Adoptive transfer of EBV-specific T cells results in sustained clinical responses in patients with locoregional nasopharyngeal carcinoma

Abstract

Patients with recurrent or refractory Epstein Barr Virus (EBV)-positive nasopharyngeal carcinoma (NPC) continue to have poor outcomes. Our earlier Phase I dose escalation clinical study of 10 NPC patients showed that infusion of EBV-specific cytotoxic T cells (EBV-CTLs) was safe and had antitumor activity. To better define the overall response rate and discover whether disease status, EBV-antigen specificity, and/or in vivo expansion of infused EBV-CTLs predicted outcome, we treated 13 additional NPC patients with EBV-CTLs in a fixed-dose, Phase II component of the study. We assessed toxicity, efficacy, specificity, and expansion of infused CTLs for all 23 recurrent/refractory NPC patients treated on this Phase I/II clinical study. At the time of CTL infusion, 8 relapsed NPC patients were in remission and 15 had active disease. No significant toxicity was observed. Of the relapsed patients treated in their second or subsequent remission, 62% (5/8) remain disease free (at 17 to 75 mo), whereas 48.7% (7/15) of those with active disease had a CR/CRu (33.3%) or PR (15.4%). In contrast to locoregional disease, metastatic disease was associated with an increased risk of disease progression (HR: 3.91, P=0.015) and decreased overall survival (HR: 5.55, P=0.022). Neither the specificity of the infused CTLs for particular EBV antigens nor their measurable in vivo expansion discernibly influenced outcome. In conclusion, treatment of patients with relapsed/refractory EBV-positive NPC with EBV-CTLs is safe and can be associated with significant, long-term clinical benefit, particularly for patients with locoregional disease.

Figure 1. Transient increase of LMP2-specific T-cell frequency after EBV-CTL infusion

The frequency of (A) EBV-, (B) LMP2-, and (C) CMV-specific T cells was determined using ELIspot assays. There was a trend towards increased LMP2-specific T cells (p=0.081) at 2 weeks after CTL infusion (- -: individual patients; –: median; NED: no evidence of disease).

Figure 2. Clinical response after EBV-CTL infusion

PET images of patient (P1668) before and 8 weeks after EBV-specific CTL infusion.

Figure 3. Overall and progression-free survival after EBV-CTL infusion

A) Overall survival, B) Overall survival by disease status at 1^st CTL infusion, C) Progression-free survival, D) Progression by disease status at 1^st CTL infusion (p-value: metastatic disease vs. remission).