Institute of Cancer, Xinqiao Hospital, Chongqing, China
Qingzhu Jia , Ling Peng , Gang Chen , Haiyang Wu , Dong Zeng , Tao Liu , Yunpeng Zhan , Si Li , Frank Su , Bo Zhu , Qi-Jing Li
Background: Nasopharyngeal carcinoma (NPC) refraction and metastasis is common, but therapeutics are limited. As adoptive immunotherapy has emerged as effective against other cancers, engineered T cells bearing a transgenic Epstein-Barr virus (EBV)-specific TCR (TCR-T) represent a viable approach to treat EBV-associated NPC. Given PD-1/PD-L1 induced T cell hypofunction, we herein report preliminary findings of a phase I trial of EBV-targeting TCR-T cells armored with secreted PD-1 blockade for patients who failed in two or more lines of standard therapies. Methods: Patients with advanced NPCs were consented and screened for EBV serotype and HLA haplotype. EBV+/HLA-A*02+ patients were enrolled in a rapid titration setting to escalate the single infusion dose from 5x106 to 1.0x107 and 5.0x107 /kg TCR-T cells. After safety evaluation, the 5.0X107 /kg cohort was expanded for further investigation of combining with IL-2 administration. Fludarabine/cyclophosphamide were administered prior to TCR-T cell transfer as pre-conditioning. Patient monitoring and peripheral blood analysis occurred weekly over the first month and then monthly until disease progression or patient withdrawal. The primary objective was to determine safety and a recommended phase 2 dose (RP2D), while the secondary objective was investigator assessed ORR (RECIST v1.1). Results: One patient per TCR-T dose was treated, and, as no dose-limiting toxicity (DLT) has been observed, dose level 3 (5.0x107 /kg) was expanded with IL-2 administration upon TCR-T cell infusion. As of January 2023, six patients have been treated. One patient (16.7%) exhibited grade 1 CRS (n=6). No grade 4 treatment-related adverse events (TRAEs) have been observed, with leukopenia and fever being the most common AEs. Two patients (33.3%) were assessed as partial response (PR), with one reaching a response duration of 9 months to date. Three patients (50%) were assessed as stable disease (SD). For all patients, pharmacokinetic analysis revealed that levels of TCR-T cells in peripheral blood peak between 3- and 14-days post-infusion, with a maximum duration of 180 days. Conclusions: EBV-targeting TCR-T cells armored with PD-1 blockade are well tolerated. Initial results from this ongoing study indicate that EBV proteins may be safe and effective TCR-T targets to achieve superior outcomes in advanced EBV-positive NPC patients. Clinical trial information: NCT04139057.
Treatment-Related Adverse Events (TRAEs) | Efficacy | ||||
---|---|---|---|---|---|
All grades | Grade 3 | Grade 4 | |||
Leukopenia | 6 (100%) | 2 (33.3%) | 0 | Complete response (CR) | 0 (0) |
Fever | 5 (83.3%) | 2 (33.3%) | 0 | Partial response (PR) | 2 (33.3%) |
Chills | 3 (50%) | 0 | 0 | Stable disease (SD) | 3 (50%) |
Anemia | 4 (66.7%) | 0 | 0 | Progressive disease (PD) | 1 (16.7%) |
Vomiting | 2 (33.3%) | 0 | 0 | Disease control rate (DCR) | 6 (100%) |
Hypoalbuminemia | 3 (50%) | 0 | 0 | ||
Hypokalemia | 1 (16.7%) | 0 | 0 | ||
Hyponatremia | 2 (33.3%) | 0 | 0 |
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