Anti-GD2 CAR-NKT cells in patients with relapsed or refractory neuroblastoma: an interim analysis

Abstract

Vα24-invariant natural killer T (NKT) cells have shown potent anti-tumor properties in murine tumor models and have been linked to favorable outcomes in patients with cancer. However, low numbers of these cells in humans have hindered their clinical applications. Here we report interim results from all three patients enrolled on dose level 1 in a phase 1 dose-escalation trial of autologous NKT cells engineered to co-express a GD2-specific chimeric antigen receptor (CAR) with interleukin-15 in children with relapsed or resistant neuroblastoma (NCT03294954). Primary and secondary objectives were to assess safety and anti-tumor responses, respectively, with immune response evaluation as an additional objective. We ex vivo expanded highly pure NKT cells (mean ± s.d., 94.7 ± 3.8%) and treated patients with 3 × 10 6 CAR-NKT cells per square meter of body surface area after lymphodepleting conditioning with cyclophosphamide/fludarabine (Cy/Flu). Cy/Flu conditioning was the probable cause for grade 3-4 hematologic adverse events, as they occurred before CAR-NKT cell infusion, and no dose-limiting toxicities were observed. CAR-NKT cells expanded in vivo, localized to tumors and, in one patient, induced an objective response with regression of bone metastatic lesions. These initial results suggest that CAR-NKT cells can be expanded to clinical scale and safely applied to treat patients with cancer.

The immune landscape of neuroblastoma: Challenges and opportunities for novel therapeutic strategies in pediatric oncology

“…Nevertheless, next-generation CAR T cells are currently under investigation in many clinical trials for neuroblastoma, targeted at L1CAM (NCT02311621) [157], B7eH3 (NCT04483778) [158], EGFR (NCT03618381) [159] and GD2 (NCT02919046, NCT02765243, NCT02761915, NCT01822652, NCT03635632, NCT03721068, NCT03294954, NCT02992210, NCT03373097, NCT01953900) [160e169]. Notably, encouraging results of CAR-NKT cell therapy for neuroblastoma were recently reported in an interim analysis [170]. A proof of principle for the exciting possibility of expanding TIL ex vivo for reinfusion therapy, which showed remarkable effectivity in melanoma and cervical carcinoma [171,172], was recently provided.…”

Low Expression of IL-15 and NKT in Tumor Microenvironment Predicts Poor Outcome of MYCN-Non-Amplified Neuroblastoma

“…Novel strategies to enhance NKT activity by the incorporation of IL-15 in GD2-based immunotherapy, such as anti-GD2 antibody or GD2-specific CAR-Ts or CAR-NKs, are being actively pursued in a phase 1 trial of autologous NKTs engineered to co-express a GD2-specific CAR with IL-15 in three children with relapsed or resistant NBL (NCT03294954). Currently, no dose-limiting toxicities have been observed, and objective response with regression of metastatic bone lesions has been noted in one patient [50]. However, in view of the extremely high cost of CAR-Ts, CAR-NKs, and CAR-NKTs cell therapies, the combination of NKT activators with IL-15 might offer a less expensive alternate approach.…”

Allogeneic CAR Cell Therapy—More Than a Pipe Dream

“…CAR-engineered iNKT cells also appear to be safe in humans and are promising for “off the shelf” use given the lack of GVHD. Preliminary results from an ongoing trial (NCT03294954) using autologous GD2-CAR iNKT cells with co-expression of IL15 for the treatment of pediatric patients with neuroblastoma have shown this approach to be feasible and safe ( 111 ). Clinical experience of allogeneic CAR iNKT cells is yet to be published so possible adverse events cannot be predicted, however an ongoing clinical trial evaluating allogeneic CAR19-iNKT cells for the treatment of hematological malignancy (NCT03774654) aims to test safety and efficacy.…”