Gemcitabine, carboplatin, and Epstein–Barr virus-specific autologous cytotoxic T lymphocytes for recurrent or metastatic nasopharyngeal carcinoma: VANCE, an international randomized phase III trial

• Published in: Annals of oncology Vol. 35; no. 12; pp. 1181 - 1190
• Main Authors: Toh, H.C., Yang, M.-H., Wang, H.-M., Hsieh, C.Y., Chitapanarux, I., Ho, K.F., Hong, R.-L., Ang, M.K., Colevas, A.D., Sirachainan, E., Lertbutsayanukul, C., Ho, G.F., Nadler, E., Algazi, A., Lulla, P., Wirth, L.J., Wirasorn, K., Liu, Y.C., Ang, S.F., Low, S.H.J., Tho, L.M., Hasbullah, H.H., Brenner, M.K., Wang, W.-W., Ong, W.S., Tan, S.H., Horak, I., Ding, C., Myo, A., Samol, J.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.12.2024
• Subjects: adoptive T-cell therapy; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; cancer immunotherapy; Carboplatin - administration & dosage; Deoxycytidine - administration & dosage; Deoxycytidine - analogs & derivatives; Deoxycytidine - therapeutic use; Epstein-Barr Virus Infections - immunology; Epstein-Barr Virus Infections - virology; Epstein–Barr virus cytotoxic T lymphocytes; Female; Gemcitabine; Herpesvirus 4, Human - genetics; Herpesvirus 4, Human - immunology; Humans; Immunotherapy, Adoptive - adverse effects; Immunotherapy, Adoptive - methods; Male; Middle Aged; nasopharyngeal carcinoma; Nasopharyngeal Carcinoma - drug therapy; Nasopharyngeal Carcinoma - immunology; Nasopharyngeal Carcinoma - pathology; Nasopharyngeal Carcinoma - therapy; Nasopharyngeal Carcinoma - virology; Nasopharyngeal Neoplasms - drug therapy; Nasopharyngeal Neoplasms - immunology; Nasopharyngeal Neoplasms - pathology; Nasopharyngeal Neoplasms - therapy; Nasopharyngeal Neoplasms - virology; Neoplasm Recurrence, Local - drug therapy; Neoplasm Recurrence, Local - immunology; Neoplasm Recurrence, Local - pathology; Neoplasm Recurrence, Local - therapy; Quality of Life; randomized phase III trial; T-Lymphocytes, Cytotoxic - immunology; Epstein–Barr virus cytotoxic T lymphocytes; nasopharyngeal carcinoma; randomized phase III trial; cancer immunotherapy; adoptive T-cell therapy
• ISSN: 0923-7534; 1569-8041; 1569-8041
• DOI: 10.1016/j.annonc.2024.08.2344

Epstein–Barr virus-specific cytotoxic T lymphocyte (EBV-CTL) is an autologous adoptive T-cell immunotherapy generated from the blood of individuals and manufactured without genetic modification. In a previous phase II trial of locally recurrent or metastatic nasopharyngeal carcinoma (R/M NPC) patients, first-line gemcitabine and carboplatin (GC) and EBV-CTL combination demonstrated objective antitumor EBV-CTL activity and a favorable safety profile. The present study explored whether this combined first-line chemo-immunotherapy strategy would produce superior clinical efficacy and better quality of life compared with conventional chemotherapy treatment. This multicenter, randomized, phase III trial evaluated the efficacy and safety of GC followed by EBV-CTL versus GC alone as first-line treatment of R/M NPC patients. Thirty clinical sites in Singapore, Malaysia, Taiwan, Thailand, and the USA were included. Subjects were randomized to first-line GC (four cycles) and EBV-CTL (six cycles) or GC (six cycles) in a 1 : 1 ratio. The primary outcome was overall survival (OS) and secondary outcomes included progression-free survival, objective response rate, clinical benefit rate, quality of life, and safety. ClinicalTrials.gov identifier: NCT02578641. A total of 330 subjects with NPC were enrolled. Most subjects in both treatment arms received four or more cycles of chemotherapy and most subjects in the GC + EBV-CTL group received two or more infusions of EBV-CTL. The central Good Manufacturing Practices (GMP) facility produced sufficient EBV-CTL for 94% of GC + EBV-CTL subjects. The median OS was 25.0 months in the GC + EBV-CTL group and 24.9 months in the GC group (hazard ratio = 1.19; 95% confidence interval 0.91-1.56; P = 0.194). Only one subject experienced a grade 2 serious adverse event related to EBV-CTL. GC + EBV-CTL in subjects with R/M NPC demonstrated a favorable safety profile but no overall improvement in OS versus chemotherapy. This is the largest adoptive T-cell therapy trial reported in solid tumors to date. •EBV-CTL treatment is very well tolerated up to six infusions—the highest number of EBV-CTL delivered to patients.•Favorable OS and PFS2 trends for subjects receiving EBV-CTL in combined USA, Taiwan, and Singapore populations.•Largest completed adoptive T-cell therapy trial in any solid tumor to be reported.•International trans-shipment from collection to manufacturing and EBV-CTL infusion achieved for >90% of patients.•Adding EBV-CTL to chemotherapy did not improve OS over chemotherapy alone (HR = 1.19; 95% CI 0.91, 1.56; P = 0.194).