by ecancer reporter Janet Fricker

A vaccine that triggers immune responses against tumour cells with specific mutations in the protein isocitrate dehydrogenase type 1(IDH1) offers the potential to provide immunisation against gliomas, reports a German study in Nature.

Monoallelic point mutations in isocitrate dehydrogenase type 1 (IDH1) represent a defining event occurring early in the development of a subgroup of gliomas and other types of tumours.

Such mutations most commonly occur in the critical arginine residue (Arg 132) in the catalytic pocket, resulting in malignant transformations.

It is known that more than 70% of diffuse grade II and grade III gliomas carry the most frequent mutation, IDH1 (R132H).

In the current study Michael Platten and colleagues, from the German Cancer Research Center, Heidelberg, argue that, IDH1 (R132H) represents a potential target for immunotherapy since it is a tumour-specific potential neo antigen with high uniformity and penetrance.

The investigators showed that IDH1 (R132H) contains an immunogenic epitope capable of producing mutation-specific antibodies that attack IDH1 (R132H)-expressing tumour cells.

Peptides encompassing the mutated region are presented on major histocompatibility complexes (MHC) class II and induce mutation-specific CD4 T helper-1 (TH1) responses.

The researchers further showed that mutant-specific immune responses can be generated in human patients harbouring IDH1 (R132H)-mutated gliomas.

“These data underline that mutant IDH may serve as a therapeutic target not only through drug-mediated inhibition of the neomorphic enzymatic function but also through T-cell-based targeting of the mutant epitope in a disease where the target is an early event in tumorigenesis and hence expressed in all tumour cells, which makes immunological escape unlikely to occur,” write the authors.

Patients with low-grade and anaplastic gliomas with a high prevalence of the IDH1 (R132H) mutation, they add, represent a patient population that would particularly benefit from the vaccine.

“Because these tumours may remain stable or minimally growing for several years but will inevitably recur, often with a more malignant phenotype and because there is currently no maintenance therapy available preventing recurrence of this diffusely infiltrating disease in this relatively young and immunologically competent patient population.”

Reference

T Schumacher, L Bunse, S Pusch, et al. A vaccine targeting mutant IDH1 induces antitumour immunity. Nature.