Antigen-Specific Immune Responses and Clinical Outcome After Vaccination With Glioma-Associated Antigen Peptides and Polyinosinic-Polycytidylic Acid Stabilized by Lysine and Carboxymethylcellulose in Children With Newly Diagnosed Malignant Brainstem and Nonbrainstem Gliomas

Abstract

A B S T R A C T PurposeDiffuse brainstem gliomas (BSGs) and other high-grade gliomas (HGGs) of childhood carry a dismal prognosis despite current treatments, and new therapies are needed. Having identified a series of glioma-associated antigens (GAAs) commonly overexpressed in pediatric gliomas, we initiated a pilot study of subcutaneous vaccinations with GAA epitope peptides in HLA-A2-positive children with newly diagnosed BSG and HGG. Patients and MethodsGAAs were EphA2, interleukin-13 receptor alpha 2 (IL-13R␣2), and survivin, and their peptide epitopes were emulsified in Montanide-ISA-51 and given every 3 weeks with intramuscular polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose for eight courses, followed by booster vaccinations every 6 weeks. Primary end points were safety and T-cell responses against vaccine-targeted GAA epitopes. Treatment response was evaluated clinically and by magnetic resonance imaging. ResultsTwenty-six children were enrolled, 14 with newly diagnosed BSG treated with irradiation and 12 with newly diagnosed BSG or HGG treated with irradiation and concurrent chemotherapy. No dose-limiting non-CNS toxicity was encountered. Five children had symptomatic pseudoprogression, which responded to dexamethasone and was associated with prolonged survival. Only two patients had progressive disease during the first two vaccine courses; 19 had stable disease, two had partial responses, one had a minor response, and two had prolonged disease-free status after surgery. Enzyme-linked immunosorbent spot analysis in 21 children showed positive anti-GAA immune responses in 13: to IL-13R␣2 in 10, EphA2 in 11, and survivin in three. ConclusionGAA peptide vaccination in children with gliomas is generally well tolerated and has preliminary evidence of immunologic and clinical responses. Careful monitoring and management of pseudoprogression is essential.

Re-defining response and treatment effects for neuro-oncology immunotherapy clinical trials

“…Extensive necrosis along with a small rim of viable tumor was noted at subsequent autopsy at many of the metastatic sites including the brain lesion [40]. Along the same lines, anecdotal reports highlight the occurrence of pseudoprogression among brain tumor patients treated with a variety of vaccine regimens [38,[41][42][43].…”

Improving vaccine efficacy against malignant glioma

“…Inclusion in this trial required patients with HLA-A2-positive status and minimal or no dexamethasone usage at the time of enrollment. 86 In a separate Phase I trial of newly diagnosed patients with HGG between the ages of 1 and 18, autologous tumor lysate-pulsed DCs were generated for 3/ 9 enrolled patients with 2 of the DC-treated individuals still alive at 40 and 51 mo post-surgery, respectively. 87 Another Phase I trial using DCs treated with tumor lysate in 33 malignant glioma patients showed an average PFS of 19 weeks and OS of 59 weeks, with 7 patients surviving at the time of publication.…”

Novel cancer antigens for personalized immunotherapies: latest evidence and clinical potential

“…A phase I study of a multi-epitope anti-survivin peptide vaccine (EMD640744) in patients with advanced solid tumors found an antigen-specific T-cell response in 63% of subjects, and 28% of vaccinated subjects achieved stable disease [Lennerz et al 2014]. Another phase I study in pediatric brainstem glioma patients using a tripeptide vaccine containing survivin and given in combination with the immunoadjuvant poly-ICLC (polyinosinicpolycytidylic acid stabilized by lysine and carboxymethylcellulose) showed evidence of survivinspecific immune responses and clinical benefit [Pollack et al 2014]. In grade 2 low-grade glioma patients, vaccination with survivin and three other glioma-associated peptides combined with poly-ICLC produced robust T H 1 immune responses [Okada et al 2015].…”