A randomized, double-blind, phase III trial of personalized peptide vaccination for recurrent glioblastoma

Abstract

Background. We conducted a phase III trial of personalized peptide vaccination (PPV) for human leukocyte antigen (HLA)-A24+ recurrent glioblastoma to develop a new treatment modality. Methods. We randomly assigned 88 recurrent glioblastoma patients to receive PPV (n = 58) or the placebo (n = 30) at a 2-to-1 ratio. Four of 12 warehouse peptides selected based on preexisting peptide-specific immunoglobulin G levels or the corresponding placebos were injected 1×/week for 12 weeks. Results. Our trial met neither the primary (overall survival [OS]) nor secondary endpoints. Unfavorable factors for OS of 58 PPV patients compared with 30 placebo patients were SART2-93 peptide selection (n = 13 vs 8, hazard ratio [HR]: 15.9), ≥70 years old (4 vs 4, 7.87), >70 kg body weight (10 vs 7, 4.11), and performance status (PS)3 (8 vs 2, 2.82), respectively. Consequently, the median OS for PPV patients without SART2-93 selection plus one of these 3 favorable factors (<70 y old, ≤70 kg, or PS0-2) was significantly longer than that for the corresponding placebo patients (HR: 0.49, 0.44, and 0.51), respectively. Preexisting immunity against both all 12 warehouse peptides besides SART2-93 and the other cytotoxic T lymphocyte epitope peptides was significantly depressed in the patients with SART2-93 selection (n = 21) compared with that of the patients without SART2-93 selection (n = 67). Biomarkers correlative for favorable OS of the PPV patients were a lower percentage of CD11b+CD14+HLA-DR low A randomized, double-blind, phase III trial of personalized peptide vaccination for recurrent glioblastoma 349 Narita et al. Recurrent GBM and peptide vaccination: phase III trial Neuro-Oncologyimmunosuppressive monocytes and a higher percentage of CD4+CD45RA− activated T cells, the intermediate levels of chemokine C-C ligand 2 (CCL2), vascular endothelial growth factor, interleukin (IL)-6, IL-17, or haptoglobin, respectively. Conclusion. This phase III trial met neither the primary nor secondary endpoints. Key Points1. This trial of personalized peptide vaccination did not meet the primary endpoint.2. Personalized peptide vaccination shortened the OS of certain patients.3. Intermediate CCL2 level was a biomarker correlative for favorable OS.The overall survival (OS) of recurrent glioblastoma (rGBM) patients is very poor, although bevacizumab has been reported to improve the progression-free survival (PFS) of rGBM patients. [1][2][3] Many clinical studies failed to provide clinical benefits for rGBM in the past decade. [4][5][6] This failure may be partly due to the unique and diverse immunological features of GBM. 4-10 GBM tumor cells produce many cytokines and chemokines as potential autocrine growth factors and subsequent immune regulators, which might in turn influence the self-proliferation in most patients. 4-10 Among the GBM-producing cytokines, granulocyte-monocyte stimulating factor (GM-CSF) and the chemokine (C-C motif) ligand 2 (CCL2) are the two major factors for immune regulation. [6][7][8][9] GM-CSF forms a cytokine network with in...

Early phase II study of mixed 19‐peptide vaccine monotherapy for refractory triple‐negative breast cancer

“…Prevaccination peptide‐specific IgG levels to each of the 20 peptides—the 19 peptides included in the vaccine and the nonvaccinated PSMA‐derived peptide—were measured using a Luminex system with a cut‐off level of 10 FIU taken as a detectable level of IgG, as reported previously 9‐14 . The positive rate of Ab in the patients’ plasma against the 20 peptides or HLA‐A‐matched peptides ranged from 36% to 100% or 17% to 100%, respectively (Table ).…”

“…The HLA‐matched peptide‐specific IgG levels in the plasma were measured using a Luminex system. Prevaccination peptide‐specific IgG levels with a cut‐off level of 10 FIU were taken as detectable levels of IgG as reported previously 9‐13 . Patients were considered to have a positive IgG response when the postvaccination IgG level against each of the peptides after the 6 vaccinations was 2 times higher than the prevaccination level, as reported previously 10‐13 .…”

“…Positive CTL responses after the 6 vaccinations were defined as a more than 25‐spot increase in the total HLA‐matched peptide‐specific IFN‐γ spots. The CEF peptide pool (MABTECH) was used as a control peptide set for measurement of peptide‐specific CTL activity, as reported previously 9‐12 . This pool consists of 23 HLA‐class I‐restricted peptides from human influenza virus, cytomegalovirus, and Epstein‐Barr virus.…”

“…Therefore, there is a need for new immunotherapy approaches not involving these 2 Abs. Peptide‐based therapeutic vaccines, including the PPVs developed by our group, might be a promising approach 8‐13 . However, none of these vaccine trials provided sufficient clinical benefits to warrant approval for advanced cancer patients.…”

“…Next, therefore, we developed a cancer vaccine consisting of a mixture of 20 peptides for more rapid and potent immune augmentation 14 . The 20 peptides were encoded by 12 different TAAs, most of which are expressed on a wide variety of cancers 8‐14 . Cytotoxic T lymphocyte epitopes of these 20 peptides were restricted to HLA‐A2 (7 peptides), HLA‐A24 (8 peptides), HLA‐A3 super type (‐A3, ‐A11, ‐A31, or ‐A33) (6 peptides), or HLA‐A26 (2 peptides) of HLA‐class A molecules, providing coverage to the vast majority of patients who have different HLA alleles 8‐14 .…”