A vaccine for glioma

cancer in translation A vaccine for glioma Despite substantial advances in understanding of the molecular features of gliomas, the therapeutic options for these aggressive tumors remain scarce. Rich, Mitchell and colleagues provide their views about a phase 1 clinical trial testing the safety and efficacy of vaccines against cancer expressing mutant metabolic enzyme IDH1 in patients with high-grade glioma. Sameer Agnihotri, Kailin Yang, Duane A. Mitchell and Jeremy N. Rich Gliomas are the most prevalent primary brain tumors and remain incurable despite extensive molecular characterization and research aimed at identifying viable therapeutic vulnerabilities. Among the various glioma subtypes, diffuse gliomas and secondary glioblastomas are driven mostly by gain-of-function oncogenic mutations in genes encoding the metabolic enzymes IDH1 and, less frequently, IDH2, and thus are genetically distinct from primary glioblastomas1,2. Mutations in IDH1 are commonly found in heterozygosis and often result in the single-amino-acid substitution of arginine (R) with histidine (H) in the catalytic site of IDH1 at codon 132 (called ‘IDH1(R132H)’ here)1–3. Mutations in IDH1 and IDH2 result in neomorphic enzymatic activities that lead to production of the oncometabolite 2-HG4–6. 2-HG inhibits the enzymatic functions of many α-ketoglutarate-dependent enzymes, including histone and DNA demethlyases, and thus causes the aberrant epigenetic reprogramming seen in the CpG island methylator phenotypes7–11. The presence of mutations in IDH1 and/or IDH2 have led to intensive preclinical and clinical research aimed at developing clinical-grade inhibitors of mutant IDH1, some of which have achieved approval from the US Food and Drug Administration for certain indications, including acute myeloid leukemia or cholangiocarcinoma expressing mutant IDH1; however, despite promising preclinical evidence in support of the efficacy of these compounds, clinical studies of these mutant IDH1–targeted compounds for glioma have not yet progressed beyond early-phase clinical trials, mostly due to concerns about their ability to overcome the blood–brain barrier. This leaves few targeted therapeutic opportunities for patients with glioblastoma, and thus there is an urgent unmet need for the development of alternative strategies that could provide a suitable path for the treatment of these aggressive tumors. 584 Writing in Nature, Platten and colleagues now report the results of a phase 1 trial testing an anti-cancer vaccine designed to target neoantigens commonly found in patients with glioma bearing IDH1 mutations12 (Fig. 1). Their results provide proof-of-concept evidence of the feasibility and efficacy of this immunotherapy modality and open the path for the development of similar therapeutic approaches for the treatment of these lethal tumors. Anti-cancer vaccination typically consists of the administration of tumor-specific antigens that elicit adaptive anti-tumor immune responses. These antigens usually comprise ‘self ’ peptides or ‘non-self ’ peptides (such as cancer testis antigens or human papillomavirus proteins, respectively), although the best responses to anti-cancer vaccines are usually achieved when these are directed against antigens expressed exclusively by tumor cells. This has led to greater interest in the use of specific antigens that arise from endogenous tumor mutational processes and are generally known as ‘neoantigens’ or ‘neoepitopes’. Even though anti-cancer vaccines have been extensively explored in various settings with relative success, they have achieved uneven activity in neuro-oncology. More than 70% of diffuse gliomas harbor the IDH1 R132H mutation, an early genetic lesion expressed nearly uniformly by tumor cells, which renders this a potentially powerful therapeutic candidate. Additionally, this neoepitope is presented via the class II major histocompatibility complex (MHC)13 and thus represents an attractive potential target for immunotherapy. Previous preclinical studies demonstrated that versions of an IDH1(R132H)-specific peptide vaccine (IDH1-vac) were capable of inducing sustained anti-tumor–specific therapeutic helper T cell responses in syngeneic MHC-humanized mice13. Platten and colleagues developed an array of peptides encompassing the R132H substitution within IDH1 and identified the peptide p123–142, IDH1-vac Mutant IDH1(R132H) 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 From the bench: Sameer Agnihotri and Jeremy N. Rich WT P R L V S G W V K P I I I G R H A Y G D Q Y R A T D F V V RH P R L V S G W V K P I I I G H H A Y G D Q Y R A T D F V V 20-mer peptide (p123–142) IDH1(R132H)+ grade III or IV gliomas without co-deletion of 1p and 19q IDH1-vac Vaccine-induced immune responses in >90% patients Neoepitope-reactive T cells CNS TILs NOA16, NCT02454634 Phase 1 trial, n = 44 patients 7 trial sites Prior therapies: TMZ, radiotherapy N = 28 Completed study N = 32 Safety N = 30 Immune profiling Fig. 1 | Summary of the NOA16 trial. A 20-amino-acid (20-mer) peptide that spans codons 123–142 of mutant IDH1 (p123–142)—and thus contains the neoepitope generated by the R132H mutation present in this subset of patients with grade III or IV glioma—was selected for the development of an IDH1-vac anti-cancer vaccine. The cohort included 44 patients from seven different trial sites, who were selected for assessment of safety and efficacy after exposure to IDH1-vac. 1p and 19q, chromosomal arms; CNS, central nervous system; TILs, tumor-infiltrating lymphocytes; TMZ, temozolomide. which spans the codons 123–142 and includes the R132H substitution, as a potent inducer of specific anti-tumor immune responses to cells expressing mutant IDH1 (Fig. 1). On the basis of this promising preclinical evidence, Platten and colleagues Nature Cancer | VOL 2 | June 2021 | 584–586 | www.nature.com/natcancer cancer in translation designed a multi-center, phase 1 clinical trial (NOA-16; ClinicalTrials.gov identifier NCT02454634) to test the safety, feasibility and efficacy of a vaccine targeting mutant IDH1 in newly diagnosed patients with World Health Organization (WHO) grade III or grade IV glioma12 (Fig. 1). In this proof-of-concept trial, Platten and colleagues demonstrated that the IDH1-targeting vaccine was safe and immunogenic and was capable of inducing both T cell and B cell immune responses across patients bearing a variety of human leukocyte antigen–encoding alleles. The authors established a mutation-specificity score to incorporate the duration and level of IDH1-vac-induced T cell immune responses and observed that patients with high scores showed predominant production of the cytokines TNF, IFN-γ and IL-17 by helper T cells, indicative of involvement of the TH1 and TH17 subtypes of helper T cells. The authors also followed up with the patients and assessed the 3-year progression-free and death-free (...truncated)