In a phase I clinical trial, 12 young neuroblastoma patients were treated with escalating doses of GD2-targeted, kill switch-containing second generation CAR T cells and lymphodepletion. CAR T cells expansion was observed only in patients with high CAR doses (≥108 cels/m2) and prior lymphodepletion, with no dose-limiting toxicities. Although objective clinical responses did not occur, three patients in the high-dose cohort showed evidence of persistent immune activation and antitumor CAR T cell activity, particularly in bone marrow and soft tissue lesions. In post-treatment biopsies, GD2 antigen expression was maintained, but CAR T cells were not detected.
Contributed by Alex Najibi
ABSTRACT: 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 ³10(8)/meter(2) 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.
Author Info: (1) Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 1EH, UK. Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK. (2) Gr
Author Info: (1) Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 1EH, UK. Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK. (2) Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 1EH, UK. Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK. (3) Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 1EH, UK. Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK. (4) Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK. (5) Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK. (6) Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK. (7) Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK. (8) UCL Cancer Institute, London WC1E 6DD, UK. Autolus Ltd., London W12 7FP, UK. (9) UCL Cancer Institute, London WC1E 6DD, UK. (10) Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 1EH, UK. (11) Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 1EH, UK. (12) UCL Cancer Institute, London WC1E 6DD, UK. (13) Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 1EH, UK. (14) Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK. (15) Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK. (16) Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK. (17) UCL Cancer Institute, London WC1E 6DD, UK. (18) UCL Cancer Institute, London WC1E 6DD, UK. (19) Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK. (20) Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK. (21) Autolus Ltd., London W12 7FP, UK. (22) Autolus Ltd., London W12 7FP, UK. (23) Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK. (24) Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK. (25) Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK. (26) Centre for Drug Development, Cancer Research UK, London E20 1JQ, UK. (27) Centre for Drug Development, Cancer Research UK, London E20 1JQ, UK. (28) Centre for Drug Development, Cancer Research UK, London E20 1JQ, UK. (29) Centre for Drug Development, Cancer Research UK, London E20 1JQ, UK. (30) Centre for Drug Development, Cancer Research UK, London E20 1JQ, UK. (31) Centre for Drug Development, Cancer Research UK, London E20 1JQ, UK. (32) Centre for Drug Development, Cancer Research UK, London E20 1JQ, UK. (33) Centre for Drug Development, Cancer Research UK, London E20 1JQ, UK. (34) Centre for Drug Development, Cancer Research UK, London E20 1JQ, UK. (35) Centre for Drug Development, Cancer Research UK, London E20 1JQ, UK. (36) Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK. (37) Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK. (38) Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK. (39) Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK. (40) Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK. (41) UCL Cancer Institute, London WC1E 6DD, UK. m.pule@ucl.ac.uk j.anderson@ucl.ac.uk. (42) Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 1EH, UK. m.pule@ucl.ac.uk j.anderson@ucl.ac.uk. Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK.
