This novel R01 application focuses on an innovative phase II clinical trial of peptide-based immunotherapy for children with low-grade astrocytomas, the most common brain tumors of childhood. Although surgical resection is curative for well-circumscribed superficial lesions, tumors that are infiltrative or arise from deep structures, such as the optic pathways, are often incurable with surgery and pose a major management challenge. Progressive tumors may respond transiently to conventional chemotherapy agents, and to molecularly targeted agents, but such lesions often recur, leading to cumulative morbidity, particularly in tumors that fail multiple treatment regimens. Accordingly, new treatment approaches are needed. In this regard, our preliminary studies demonstrated the safety and tolerability of glioma-associated antigen (GAA)-based vaccines targeting a series of proteins that we have shown to be overexpressed in pediatric gliomas, including IL13R?2, EphA2, and survivin, in children with newly diagnosed and recurrent astrocytomas. These pilot studies demonstrated intriguing immunological and clinical responses, particularly in children with recurrent low-grade astrocytomas, in whom 3 of 10 evaluable patients had sustained tumor regression on magnetic resonance imaging (MRI). Building upon these data, the proposed study will systematically evaluate clinical and immunological efficacy of peptide-based vaccine therapy in children with recurrent low-grade astrocytomas. We will treat 25 patients with subcutaneous GAA epitope vaccinations every 3 weeks for 8 courses combined with intramuscular poly-ICLC. Participants will be evaluated for regimen limiting toxicity (RLT) and treatment response by clinical, MRI, and laboratory evaluations. Patients demonstrating disease stabilization or regression without RLT may receive additional vaccinations. These studies take advantage of unique institutional resources provided by our Immunologic Monitoring Laboratory, which are integrated into the clinical trial. The proposed studies will test the hypothesis that peptide-base immunotherapy has sufficient clinical efficacy to warrant broader therapeutic examination in these tumors, and that clinical response will be associated with immunological reactivity. To address these hypotheses, we propose studies with the following aims: 1. Determine the efficacy of vaccination with GAA peptides for children with recurrent low-grade astrocytomas, using objective measures of MRI-based tumor response and progression-free survival. 2. Characterize the rate and magnitude of immune response in post-vaccine peripheral blood mononuclear cells against vaccine-targeted antigens, using IFN-?-enzyme-linked immunosorbent spot (ELISPOT) and tetramer assays, and correlate immunological response with clinical responses to the vaccine. In addition, the proposed studies will examine associations between antigen expression in the tumor and treatment response, and mechanisms of immune escape in tumors that progress after immunotherapy. The results from this study will provide a basis for determining if this modality should be examined further as a potential therapy for these challenging tumors.

Public Health Relevance

The proposed study constitutes the first vaccine trial for childhood brain tumors, and in particular low-grade astrocytomas, which will define both immunological and clinical efficacy as central objectives, providing a foundation for determining if this innovative multipeptide epitope-based strategy should be examined further as a potential therapy for these challenging tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA187219-01A1
Application #
9027315
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Timmer, William C
Project Start
2016-01-08
Project End
2020-12-31
Budget Start
2016-01-08
Budget End
2016-12-31
Support Year
1
Fiscal Year
2016
Total Cost
$357,496
Indirect Cost
$122,139
Name
University of Pittsburgh
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Müller, Sören; Agnihotri, Sameer; Shoger, Karsen E et al. (2018) Peptide vaccine immunotherapy biomarkers and response patterns in pediatric gliomas. JCI Insight 3:
Furtado, Andre D; Ceschin, Rafael; Blüml, Stefan et al. (2017) Neuroimaging of Peptide-based Vaccine Therapy in Pediatric Brain Tumors: Initial Experience. Neuroimaging Clin N Am 27:155-166
Pollack, Ian F; Jakacki, Regina I; Butterfield, Lisa H et al. (2016) Immune responses and outcome after vaccination with glioma-associated antigen peptides and poly-ICLC in a pilot study for pediatric recurrent low-grade gliomas. Neuro Oncol 18:1157-68
Pollack, Ian F; Jakacki, Regina I; Butterfield, Lisa H et al. (2016) Antigen-specific immunoreactivity and clinical outcome following vaccination with glioma-associated antigen peptides in children with recurrent high-grade gliomas: results of a pilot study. J Neurooncol 130:517-527