Phase I clinical study of GD2-CART for refractory/relapsed neuroblastoma (NCT02761915).
Trial design: The therapeutic (1RG-CART) is autologous T-cells transduced with a gamma-retroviral vector encoding both an anti-GD2 CAR and the RQR8 suicide gene. The CAR comprises a humanized anti-GD2 single chain variable fragment derived from the K666 antibody and CD28/CD3ζ signalling domains. Both lymphodepletion and CART dose were escalated as follows: dose level (DL) 1 without lymphodepletion, DL2 with 1.2 g/m2 cyclophosphamide and DL3 and beyond 1.2 g/m2 cyclophosphamide and 125 mg/m2 fludarabine followed by administration of a single intravenous dose of 1x107/m2 (DL1-3) or 1x108/m2 (DL4) 1RG-CART. Primary objectives are to assess safety and tolerability.
Results: To date, 12 patients have been enrolled. All had relapsed/refractory neuroblastoma with measurable disease in bone (n=11), bone marrow (n=7) and/or soft tissue sites (n=9). Cell products were successfully manufactured for all patients. Median transduction efficiency was 34.5% (range 16-54%). Nine patients have been treated on DL1 (n=4), DL2 (n=1), DL3 (n=1) and DL4 (n=3) respectively. No dose limiting toxicity (DLT) was seen. For patients treated on DL1-3 (1x107/m2), 1RG-CART could not be detected in peripheral blood, and no clinical responses were seen. In contrast, expansion of 1RG-CART cells as detected by flow cytometry and qPCR was seen in the 3 patients treated on DL4 (1x108/m2). In two DL4 patients, 1RG-CART expansion was still limited and transient (marking levels <10,000 copies/μg DNA). These patients had disease progression as measured at Day +28. In one DL4 patient however, 1RG-CART marking levels of >40,000 copies/μg DNA were achieved. This patient developed Grade 2 cytokine release syndrome (Day +5) and biochemical evidence of tumour lysis (Day +21). Disease reassessment on Day +28 showed response in many sites of bone/marrow disease as measured by mIBG scintigraphy, and near complete tumour clearance in bone marrow which at baseline was heavily infiltrated with neuroblastoma. Disease progression occurred on Day +45 at which time 1RG-CART were no longer detectable. In the absence of DLT this prompted us to continue with DL5 (1x109/m2).
Conclusions: These preliminary results are the first to demonstrate on-target activity in bone and bone marrow of GD2-CART in this childhood solid tumour. Further 1RG-CART dose escalation is warranted, and under way.
Citation Format: Karin Straathof, Barry Flutter, Rebecca Wallace, Simon Thomas, Gordon Cheung, Angela Collura, Talia Gileadi, Jack Barton, Gary Wright, Sarah Inglott, David Edwards, Claire Barton, Karen Dyer, Nigel Westwood, Thalia Loka, Sarita Depani, Karen Howe, Giuseppe Barone, Martin Pule, John Anderson. A Cancer Research UK phase I trial of anti-GD2 chimeric antigen receptor (CAR) transduced T-cells (1RG-CART) in patients with relapsed or refractory neuroblastoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT145.
Dog vaccination and sterilisation remain the only effective means of preventing human rabies in the long term and can reduce the incidence of dog bite.4 Implementation is challenging, but ...difficulties can be overcome.5 This is important in settings such as Malawi where many dog-bite victims do not seek or do not have access to post-exposure prophylaxis.
Summary
There is a paucity of data on the treatment outcome in children with relapsed or poorly responsive nodular lymphocyte predominant Hodgkin lymphoma (nLPHL). This retrospective report evaluates ...the treatment outcome in a national cohort of children with relapsed or poorly responsive nLPHL. A total of 37 patients, 22 with relapsed and 15 with poorly responding disease, are the subjects of this report. Of the 22 patients with relapsed nLPHL, 11 had relapsed after primary excision biopsy, 10 after chemotherapy and 1 after chemotherapy and involved field radiotherapy. The majority had localized disease at relapse. The median time to relapse was 8 months after chemotherapy and 11 months after excision biopsy. Seven of the 15 patients with poorly responding nLPHL had variant histology. Three patients with initial poor response did not receive any further treatment and have had no disease progression. Transformation to diffuse large B cell lymphoma, in addition to evolution from typical to variant nLPHL occurred in one patient each. Thirty‐four patients have been successfully re‐treated with second chemotherapy or radiotherapy. Multiple relapses were uncommon but treatable. Relapse or poorly responsive nLPHL is fully salvageable with either additional chemotherapy and or radiotherapy.
Abstract only
10022
Background: Adolescents with extracranial malignant germ cell tumors (GCTs) are often treated on the same regimens developed for children, but more closely resemble the clinical ...characteristics of young adult patients. We sought to determine whether event-free survival (EFS) for adolescents with GCTs was more like that of children or young adults. Methods: We assembled an individual patient database of ten GCT trials: seven conducted by pediatric cooperative groups and three by an adult group. We selected male patients aged 0-30 years old treated with platinum-based chemotherapy for non-seminomatous malignant GCTs of the testis, retroperitoneum, or mediastinum. We categorized age-group as children (0 to < 11 years), adolescents (11 to < 18 years), or young adults (18 to < 30 years old). We compared EFS among age groups, and adjusted for calculated IGCCCG risk-group using Cox proportional hazards analysis. Results: 593 patients met inclusion criteria, of whom 90 were children, 109 were adolescents, and 394 were young adults. The 5-year EFS for adolescents (72%; CI = 62-79%) was significantly lower than for children (90%; CI = 81-95%, p = 0.003) and for young adults (88%; CI = 84-91%, p < 0.001). Risk-group was significantly associated with EFS in the adolescent age-group (p = 0.002). In a Cox multivariable analysis, the difference between adolescents and children remained statistically significant (HR = 0.30, p = 0.001), but the difference between adolescents and young adults did not (HR 0.66, p = 0.114). Conclusions: EFS for adolescent patients with extracranial malignant GCTs was similar to young adults but significantly worse than children. This finding may have important implications for how adolescent patients are treated.
The survival of children with DIPG remains dismal, with new treatments desperately needed. In a prospective biopsy-stratified clinical trial, we combined detailed molecular profiling and drug ...screening in newly-established patient-derived models
in vitro
and
in vivo
. We identified
in vitro
sensitivity to MEK inhibitors in DIPGs harbouring MAPK pathway alterations, however treatment of PDX models and a patient at relapse failed to elicit a significant response. We generated trametinib-resistant clones in a
BRAF
_G469V model through continuous drug exposure, and identified acquired mutations in
MEK1/2
with sustained pathway up-regulation. These cells showed hallmarks of mesenchymal transition, and expression signatures overlapping with inherently trametinib-insensitive patient-derived cells, predicting sensitivity to dasatinib. Combined trametinib and dasatinib showed highly synergistic effects
in vitro
and on
ex vivo
brain slices. We highlight the MAPK pathway as a therapeutic target in DIPG, and show the importance of parallel resistance modelling and combinatorial treatments for meaningful clinical translation.
Hereditary leiomyomatosis and renal cell cancer is a hereditary cancer syndrome in which affected individuals are at risk for cutaneous and uterine leiomyomas, and renal cancer. Previous reports have ...stressed the aggressiveness of the renal tumours, often with early metastasis, despite small primary tumour size. Almost all the previously reported patients were adults, and different studies showed variability in penetrance for the renal tumours. We report a patient in whom renal cancer was detected at the age of 11 years at his first routine screening imaging after he was found to carry a fumarate hydratase gene mutation (c.1189G > A) transmitted from his mother. This report serves to emphasize the need to improve guidelines for screening of at risk individuals, including the necessity for predictive genetic testing and early institution of tumour surveillance in childhood.
Extensive subclinical venous sinus thrombosis in the dehydrated infant Locke, Christie; Depani, Sarita; Gray, Martin
The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians,
05/2010, Letnik:
23, Številka:
5
Report
PDF
