| Title: |
Antitumor activity without on-target off-tumor toxicity of GD2–chimeric antigen receptor T cells in patients with neuroblastoma. |
| Authors: |
Straathof, Karin; Flutter, Barry; Wallace, Rebecca; Jain, Neha; Loka, Thalia; Depani, Sarita; Wright, Gary; Thomas, Simon; Cheung, Gordon Weng-Kit; Gileadi, Talia; Stafford, Sian; Kokalaki, Evangelia; Barton, Jack; Marriott, Clare; Rampling, Dyanne; Ogunbiyi, Olumide; Akarca, Ayse U.; Marafioti, Teresa; Inglott, Sarah; Gilmour, Kimberly |
| Source: |
Science Translational Medicine; 11/25/2020, Vol. 12 Issue 571, p1-12, 12p |
| Subject Terms: |
Antigen receptors; CD19 antigen; Cell receptors; Child patients; Cytokine release syndrome; Bone marrow diseases; Rituximab |
| Abstract: |
CARs to drive off neuroblastoma: Neuroblastoma is one of the most common types of pediatric cancer, and it can be difficult to treat. This tumor typically has high expression of the ganglioside GD2, and there have been previous attempts at targeting these tumors via GD2. Unfortunately, these have not been entirely successful, in part, because some GD2 is also present on nonmalignant nervous tissue. Straathof et al. report the results of a clinical trial in 12 pediatric patients with neuroblastoma, treated with chimeric antigen receptor (CAR) T cells against GD2. The treatment was well tolerated without on-target off-tumor toxicity but did not achieve objective clinical responses. 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. [ABSTRACT FROM AUTHOR] |
| : |
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| Database: |
Complementary Index |