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Published on: February 17, 2022
Anti-GD2 CAR-NKT cells in relapsed or refractory neuroblastoma: updated phase 1 trial interim results
Andras Heczey1,2, Xin Xu3, Amy N Courtney3
1Department of Pediatrics, Center for Advanced Innate Cell Therapy, Baylor College of Medicine, Houston, TX, USA. heczey@bcm.edu.
Abstract:
Vα24-invariant natural killer T cells (NKTs) have anti-tumor properties that can be enhanced by chimeric antigen receptors (CARs). Here we report updated interim results from the first-in-human phase 1 evaluation of autologous NKTs co-expressing a GD2-specific CAR with interleukin 15 (IL15) (GD2-CAR.15) in 12 children with neuroblastoma (NB). The primary objectives were safety and determination of maximum tolerated dose (MTD). The anti-tumor activity of GD2-CAR.15 NKTs was assessed as a secondary objective. Immune response evaluation was an additional objective. No dose-limiting toxicities occurred; one patient experienced grade 2 cytokine release syndrome that was resolved by tocilizumab. The MTD was not reached. The objective response rate was 25% (3/12), including two partial responses and one complete response. The frequency of CD62L+NKTs in products correlated with CAR-NKT expansion in patients and was higher in responders (n = 5; objective response or stable disease with reduction in tumor burden) than non-responders (n = 7). BTG1 (BTG anti-proliferation factor 1) expression was upregulated in peripheral GD2-CAR.15 NKTs and is a key driver of hyporesponsiveness in exhausted NKT and T cells. GD2-CAR.15 NKTs with BTG1 knockdown eliminated metastatic NB in a mouse model. We conclude that GD2-CAR.15 NKTs are safe and can mediate objective responses in patients with NB. Additionally, their anti-tumor activity may be enhanced by targeting BTG1. ClinicalTrials.gov registration: NCT03294954 .
Insights
Chimeric antigen receptor (CAR) engineered natural killer T cells (NKTs) targeting GD2 showed safety and efficacy in children with neuroblastoma. Targeting BTG1 may further enhance anti-tumor activity of these CAR-NKTs.
Area of Science:
- Immunology
- Oncology
- Cell Therapy
Background:
- Vα24-invariant natural killer T cells (NKTs) possess inherent anti-tumor capabilities.
- Chimeric antigen receptors (CARs) can augment the anti-tumor potential of NKTs.
- Neuroblastoma (NB) is a pediatric cancer with limited treatment options.
Purpose of the Study:
- To evaluate the safety and maximum tolerated dose (MTD) of autologous GD2-specific CAR-engineered NKTs co-expressing IL15 (GD2-CAR.15) in children with NB.
- To assess the anti-tumor activity and immune response to GD2-CAR.15 NKTs.
- To identify predictive biomarkers for response.
Main Methods:
- Phase 1 clinical trial of GD2-CAR.15 NKTs in 12 children with NB.
- Safety assessments included monitoring for dose-limiting toxicities and cytokine release syndrome (CRS).
- Anti-tumor activity was evaluated by objective response rate, and immune responses were analyzed, including CD62L+ NKT frequency and BTG1 expression.
Main Results:
- No dose-limiting toxicities were observed; MTD was not reached.
- One patient experienced manageable grade 2 CRS.
- Objective response rate was 25% (3/12), with 2 partial and 1 complete response.
- Higher frequency of CD62L+ NKTs correlated with CAR-NKT expansion and response.
- BTG1 upregulation was observed in GD2-CAR.15 NKTs, and its knockdown enhanced anti-tumor activity in a mouse model.
Conclusions:
- Autologous GD2-CAR.15 NKTs are safe and demonstrate objective anti-tumor responses in pediatric neuroblastoma.
- CD62L expression on NKTs may predict expansion and response.
- Targeting BTG1 presents a potential strategy to enhance the efficacy of CAR-NKTs in neuroblastoma.
