Epstein‐Barr virus‐specific adoptive immunotherapy for recurrent, metastatic nasopharyngeal carcinoma

Abstract

BACKGROUND: Early-stage and intermediate-stage nasopharyngeal cancer (NPC) generally carry a good prognosis, but for patients with recurrent, metastatic disease, options are limited. In the current study, the authors present a phase 1/2 study to evaluate the efficacy of Epstein-Barr virus (EBV)-stimulated cytotoxic T-lymphocyte (EBV-CTL) immunotherapy in this patient population. METHODS: Screening for patients with active, recurrent, metastatic EBV-associated NPC began in February 2007, and the study was closed to accrual in January 2012. After informed consent was obtained, patients had their blood drawn to initiate manufacturing of the EBV-CTL product. During product manufacturing, patients were placed on interim standard-of-care chemotherapy, and only after disease progression on the interim chemotherapy did patients receive investigational immunotherapy. Patients were restaged every 2 months until disease progression and then followed for survival. RESULTS: A total of 28 patients were enrolled, and 21 patients were treated. There was 1 complete response achieved, and at the time of last follow-up, the patient had been in remission for >8 years since treatment. The median progression-free survival was 2.2 months, and the median overall survival was 16.7 months. Two other patients, after failing EBV-CTL immunotherapy, unexpectedly demonstrated strong responses to the chemotherapy regimens they had previously failed. Patient EBV viral load and EBV-CTL specificity for tumor-associated viral antigens did not appear to correlate with clinical response. CONCLUSIONS: A durable response was observed with EBV-CTL immunotherapy, but the overall response rate for patients with recurrent, metastatic NPC was low. Further research is necessary to increase the efficacy of EBV-specific immunotherapy in patients with incurable NPC, and to characterize mechanisms for refacilitation to chemotherapy.

Artificial antigen-presenting cells are superior to dendritic cells at inducing antigen-specific cytotoxic T lymphocytes

“…EBV is a herpes virus that is associated with a variety of malignancies such as Hodgkin's disease, Burkitt's lymphoma, nasopharyngeal carcinoma, and gastric carcinoma. There is strong evidence that EBV-stimulated antigen-specific CTLs in patients with nasopharyngeal carcinoma have antitumor activity [28,39,40]. Thus, CTL preparation specific for cancer-testis antigens or virus antigens could provide a significant clinical benefit for adoptive immunotherapy.…”

“…Epstein-Barr virus (EBV) is associated with a broad range of malignancies that are distinguished by three distinct viral latency-related gene expression patterns. Several groups have developed in vitro stimulation protocols to facilitate the generation of LMP1-and LMP2specific T-cells and have demonstrated objective long-lasting clinical responses [5,7,28]. Therefore, generating a sufficient number of antigen-specific CTLs targeted to CT or EBV antigens hold tremendous promise for adoptive immunotherapy.…”

Emerging patient-specific treatment modalities in head and neck cancer – a systematic review

“…In two studies [34,35], only EBV latent membrane protein (LMP) 2-specific CTLs targeting tumor cells were prepared. In other two studies [36][37][38], CTLs targeting a broader spectrum of antigens were utilized. Similar techniques are being used in the ongoing NCT02421640 and NCT02578641 studies also targeting EBV(+) nasopharyngeal carcinoma.…”

“…Among the remaining six studies including R/M disease, none indicate a modality, which necessarily seems to be worth pursuing. In two of them experimenting on EBV+ nasopharyngeal carcinoma with autologous EBV-antigen-specific CTLs [36][37][38], a total of 4 out of 56 patients showed complete remission. But, these patients also received chemotherapy while waiting for the experimental therapy, where durable complete remission in selected cases with chemotherapy is not a very rare observation [48].…”

Establishment and Validation of a Nomogram with Intratumoral Heterogeneity Derived from 18F-FDG PET/CT for Predicting Individual Conditional Risk of 5-Year Recurrence before Initial Treatment of Nasopharyngeal Carcinoma

“…As it only considers the anatomical information of tumor and ignoring the biological heterogeneity, the TNM staging system couldn't serve as a perfect prognostic tool for estimating the risk of recurrence [10,11]. Instead, many other factors, such as age [12], sex [13], body mass index (BMI) [14], serum lactate dehydrogenase (LDH)[10], inflammatory biomarkers [15], and pretreatment EBV DNA load [16], have been reported as individual prognostic biomarkers for survival prediction. However, these prognostic models still lack accuracy, and couldn't directly reflect the intratumoral information, which may play a more important role in survival prediction.Research over decades has demonstrated that intratumoral heterogeneity has an enormous effect on patient treatment and outcome [17].…”