Regulatory T-cell inhibition plus antitumor immunotherapy targeted against cytomegalovirus (CMV) in patients with newly diagnosed glioblastoma multiforme (GBM).
ABSTRACT
Background: Despite aggressive surgery, high-dose focused radiation, and toxic, multimechanistic chemotherapy, malignant gliomas (MG) remain almost universally fatal. The inherent biologic specificity of immunotherapy offers the prospect of targeting neoplastic cells more precisely. Dendritic cells (DCs) are endowed with an extraordinary ability to activate CD4+ and CD8+ T-cells, and DCs loaded with antigens derived from tumor cells (CMV pp65-LAMP mRNA) have the potential to induce potent antitumor immunity. Furthermore, regulatory T-cells (TRegs) which induce a state of reversible immunosuppression in MG and can be functionally inactivated with anti-CD25 antibody (Ab), while dramatically enhancing vaccine-induced immune responses.
Methods: Eligible were gross totally resected patients (pts) with newly diagnosed GBM. Pts underwent leukapheresis followed by standard of care radiation/temozolomide (XRT/TMZ) therapy. After completion of XRT/TMZ, up to 12 cycles of TMZ 200 mg/m2/x5d were administered. Around Day 21 of the 1st cycle pts also received: anti-CD25 Ab treatment, vaccine #1, and non-specific autologous lymphocyte transfer (ALT). Vaccines #2 and #3 were given biweekly following vaccine#1. A 2nd leukapheresis was conducted prior to the 2nd cycle of TMZ. On Day 21 of the 2ndTMZ cycle Vaccine #4 was administered. Pts were followed with serial MRIs until disease progression.
Results: 7 patients (5 males) were treated. No adverse events attributable to vaccine treatment were observed. Median progression free survival was 23.5 months (95% CI:1.7 to 54.1). Median overall survival was 30.3 months (95% CI:11.8 to 60.8). Overall survival was calculated from the start of vaccine therapy to time of death or last contact if alive.
Conclusions: Treatment with XRT/TMZ, DC vaccine and anti- CD25 Ab was well tolerated and results are promising. Due to the lack of adverse events, the protocol has been amended for future patients in this ongoing study. The number of vaccines had been increased to 8 (vs. 4) and anti-CD25 antibody is being given with the first two cycles (vs. with 1st cycle only) of adjuvant TMZ. Clinical trial information: 00626483.