Peptide Vaccine Demonstrates Safety & Immunogenicity in Patients with Astrocytomas

At the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois, researchers presented phase 1 trial data pertaining to a mutation-specific peptide vaccine targeting IDH1R132H in patients who had been newly diagnosed with malignant astrocytomas.

Astrocytoma is a rare, cancerous brain tumor that develops from brain cells called astrocytes, which are responsible for protecting nerve cells in the brain and spinal cord. The cause of these tumors typically remains unknown, according to the National Institutes of Health’s Genetic and Rare Disease Information Center.

“Hot-spot point mutations in the gene for isocitrate dehydrogenase type 1 (IDH1R132H) are a frequent founder event in gliomas and other tumors,” the authors write. “Preclinical studies have defined IDH1R132H as a clonal neoantigen presented on MHC class II to induce tumor-specific therapeutic T helper cell responses.”

Knowing this, investigators launched a first-in-man phase 1 trial, called NOA-16, where they enrolled a total of 33 participants, all of whom had been newly diagnosed with WHO grade III and grade IV astrocytomas that had IDH1R132H mutations.

After patients completed radiochemotherapy, investigators from the German Neurooncology Working Group administered 8 subcutaneous vaccinations with an IDH1R132H peptide in incomplete Freud’s adjuvant “at a central GMP site” with topical imiquimod for the duration of 32 weeks; they did this together with maintenance temozolomide. The primary endpoints of the study were defined to be safety and immunogenicity.

In total, 249 vaccines were given to 32 patients, as one patient withdrew from the trial after screening. The authors note that a total of 29 patients received all 8 vaccines, and all vaccine-related adverse events (AE) had been restricted to grade 1 reactions per common toxicity criteria for AE. Only 2 serious AEs were documented in 2 patients; investigators posit only 1 of them may have been related to the peptide vaccine.

“28/30 patients (93.3%) evaluable for immunogenicity displayed IDH1R132H-specific T cellular (detected by ELISPOT assays in 24/30 (80%)) or humoral (detected by ELISA in 26/30 patients (87%)) immune responses not detectable before vaccination,” the authors report.

Furthermore, 4 out of the 32 patients (12.5%) had progressive disease until week 32, defined as end of study, according to RANO criteria. However, the majority of the patients, 87.5%, proved to have stable disease, according to the authors. They added that 12 out of the 32 patients (37.5%) displayed pseudoprogressions. Through sequencing, the investigators were able to identify IDH1R132H-specific single-cell T cell receptors (TCR).

Overall, the mutation-specific IDH1R132H peptide vaccine was found to demonstrate safety and immunogenicity, thus meeting the trial’s primary endpoints.

“Pseudoprogressions observed after the initiation of the vaccine may indicate intratumoral immune reactions warranting further development, including TCR cell therapy,” the authors conclude.

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Feature Picture Source: Oregon State University / flickr / Creative Commons.