The reprogramming of a patient’s immune system through genetic modification of the T cell compartment with chimeric antigen receptors (CARs) has led to durable remissions in chemotherapy-refractory B cell cancers. Targeting of solid cancers by CAR-T cells is dependent on their infiltration and expansion within the tumor microenvironment, and thus far, fewer clinical responses have been reported. Here, we report a phase 1 study (NCT02761915) in which we treated 12 children with relapsed/refractory neuroblastoma with escalating doses of second-generation GD2-directed CAR-T cells and increasing intensity of preparative lymphodepletion. Overall, no patients had objective clinical response at the evaluation point +28 days after CAR-T cell infusion using standard radiological response criteria. However, of the six patients receiving ≥108/meter2 CAR-T cells after fludarabine/cyclophosphamide conditioning, two experienced grade 2 to 3 cytokine release syndrome, and three demonstrated regression of soft tissue and bone marrow disease. This clinical activity was achieved without on-target off-tumor toxicity. Targeting neuroblastoma with GD2 CAR-T cells appears to be a valid and safe strategy but requires further modification to promote CAR-T cell longevity.
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.
Aurora kinases regulate mitosis and are commonly overexpressed in leukemia. This phase I/IIa study of AT9283, a multikinase inhibitor, was designed to identify maximal tolerated doses, safety, pharmacokinetics, and pharmacodynamic activity in children with relapsed/refractory acute leukemia. The trial suffered from poor recruitment and terminated early, therefore failing to identify its primary endpoints. AT9283 caused tolerable toxicity, but failed to show clinical responses. Future trials should be based on robust preclinical data that provide an indication of which patients may benefit from the experimental agent, and recruitment should be improved through international collaborations and early combination with established treatment strategies.
Background: Poor diet is associated with the development of colorectal cancer with the greatest risk from diets low in vegetables, fruits and fibres and high in red and processed meats (Wilmink, 1997; Bingham, 2000). Improving people's diet remains a challenge, but evidence suggests that those attending cancer‐screening clinics may be more receptive to dietary advice than the general population (Baker and Wardle, 2002). This study aimed to establish the impact of a needs‐based nutrition education leaflet when used in a colorectal cancer‐screening clinic. Method: Fifty subjects (mean ± SD age, 62 ± 15.1 years; male : female, 22 : 28) attending a colorectal clinic were interviewed at baseline using a validated, semi‐structured questionnaire (Dyer et al., in press). The interview was used to establish subjects’ nutritional knowledge, attitudes and understanding. Using these interviews as a form of needs‐assessment, a nutrition education leaflet was designed by the authors. Thirty‐five of the original 50 subjects agreed to participate in evaluation of the leaflet and have their knowledge re‐tested. A second group (n = 52) of colorectal clinic patients was recruited and their nutrition knowledge was tested immediately after exposure to the leaflet and again 1 month later (mean age 52 ± 15.0 years; male : female, 23 : 29). All interviews were conducted by the researcher (KD). Results were analysed using paired and unpaired t‐tests and level of significance was set at P < 0.05. Results: After exposure to the leaflet, there was a significant increase in awareness of the messages ‘5 fruit and vegetables a day’ (46% vs 91%, P < 0.001) and ‘what constitutes a portion of fruit and vegetable’ (38% vs 71%, P < 0.05). This significant increase in nutrition knowledge was sustained over a 1‐month period. During this time, 12 (23%) out of 52 reported improvement in their fruit and vegetable intake. Conclusion: This small study suggests that a targeted education leaflet can lead to a significant increase in nutrition knowledge that may be sustainable. Although education alone cannot guarantee behavioural change, it appears to challenge people's attitude towards the adequacy of their fruit and vegetable intake. Targeting this leaflet at attendees of a colorectal clinic led to reported behavioural change in nearly a quarter of the group studied. Further, robust work is needed to confirm the sustainability and longevity of this positive change in diet. References: Baker, A.H. & Wardle, J. (2002) Increasing fruit andvegetable intake among adults attending colorectal cancer screening: the efficacy of a brief tailored intervention. Cancer Epidemiol. Biomarkers Prev. 11, 203–206. Bingham, S.A. (2000) Diet and colorectal cancer prevention. Biochem. Soc. Trans.28, 12–16. Dyer, K.J., Fearon, K.C.F., Buckner, K. & Richardson, R.A.Diet and colorectal cancer: baseline dietary knowledge of colorectal patients. Health Educ. J. in press. Wilmink, A.B.M. (1997) Overview of the epidemiology ofcolorectal cancer. Diseases Colon. Rectum. 40, 483–4...
Objective To establish the dietary knowledge, attitudes and potential barriers to change of patients attending a colorectal outpatient clinic. Design Use of a semistructured interview to generate qualitative and quantitative data. Setting A regional colorectal outpatient clinic within Edinburgh. Method Patients attending clinic with colorectal symptoms were invited to participate in a semistructured interview using a validated questionnaire. Results Fifty patients (mean age 62 ± SD 15.1 years; male:female = 22:28) were interviewed. Twenty-three (46 per cent) knew that five portions of fruit and vegetable were recommended daily, but 31 (62 per cent) were unclear what constituted a portion. Only three (6 per cent) and two (4 per cent) could name three foods high in fat and fibre, respectively. Twenty-three (46 per cent) were unable to identify why healthy eating is important, while only four (8 per cent) were aware of an association between diet and cancer. Women had significantly higher nutrition knowledge scores than men (16.3 & p l u s m n ; SD7.1 v 12.3 ± SD5.1, p<0.05 ). There was a significant relationship between educational attainment and nutritional knowledge ( r=0.534, p<0.001 ). Potential barriers to change included the belief that their diet was already healthy ( n =35, 70 per cent) and lack of time ( n =25, 50 per cent).Conclusion Patients attending a colorectal clinic lack practical dietary knowledge and the majority are unaware of the link between diet and cancer. Targeted health promotion strategies are needed to raise awareness in this group.
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