This Article demonstrates that tumour-associated IDH1 somatic mutations result in a gain of enzyme function that causes the accumulation of R(-)-2-hydroxyglutarate (2HG). We proposed that accumulation of 2HG might drive oncogenesis, and referenced work demonstrating 2HG accumulation in patients with 2-hydroxyglutaric aciduria 1 . As a plausible mechanism of oncogenesis, we proposed that R(-)-2HG induces redox stress owing to impairment of the respiratory chain. This hypothesis suggests that R(-)-2HG may promote cancer mutations, and is consistent with the latency observed in glioma development and the fact that gliomas increase in incidence with age. Nonetheless, we do appreciate that there are other possible mechanisms by which R(-)-2HG may promote tumour formation. Further work has identified that the abnormal production of 2HG is associated with tumours bearing a mutation in either IDH1 or IDH2 and supports a link between 2HG accumulation and cancer. So far, we have not found any tumour samples containing IDH1 or IDH2 mutations that do not have increased 2HG levels. Determining the mechanistic link between 2HG accumulation and cancer formation, and how each stereoisomer of 2HG may drive malignancy by the same or distinct mechanism is the subject of continuing investigation by our group and others. Hum Genet. 2005; 76:358-360. [PubMed: 15609246] NIH Public Access
Glioblastoma is the most common primary malignant brain tumor in adults and associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical PD-1 blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell and interferon-γ-related gene expression, but downregulation of cell cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 (PD-L1) in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells, and a decreasing monocytic population was observed more frequently in the neoadjuvant group than patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances the local and systemic anti-tumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.
Immunotherapy represents a promising area of therapy among neuro-oncology patients. However, early phase studies reveal unique challenges associated with assessment of radiological changes reflecting delayed responses or therapy-induced inflammation. Clinical benefit, including long-term survival and tumor regression, can still occur following initial apparent progression or appearance of new lesions. Refinement of response assessment criteria for neuro-oncology patients undergoing immunotherapy is therefore warranted. A multinational and multidisciplinary panel of neuro-oncology immunotherapy experts describes immunotherapy response assessment for neuro-oncology (iRANO) criteria that are based on guidance for determination of tumor progression outlined by the immune-related response criteria (irRC) and the response assessment in neuro-oncology (RANO) working group. Among patients who demonstrate imaging findings meeting RANO criteria for progressive disease (PD) within six months of initiating immunotherapy including the development of new lesions, confirmation of radiographic progression on follow-up imaging is recommended provided that the patient is not significantly worse clinically. The proposed criteria also include guidelines for use of corticosteroids. The role of advanced imaging techniques and measurement of clinical benefit endpoints including neurologic and immunologic functions are reviewed. The iRANO guidelines put forth herein will evolve successively to improve their utility as further experience from immunotherapy trials in neuro-oncology accumulate.
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