Induction of robust type-I CD8+ T-cell responses in WHO grade 2 low-grade glioma patients receiving peptide-based vaccines in combination with poly-ICLC

Abstract

Purpose: WHO grade 2 low-grade gliomas (LGG) with high risk factors for recurrence are mostly lethal despite current treatments. We conducted a phase I study to evaluate the safety and immunogenicity of subcutaneous vaccinations with synthetic peptides for glioma-associated antigen (GAA) epitopes in HLA-A2(+) adults with high-risk LGGs in the following three cohorts: (i) patients without prior progression, chemotherapy, or radiotherapy (RT); (ii) patients without prior progression or chemotherapy but with prior RT; and (iii) recurrent patients.

Experimental design: GAAs were IL13Rα2, EphA2, WT1, and Survivin. Synthetic peptides were emulsified in Montanide-ISA-51 and given every 3 weeks for eight courses with intramuscular injections of poly-ICLC, followed by q12 week booster vaccines.

Results: Cohorts 1, 2, and 3 enrolled 12, 1, and 10 patients, respectively. No regimen-limiting toxicity was encountered except for one case with grade 3 fever, fatigue, and mood disturbance (cohort 1). ELISPOT assays demonstrated robust IFNγ responses against at least three of the four GAA epitopes in 10 and 4 cases of cohorts 1 and 3, respectively. Cohort 1 patients demonstrated significantly higher IFNγ responses than cohort 3 patients. Median progression-free survival (PFS) periods since the first vaccine are 17 months in cohort 1 (range, 10-47+) and 12 months in cohort 3 (range, 3-41+). The only patient with large astrocytoma in cohort 2 has been progression-free for more than 67 months since diagnosis.

Conclusion: The current regimen is well tolerated and induces robust GAA-specific responses in WHO grade 2 glioma patients. These results warrant further evaluations of this approach. Clin Cancer Res; 21(2); 286-94. ©2014 AACR.

Figure 1. IFN-γ ELISPOT assays on each of vaccine-targeted antigens in Cohorts 1 and 3

Time course of glioma-associated antigen epitope-specific T-cell responses evaluated by IFN-γ enzyme-linked immunosorbent spot (ELISPOT) analyses in 11 and 9 patients in Cohorts 1 (upper panels) and 3 (lower panels), respectively, who received at least 5 vaccinations. The Week 0 spot numbers are included and post-vaccine spot numbers are not subtracted by Week 0 spot numbers.

Figure 2. PFS and OS since the 1st vaccine

In parentheses, months indicate median PFS or OS for the group. OA, oligoastrocytoma; A, astrocytoma; O, oligodendrioglioma. P>0.2 for all inter-pathological type comparisons (Log-rank test).