Page 166 - Read Online

Page 4 of 11 Sager et al. Neuroimmunol Neuroinflammation 2018;5:25 I http://dx.doi.org/10.20517/2347-8659.2018.12

Peptide vaccines
This strategy is a targeted approach including the direct administration of a selected protein or peptide
antigen frequently used with an adjuvant such as keyhole limpet hemocyanin (KLH) to enhance the
immunogenicity [10,40,41] .

In the context of peptide vaccines, most extensive study has focused on targeting of EGFRvIII [42-44] . EGFRvIII
is a TSA which is solely expressed by GB cells and not expressed by normal tissues . This kind of targeting
[45]
single tumor specific antigens has the advantage of theoretically eliminating normal tissue toxicity. The mutant
form of the EGFR gene containing an in-frame deletion of exons 2-7 is found in approximately 20%-30% of
patients with GB and causes tumor cell proliferation [46-49] .

In the recent phase II randomized ReACT study assessing association of rindopepimut and BEV in EGFRvIII-
positive relapsed GB patients reported the benefit of rindopepimut treatment with regard to multiple
endpoints including the 2-year OS and PFS rates, and the authors concluded that rindopepimut administered
with BEV induced a potent EGFRvIII-specific immune response leading to tumor regression and prolonged
survival of recurrent GB patients . Another phase II multicenter study of EGFRvIII peptide vaccination in
[50]
newly diagnosed GB patients, Sampson et al. reported significantly improved OS in vaccinated patients. A
[45]
notable finding in this study was the loss of EGFRvIII antigen in most patients relapsing after vaccination,
indicating a critical role for vaccine-induced immune response in tumor eradication. They concluded that a
randomized phase III trial was needed to establish the role of EGFRvIII-targeted vaccination for management
of GB patients .
[45]

However, randomized phase III trial of rindopepimut for newly diagnosed EGFRvIII-positive GB patients
failed to show an OS benefit in preplanned interim analysis, leading to early closure of the study .
[51]

Overall, studies of Rindopepimut have demonstrated encouraging results worth further testing [52-54] .
Nevertheless, GB TSAs with higher expression levels may achieve improved treatment results.

Other than EGFR related peptides, personalized peptide vaccination has been another area of investigation,
resulting in encouraging therapeutic outcomes [55,56] . IDH-1 R132H mutation is a newer appealing TSA with a
typically lower prevalence in primary GB compared to secondary GB and is being currently tested in clinical
studies .
[57]
DC vaccines
DCs are efficacious antigen-presenting cells (APCs) capable of vigorously activating the T-cells to attain
a durable immune response through slow processing of antigens [58-61] . These professional APCs have been
judiciously utilized for GB management since they are appealing candidates for therapeutic exploitation. DCs
can be categorized into myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) [62,63] . In the study by Dey et al. ,
[63]
mice vaccinated with mDCs generated an improved antitumor T cell response compared to pDC vaccinated
mice. The use of DC-based vaccines achieved impressive results for newly diagnosed GB patients .
[61]

In the study by Prins et al. , safety, feasibility, and immune responses were comparatively assessed for GB
[64]
patients treated using DC pulsed with autologous tumor lysate or with synthetic glioma-associated antigens.
The study revealed that DCs pulsed with autologous tumor lysates achieved improved anti-tumor immune
response compared to DCs pulsed with synthetic glioma-associated antigens . Nevertheless, DC vaccines
[64]
may yet be skeptical in human clinical trials notwithstanding the promising results in animal models.

A recent study by Mitchell et al. revealed that the efficacy of DC vaccination could be enhanced through
[65]
pre-conditioning of the vaccination site with a recall antigen such as tetanus/diphtheria toxoid.