Mass cytometry detects H3.3K27M-specific vaccine responses in diffuse midline glioma

Mueller, Sabine; Taitt, Jared; Villanueva-Meyer, Javier; Bonner, Erin R; Nejo, Takahide; Lulla, Rishi; Goldman, Stewart; Banerjee, Anu; Susan, N.; Whipple, Nicholas; Crawford, John R.; Gauvain, Karen; Nazemi, Kellie; Watchmaker, Payal; Almeida, Neil D.; Okada, Kaori; Salazar, Andrés M.; Gilbert, Ryan; Nazarian, Javad; Molinaro, Annette M.; Butterfield, Lisa H.; Prados, Michael D.; Okada, Hideho

doi:10.1172/jci140378

Cited by 82 publications

(84 citation statements)

References 52 publications

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“…For instance, patients with melanoma with lower levels of circulating M-MDSCs at baseline were significantly more likely to achieve prolonged overall survival following anti-CTLA4 ICI 139 – 143 . Similarly, in patients with diffuse midline glioma, lower frequencies of M-MDSCs in peripheral blood predict improved response to neoantigen vaccine immunotherapy 144 . Beyond myeloid suppressive cells, a recent study demonstrated that the baseline abundance of a subset of circulating T reg cells defined as CD45RA − FOXP3 hi were predictive of relapse after patients with breast cancer underwent surgery 53 .…”

Section: Systemic Immune Biomarkers For Cancermentioning

confidence: 99%

Systemic immunity in cancer

2021

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Immunotherapy has revolutionized cancer treatment, but efficacy remains limited in most clinical settings. Cancer is a systemic disease that induces many functional and compositional changes to the immune system as a whole. Immunity is regulated by interactions of diverse cell lineages across tissues. Therefore, an improved understanding of tumour immunology must assess the systemic immune landscape beyond the tumour microenvironment (TME). Importantly, the peripheral immune system is required to drive effective natural and therapeutically induced antitumour immune responses. In fact, emerging evidence suggests that immunotherapy drives new immune responses rather than the reinvigoration of pre-existing immune responses. However, new immune responses in individuals burdened with tumours are compromised even beyond the TME. Herein, we aim to comprehensively outline the current knowledge of systemic immunity in cancer.

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Section: Systemic Immune Biomarkers For Cancermentioning

confidence: 99%

Systemic immunity in cancer

2021

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“…As we can see, the tumor site was not associated with prognosis in our study. Patients with diffuse midline gliomas (DMGs) have dismal outcomes (Mueller and Taitt et al, 2020). Furthermore, DMGs are mainly located in the brainstem in pediatric patients (Mackay and Burford et al, 2017;Mueller and Jain et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

A Prognostic Nomogram and Risk Stratification in Pediatric With Hemisphere Lower-Grade Gliomas: a SEER-Based Study 1998-2016

Che¹,

Xu²,

Xu³

et al. 2021

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BackgroundPediatric lower-grade gliomas (pLGGs) are a rare intracranial tumor that lacks a prognostic prediction model for clinical application. The present study aimed to construct a novel nomogram to predict overall survival for pLGGs.MethodsBased on data from the Surveillance, Epidemiology, and End Results (SEER) database, 746 pediatrics diagnosed with cerebral hemispheres lower-grade gliomas from 1998 to 2016 were enrolled for the research. All patients were randomly divided into training and validation datasets at a ratio of 7:3. The Cox and stepwise regression analysis was used to screen the independent prognosticators for developing the nomogram. The discriminating abilities and calibration of the nomogram were assessed by concordance index (C-index), receiver operating characteristic curves (ROCs), area under the ROCs (AUCs), and calibration curves. The accuracy and net benefits of the nomogram were evaluated by comparing it to the traditional prediction method by the net reclassification improvement (NRI), the integrated discrimination improvement (IDI), and the decision curve analysis (DCA). Finally, we employed risk stratifications for pLGGs. ResultsFive independent predicted indicators were associated with OS rates. The constructed nomogram showed reliable discrimination by the C-indexes of the novel nomogram for OS, which were 0.830 and 0.871, much higher than that in the traditional prediction method (0.749 and 0.728, respectively). The plotted calibration curves showed good consistency between the prediction survival rates and actual observed survival rates in both the training and validation dataset. IDI, NRI, and DCA showed the nomogram had a comparable clinical application to the traditional prediction method. Kaplan-Meier survival curves showed a significant difference among the three risk classifications.ConclusionIn conclusion, we developed a novel prognostic nomogram with improved accuracy, better clinical utility, and a more precise prediction of OS rates for hemisphere pLGGs than the traditional prediction method.

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“…In addition, patients are also often treated with dexamethasone, a synthetic glucocorticoid, for peri-operative control of intracerebral edema and consequent neurological symptoms (e.g., headaches, confusion, weakness, other focal neurological deficits, and seizures). However, dexamethasone and other glucocorticoids significantly dampen the overall immune response and can reduce therapeutic benefit of immunotherapies, resulting in consensus recommendations that their use be minimized prior to and during immunotherapy trials [54][55][56]. For example, it was recently reported that use of dexamethasone hampered vaccine-reactive T cell responses during neoantigen vaccine priming in patients with newly diagnosed malignant glioma [56,57].…”

Section: Suppression Of the Immune Response By Standard Therapy And Cmentioning

confidence: 99%

“…In a recent multicenter pilot study, vaccine targeting H3.3K27M, along with Toll-like receptor 3 agonist, polyinosinicpolycytidylic acid stabilized with polylysine and carboxymethylcellulose (poly-ICLC), was administered to HLA-A02.201+ pediatric patients with H3.3K27M+ diffuse midline glioma (DMG). A subset of patients (n = 18) were selected for available multi-timepoint blood draws and 39% exhibited an expansion of H3.3K27M-reactive CD8 + T cells (mOS 16.3 months) and showed significantly prolonged OS compared to tumors who failed to demonstrate a T cell response (mOS 9.9 months) [56]. Furthermore, dexamethasone administration is inversely associated with H3.3K27M-reactive CD8 + T cell responses [56].…”

Section: Vaccine Therapymentioning

confidence: 99%

Current Advances in Immunotherapy for Glioblastoma

et al. 2021

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Purpose of Review This review seeks to inform oncology clinicians and researchers about the development of novel immunotherapies for the treatment of glioblastoma. An enumeration of ongoing and recently completed clinical trials will be discussed with special attention given to current technologies implemented to overcome central nervous system–specific challenges including barriers to the peripheral immune system, impaired antigen presentation, and T cell dysfunction. Recent Findings The success of immunotherapy in other solid cancers has served as a catalyst to explore its application in glioblastoma, which has limited response to other treatments. Recent developments include multi-antigen vaccines that seek to overcome the heterogeneity of glioblastoma, as well as immune checkpoint inhibitors, which could amplify the adaptive immune response and may have promise in combinatorial approaches. Additionally, oncolytic and retroviruses have opened the door to a plethora of combinatorial approaches aiming to leverage their immunogenicity and/or ability to carry therapeutic transgenes. Summary Treatment of glioblastoma remains a serious challenge both with regard to immune-based as well as other therapeutic strategies. The disease has proven to be highly resistant to treatment due to a combination of tumor heterogeneity, adaptive expansion of resistant cellular subclones, evasion of immune surveillance, and manipulation of various signaling pathways involved in tumor progression and immune response. Immunotherapeutics that are efficacious in other cancer types have unfortunately not enjoyed the same success in glioblastoma, illustrating the challenging and complex nature of this disease and demonstrating the need for development of multimodal treatment regimens utilizing the synergistic qualities of immune-mediated therapies.

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Mass cytometry detects H3.3K27M-specific vaccine responses in diffuse midline glioma

Abstract: CONCLUSION. Administration of the H3.3K27M-specific vaccine was well tolerated. Patients with H3.3K27M-specific CD8 + immunological responses demonstrated prolonged OS compared with nonresponders. TRIAL REGISTRATION. ClinicalTrials.gov NCT02960230.

Cited by 82 publications

References 52 publications

Systemic immunity in cancer

Systemic immunity in cancer

A Prognostic Nomogram and Risk Stratification in Pediatric With Hemisphere Lower-Grade Gliomas: a SEER-Based Study 1998-2016

Current Advances in Immunotherapy for Glioblastoma

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