OS2.1 Immune responses to a mutation-specific peptide vaccine targeting IDH1R132H in patients with IDH1R132H-mutated gliomas

ABSTRACT: Abstract Immunotherapeutic concepts for brain tumors have been hampered by lack of selective measures to target the CNS and lack of truly tumor-specific antigens. But the concept of an immune privileged CNS has to be questioned due to survey of the brain by specific T-cells, CNS autoimmunity and presence of lymphatics. As tumor-specific antigens, mutated antigens have come into focus for all tumor entities. Mutations in the gene for isocitrate dehydrogenase 1 frequently occur in diffuse gliomas, mostly astrocytomas, resulting in a point mutation (mostly IDH1R132H). IDH1R132H is an ideal tumor-specific antigen, because it is tumor-specific, homogenously expressed and considered a driving mutation in glioma. Preclinical studies have shown that mutation-specific Th cell responses spontaneously occur in patients with IDH1-mutated gliomas and that a peptide vaccine encoding IDH1R132H is therapeutic in a humanized mouse tumor model. Based on these data we have initiated a multicenter, first-in-man, phase I clinical vaccine trial, which is planned to enroll 39 patients with newly diagnosed malignant IDH1R132H+ astrocytomas at eight German sites: NOA-16 (NCT02454634). The vaccine is made of an IDH1R132H peptide emulsified in mineral oil and administered with topical imiquimod. Vaccination is implemented into primary standard therapy. Primary end points are safety and immunogenicity as measured by IDH1R132H-specific antibodies and T cell responses. As of March 2016, 13 patients have been enrolled in the trial; no severe adverse events have been reported. We report here on 3 patients treated with the vaccine on a compassionate use basis. No patient experienced a regime-limiting toxicity as defined in the trial protocol. Two patients received all 8 doses of the vaccine; both developed IDH1-specific antibody responses, which were mutation-specific early after vaccination. Of these, one patient developed a vaccination-induced mutation-specific cellular response. The second patient had a high baseline mutation-specific T cell response, which was temporarily boosted by the vaccine. IFN-? catch assays from PBMCs of this patient revealed a Th cell-mediated response. To identify and clone IDH1R132H-specific TCR(s) for adoptive T cell therapy, single T cells from this patient specifically responding to IDH1R132H were sorted and subjected to TCR sequencing. 11 TCRs have been identified so far and will be cloned and validated. In summary, we demonstrate for the first time the induction of a mutation-specific humoral and cellular immune response to the IDH1R132H neoepitope after peptide vaccination of patients with IDH1R132H-mutated gliomas. The ongoing trial will analyze safety and immunogenicity of the vaccine in a defined patient cohort, which also allows for collecting data on therapeutic efficacy.

SUBMITTER: Bunse T 

PROVIDER: S-EPMC5782511 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature