Association of increased progression-free survival in primary glioblastomas with lymphopenia at baseline and activation of NK and NKT cells after dendritic cell immunotherapy.
ABSTRACT
Background: DENDR1 is a phase I-II phase study aimed at evaluating dendritic cell (DC) immunotherapy in patients with first diagnosis of glioblastoma multiforme (GBM). Here we provide results of the interim analysis on 22 patients
Methods: Patients with post-surgery volume ≤10 cc underwent leukapheresis before radiotherapy and chemotherapy with temozolomide (TMZ) (Stupp et al, 2005). DC prepared under GMP procedures were loaded with whole tumor lysate (Nava et al, 2012). Three intradermal injections of mature DC were done before adjuvant chemotherapy. The subsequent 4 injections were performed 17 ±3 days after adjuvant TMZ. MRI, clinical and immunological follow-up were performed every 2 months
Results: Median age at surgery was 54.5 years (28-69). After a median follow up of 14 months (6-27), the median progression-free survival (PFS) was 9 mo, with PFS6 90% (C. I. 0.78-1.029%) and PFS12 42% (C. I: 0.20-0.64) at Kaplan Meier analysis. Median overall survival (OS) was 22 mo with OS 12 70%. (C. I. 0.50-0.9). RT-TMZ induced significant lymphopenia (<1000 lymphocytes/microl) in 17/22 patients (77.2%). Patients with >1000 lymphocytes/microl (5/22) before first vaccination had shorter PFS than others (p<0.005). Peripheral Blood Lymphocytes (PBLs) were analyzed by flow cytometry to identify CD8+ T cells, NK and NKT cells before and after DC vaccines. The ratio of vaccination/baseline cell frequencies (V/B ratio) was calculated for each patient and the median of all values used as the cut off value to separate patients. Increased V/B ratio for NK cells and NKT cells, but not for CD8 T lymphocytes, was significantly associated with prolonged PFS (median PFS 14 vs 8.0 mo, p=0.01; 15.0 vs 8.0 mo). 2/4 patients with MGMT methylation were in the group of high V/B ratio. Interferon-gamma in peripheral blood was significantly higher in patients with PFS12 (p<0.02).
Conclusions: The results show significant positive association between PFS and increased peripheral levels of NK and NKT cells, encouraging the expansion of this study to a larger number of primary GBM. Clinical trial information: 2008-005035-15.