| Title: |
Anti-tumor activity without on-target off-tumor toxicity of GD2-Chimeric Antigen Receptor T cells in patients with neuroblastoma |
| Authors: |
Straathof, K; Flutter, B; Wallace, R; Jain, N; Loka, T; Depani, S; Wright, G; Thomas, S; Cheung, GW-K; Gileadi, T; Stafford, S; Kokalaki, E; Barton, J; Marriott, C; Rampling, D; Ogunbiyi, O; Akarca, A; Marafioti, T; Inglott, S; Gilmour, K; Al-Hajj, M; Day, W; McHugh, K; Biassoni, L; Sizer, N; Barton, C; Edwards, D; Dragoni, I; Silvester, J; Dyer, K; Traub, S; Elson, L; Brook, S; Westwood, N; Robson, L; Bedi, A; Howe, K; Barry, A; Duncan, C; Barone, G; Pule, M; Anderson, J |
| Source: |
Science Translational Medicine , 12 (571) , Article eabd6169. (2020) |
| Publisher Information: |
American Association for the Advancement of Science |
| Publication Year: |
2020 |
| Collection: |
University College London: UCL Discovery |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
text |
| Language: |
English |
| Relation: |
https://discovery.ucl.ac.uk/id/eprint/10115634/3/Anderson_1RGCART_STM_manuscript_FINAL2.pdf; https://discovery.ucl.ac.uk/id/eprint/10115634/ |
| Availability: |
https://discovery.ucl.ac.uk/id/eprint/10115634/3/Anderson_1RGCART_STM_manuscript_FINAL2.pdf; https://discovery.ucl.ac.uk/id/eprint/10115634/ |
| Rights: |
open |
| Accession Number: |
edsbas.B7F256E4 |
| Database: |
BASE |