A vaccine targeting mutant IDH1 induces antitumour immunity

Abstract

Monoallelic point mutations of isocitrate dehydrogenase type 1 (IDH1) are an early and defining event in the development of a subgroup of gliomas and other types of tumour. They almost uniformly occur in the critical arginine residue (Arg 132) in the catalytic pocket, resulting in a neomorphic enzymatic function, production of the oncometabolite 2-hydroxyglutarate (2-HG), genomic hypermethylation, genetic instability and malignant transformation. More than 70% of diffuse grade II and grade III gliomas carry the most frequent mutation, IDH1(R132H) (ref. 3). From an immunological perspective, IDH1(R132H) represents a potential target for immunotherapy as it is a tumour-specific potential neoantigen with high uniformity and penetrance expressed in all tumour cells. Here we demonstrate that IDH1(R132H) contains an immunogenic epitope suitable for mutation-specific vaccination. Peptides encompassing the mutated region are presented on major histocompatibility complexes (MHC) class II and induce mutation-specific CD4(+) T-helper-1 (TH1) responses. CD4(+) TH1 cells and antibodies spontaneously occurring in patients with IDH1(R132H)-mutated gliomas specifically recognize IDH1(R132H). Peptide vaccination of mice devoid of mouse MHC and transgenic for human MHC class I and II with IDH1(R132H) p123-142 results in an effective MHC class II-restricted mutation-specific antitumour immune response and control of pre-established syngeneic IDH1(R132H)-expressing tumours in a CD4(+) T-cell-dependent manner. As IDH1(R132H) is present in all tumour cells of these slow-growing gliomas, a mutation-specific anti-IDH1(R132H) vaccine may represent a viable novel therapeutic strategy for IDH1(R132H)-mutated tumours.

Long-peptide vaccination with driver gene mutations in p53 and Kras induces cancer mutation-specific effector as well as regulatory T cell responses

“…To investigate the tumor protective capacity of the mutated oncogene-derived long-peptide vaccine in vivo we generated syngenic A2.DR1 dtg sarcoma lines by carcinogen-induced tumorigenesis 35 and subsequent passaging in vitro and in vivo within immune deficient NOD/SCID mice and immunocompetent A2.DR1 mice (see Supplementary Figure 8A). Several A2.DR1 dtg sarcoma cell lines were established and characterized by histology to be fibrosarcomas displaying a spindle-like morphology, expression of the mesenchymal marker vimentin, and the endothelial marker CD29/integrin β1 (exemplarily shown for sarcoma line 2277-NS 35 in Supplementary Figures 8B and 5C, respectively).…”

“…Several A2.DR1 dtg sarcoma cell lines were established and characterized by histology to be fibrosarcomas displaying a spindle-like morphology, expression of the mesenchymal marker vimentin, and the endothelial marker CD29/integrin β1 (exemplarily shown for sarcoma line 2277-NS 35 in Supplementary Figures 8B and 5C, respectively). CD31 expression of in vivo established tumors suggested their micro-vascularization.…”

“…Mouse Tp53 and/or Kras mutations were found in numerous tumor cell lines but none of them expressed the hotspot mutations of interest (Figure 4, Supplementary Table 6). We therefore stably introduced a doxycycline (DOX)-inducible transgene for KRAS G12V and TP53 R248W joined by a linker and fused to an HA-tag into the Rosa26 locus of the cell line 2277-NS 35 by site-directed recombination (Supplementary Figure 8D-G, Supplementary Figure 9).…”

“…In that study vaccination with a single mutated IDH-1 HLA-DRB1-restricted epitope elicited a T H 1 effector CD4 + T cell response that was sufficient to delay the outgrowth of IDH-1 mutant sarcomas in A2.DR1 dtg mice. 35 …”

“…34 In addition, T H cells can exert direct tumor-eradicating functions. 35 Moreover, combining several TSAs in one vaccine might broaden the responses towards sub-dominant epitopes 36,37 and thereby prevent or delay the tumor’s escape from immune surveillance through emergence of Ag-loss variants. 11 …”