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 II low-grade gliomas (LGGs) 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: 1) patients without prior progression, chemotherapy or radiation therapy (RT); 2) patients without prior progression or chemotherapy but with prior RT, and 3) recurrent patients. METHODS GAAs were IL-13Rα2, EphA2, WT1, and Survivin. Synthetic peptides were emulsified in Montanide-ISA-51 and given every 3 weeks for 8 courses with intramuscular injections of poly-ICLC, followed by q12week 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 IFN-γ responses against at least 3 of the 4 GAA epitopes in 10 and 4 cases of Cohorts 1 and 3, respectively. Cohort 1 patients demonstrated significantly higher IFN-γ responses than Cohort 3 patients. Median progression-free survival (PFS) periods since the 1st 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 over 67 months since diagnosis. CONCLUSION The current regimen is well tolerated and induces robust GAA-specific responses in WHO grade II glioma patients. These results warrant further evaluations of this approach.

Trial watch: Peptide-based vaccines in anticancer therapy

“…The TAAs harnessed for the construction of peptide-based vaccines in these studies included the cancer/testis antigen 1B (CTAG1B; best known as NY-ESO-1), 144 MAGE family member A3 (MAGEA3), 140,146,147 TTK protein kinase (TTK), 158 WT1, 151,166 baculoviral IAP repeat containing 5 (BIRC5; best known as survivin), 149 mutant epidermal growth factor receptor (EGFRvIII), 153 erb-b2 receptor tyrosine kinase 2 (ERBB2; best known as HER2), 148 indoleamine 2,3 dioxygenase 1 (IDO1), 157 TCR gamma alternative reading frame protein (TARP), 154 and multiple glioma-associated antigens. 152 Most often, peptide-based vaccines were well tolerated and no severe side effects were reported. Mild side effects were sporadic and included flu-like symptoms, fatigue and minor reactions at the injection site.…”

“…Peptide-based vaccination was employed as a standalone adjuvanted intervention, 140-146 or combined with chemotherapy 147-149 radiation therapy 147,150 or other forms of treatment including other immunotherapies. 148,149,151-158 These studies enrolled patients with hematological malignancies, 151,159 brain tumors, 152,153 non-small cell lung carcinoma (NSCLC), 140,147,160 breast cancer, 141,148,161 , prostate carcinoma, 142,154 melanoma, 144-146,155-158,162 . ovarian cancer.…”

“…Mild side effects were sporadic and included flu-like symptoms, fatigue and minor reactions at the injection site. Immunes responses driven by vaccination were documented in a variety of studies based on (1) interferon gamma (IFNG) production by T cells with enzyme-linked immunospot (ELISPOT) assays, 142,151,152,154,155 (2) tumor infiltration by CD4 + and CD8 + lymphocyte infiltration, 144,145,147,157,158 or (3) presence of peptide-specific antibodies in the serum. 158 Sporadic clinical responses were also documented (see below).…”

Cellular immunotherapy for malignant gliomas

“…Efforts are being undertaken to modulate the function of these cells and promote their function as type-1 APCs. In regard to T-cell homing to brain tumors, although T-cells are able to traverse the blood-brain-barrier via chemokine axes and multistep adhesion processes, homing of effector CTL is weaker in brain tumors compared with cancer in other organs 100, 101 . To date, there have not been many immunotherapy regimens for brain tumors incorporating therapeutic agents that can facilitate T-cell homing to the brain tumor site.…”

Immunotherapy of Brain Cancer

“…Therefore, vaccines have been developed that rely on several antigens, which may, at least theoretically, increase the probability of mounting an immune response against 1 or several targets and preclude immediate immune escape due to loss of antigen expression. A multi-peptide vaccine consisting of peptides derived from several glioma-associated antigens has been assessed in 2 phase I studies in children and adults, respectively [57,58]. The approach was considered safe and antigen-specific T cell responses were observed.…”