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Article: Correction: Gallus et al. Immunotherapy Approaches in Isocitrate-Dehydrogenase-Mutant Low-Grade Glioma.

Gallus, Marco / Kwok, Darwin / Lakshmanachetty, Senthilnath / Yamamichi, Akane / Okada, Hideho

2023 Volume 16, Issue 1

Abstract: It has come to our attention that the previously published manuscript contained an outdated iteration of Table 1 [ ... ]. ...

Abstract	It has come to our attention that the previously published manuscript contained an outdated iteration of Table 1 [...].
Language	English
Publishing date	2023-12-26
Publishing country	Switzerland
Document type	Published Erratum
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers16010119
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Immunotherapy Approaches in Isocitrate-Dehydrogenase-Mutant Low-Grade Glioma.

Gallus, Marco / Kwok, Darwin / Lakshmanachetty, Senthilnath / Yamamichi, Akane / Okada, Hideho

Cancers

2023 Volume 15, Issue 14

Abstract: Low-grade gliomas (LGGs) are slow-growing tumors in the central nervous system (CNS). Patients characteristically show the onset of seizures or neurological deficits due to the predominant LGG location in high-functional brain areas. As a molecular ... ...

Abstract	Low-grade gliomas (LGGs) are slow-growing tumors in the central nervous system (CNS). Patients characteristically show the onset of seizures or neurological deficits due to the predominant LGG location in high-functional brain areas. As a molecular hallmark, LGGs display mutations in the isocitrate dehydrogenase (IDH) enzymes, resulting in an altered cellular energy metabolism and the production of the oncometabolite D-2-hydroxyglutarate. Despite the remarkable progress in improving the extent of resection and adjuvant radiotherapy and chemotherapy, LGG remains incurable, and secondary malignant transformation is often observed. Therefore, novel therapeutic approaches are urgently needed. In recent years, immunotherapeutic strategies have led to tremendous success in various cancer types, but the effect of immunotherapy against glioma has been limited due to several challenges, such as tumor heterogeneity and the immunologically "cold" tumor microenvironment. Nevertheless, recent preclinical and clinical findings from immunotherapy trials are encouraging and offer a glimmer of hope for treating IDH-mutant LGG patients. Here, we aim to review the lessons learned from trials involving vaccines, T-cell therapies, and IDH-mutant inhibitors and discuss future approaches to enhance the efficacy of immunotherapies in IDH-mutant LGG.
Language	English
Publishing date	2023-07-22
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers15143726
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Article ; Online: Correspondence on 'H3.3K27M mutation is not a suitable target for immunotherapy in HLA-A2+ patients with diffuse midline glioma' by Immisch

Chheda, Zinal S / Mueller, Sabine / Hegde, Bindu / Yamamichi, Akane / Butterfield, Lisa H / Okada, Hideho

Journal for immunotherapy of cancer

2023 Volume 11, Issue 3

MeSH term(s)	Humans ; HLA-A2 Antigen/genetics ; Histones/genetics ; Immunotherapy ; Glioma/genetics ; Glioma/therapy ; Mutation
Chemical Substances	HLA-A2 Antigen ; Histones
Language	English
Publishing date	2023-03-10
Publishing country	England
Document type	Letter ; Comment
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2022-006617
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Article: IRF8-driven reprogramming of the immune microenvironment enhances anti-tumor adaptive immunity and reduces immunosuppression in murine glioblastoma.

Montoya, Megan / Collins, Sara A / Chuntova, Pavlina / Patel, Trishna S / Nejo, Takahide / Yamamichi, Akane / Kasahara, Noriyuki / Okada, Hideho

bioRxiv : the preprint server for biology

2024

Abstract: Background: Glioblastoma (GBM) has a highly immunosuppressive tumor immune microenvironment (TIME), largely mediated by myeloid-derived suppressor cells (MDSCs). Here, we utilized a retroviral replicating vector (RRV) to deliver Interferon Regulatory ... ...

Abstract	Background: Glioblastoma (GBM) has a highly immunosuppressive tumor immune microenvironment (TIME), largely mediated by myeloid-derived suppressor cells (MDSCs). Here, we utilized a retroviral replicating vector (RRV) to deliver Interferon Regulatory Factor 8 (IRF8), a master regulator of type 1 conventional dendritic cell (cDC1) development, in a syngeneic murine GBM model. We hypothesized that RRV-mediated delivery of IRF8 could "reprogram" intratumoral MDSCs into antigen-presenting cells (APCs) and thereby restore T-cell responses. Methods: Effects of RRV-IRF8 on survival and tumor growth kinetics were examined in the SB28 murine GBM model. Immunophenotype was analyzed by flow cytometry and gene expression assays. We assayed functional immunosuppression and antigen presentation by Results: Mice with RRV-IRF8 pre-transduced intracerebral tumors had significantly longer survival and slower tumor growth compared to controls. RRV-IRF8 treated tumors exhibited significant enrichment of cDC1s and CD8+ T-cells. Additionally, myeloid cells derived from RRV-IRF8 tumors showed decreased expression of the immunosuppressive markers Arg1 and IDO1 and demonstrated reduced suppression of naïve T-cell proliferation in Conclusions: Our results indicate that reprogramming of glioma-infiltrating myeloid cells by
Language	English
Publishing date	2024-04-03
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.04.02.587608
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Article ; Online: Enhancing CAR-T cell metabolism to overcome hypoxic conditions in the brain tumor microenvironment.

Hatae, Ryusuke / Kyewalabye, Keith / Yamamichi, Akane / Chen, Tiffany / Phyu, Su / Chuntova, Pavlina / Nejo, Takahide / Levine, Lauren S / Spitzer, Matthew H / Okada, Hideho

JCI insight

2024 Volume 9, Issue 7

Abstract: The efficacy of chimeric antigen receptor T cell (CAR-T) therapy has been limited against brain tumors to date. CAR-T cells infiltrating syngeneic intracerebral SB28 EGFRvIII gliomas revealed impaired mitochondrial ATP production and a markedly hypoxic ... ...

Abstract	The efficacy of chimeric antigen receptor T cell (CAR-T) therapy has been limited against brain tumors to date. CAR-T cells infiltrating syngeneic intracerebral SB28 EGFRvIII gliomas revealed impaired mitochondrial ATP production and a markedly hypoxic status compared with ones migrating to subcutaneous tumors. Drug screenings to improve metabolic states of T cells under hypoxic conditions led us to evaluate the combination of the AMPK activator metformin and the mTOR inhibitor rapamycin (Met+Rap). Met+Rap-pretreated mouse CAR-T cells showed activated PPAR-γ coactivator 1α (PGC-1α) through mTOR inhibition and AMPK activation, and a higher level of mitochondrial spare respiratory capacity than those pretreated with individual drugs or without pretreatment. Moreover, Met+Rap-pretreated CAR-T cells demonstrated persistent and effective antiglioma cytotoxic activities in the hypoxic condition. Furthermore, a single intravenous infusion of Met+Rap-pretreated CAR-T cells significantly extended the survival of mice bearing intracerebral SB28 EGFRvIII gliomas. Mass cytometric analyses highlighted increased glioma-infiltrating CAR-T cells in the Met+Rap group, with fewer Ly6c+CD11b+ monocytic myeloid-derived suppressor cells in the tumors. Finally, human CAR-T cells pretreated with Met+Rap recapitulated the observations with murine CAR-T cells, demonstrating improved functions under in vitro hypoxic conditions. These findings advocate for translational and clinical exploration of Met+Rap-pretreated CAR-T cells in human trials.
MeSH term(s)	Mice ; Humans ; Animals ; Tumor Microenvironment ; AMP-Activated Protein Kinases/metabolism ; Xenograft Model Antitumor Assays ; Cell Line, Tumor ; Brain/metabolism ; Glioma ; T-Lymphocytes ; TOR Serine-Threonine Kinases/metabolism
Chemical Substances	AMP-Activated Protein Kinases (EC 2.7.11.31) ; TOR Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2024-04-08
Publishing country	United States
Document type	Journal Article
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.177141
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Article ; Online: Tumor antigens in glioma.

Nejo, Takahide / Yamamichi, Akane / Almeida, Neil D / Goretsky, Yitzhar E / Okada, Hideho

Seminars in immunology

2020 Volume 47, Page(s) 101385

Abstract: Immunotherapy applications to glioblastoma represent a new treatment frontier. Antigen-targeted immunotherapy approaches hold enormous potential to elicit antigen-specific anti-tumor effects in central nervous system tumors. Still, the paucity of ... ...

Abstract	Immunotherapy applications to glioblastoma represent a new treatment frontier. Antigen-targeted immunotherapy approaches hold enormous potential to elicit antigen-specific anti-tumor effects in central nervous system tumors. Still, the paucity of effective antigen targets remains a significant obstacle in safely and effectively treating glioblastoma and other malignant gliomas with relatively low mutation loads. In this review, we highlight the current understanding of and development of immunotherapy to target 1) shared non-mutant antigens 2) shared mutant antigens (neoantigens) derived from cancer-specific mutations 3) personalized neoantigens derived from tumor-specific genetic alterations containing de novo peptide sequences and 4) virus-derived antigens. We also discuss strategies to enhance tumor immunogenicity and neoantigen prediction. Spatial heterogeneity remains a formidable challenge for immunotherapy of glioma; recent advances in targeting multiple antigens and refining the antigen selection pipeline hold great promise to turn the tide against glioma.
MeSH term(s)	Animals ; Antigens, Neoplasm/immunology ; Clinical Trials as Topic ; Disease Management ; Disease Susceptibility ; Drug Evaluation, Preclinical ; Glioma/diagnosis ; Glioma/immunology ; Glioma/therapy ; Humans ; Immunotherapy/adverse effects ; Immunotherapy/methods ; Precision Medicine
Chemical Substances	Antigens, Neoplasm
Language	English
Publishing date	2020-02-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1018141-6
ISSN	1096-3618 ; 1044-5323
ISSN (online)	1096-3618
ISSN	1044-5323
DOI	10.1016/j.smim.2020.101385
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Article: Enhancing CAR-T Cell Metabolism to Overcome Hypoxic Conditions in the Brain Tumor Microenvironment.

Hatae, Ryusuke / Kyewalabye, Keith / Yamamichi, Akane / Chen, Tiffany / Phyu, Su / Chuntova, Pavlina / Nejo, Takahide / Levine, Lauren S / Spitzer, Matthew H / Okada, Hideho

bioRxiv : the preprint server for biology

2023

Abstract: The efficacy of chimeric antigen receptor (CAR)-T therapy has been limited against brain tumors to date. CAR-T cells infiltrating syngeneic intracerebral SB28-EGFRvIII glioma revealed impaired mitochondrial ATP production and a markedly hypoxic status ... ...

Abstract	The efficacy of chimeric antigen receptor (CAR)-T therapy has been limited against brain tumors to date. CAR-T cells infiltrating syngeneic intracerebral SB28-EGFRvIII glioma revealed impaired mitochondrial ATP production and a markedly hypoxic status compared to ones migrating to subcutaneous tumors. Drug screenings to improve metabolic states of T cells under hypoxic conditions led us to evaluate the combination of AMPK activator Metformin and the mTOR inhibitor Rapamycin (Met+Rap). Met+Rap-pretreated mouse CAR-T cells showed activated PPAR-gamma coactivator 1α (PGC-1α) through mTOR inhibition and AMPK activation, and a higher level of mitochondrial spare respiratory capacity than those pretreated with individual drugs or without pretreatment. Moreover, Met+Rap-pretreated CAR-T cells demonstrated persistent and effective anti-glioma cytotoxic activities in the hypoxic condition. Furthermore, a single intravenous infusion of Met+Rap-pretreated CAR-T cells significantly extended the survival of mice bearing intracerebral SB28-EGFRvIII gliomas. Mass cytometric analyses highlighted increased glioma-infiltrating CAR-T cells in the Met+Rap group with fewer Ly6c+ CD11b+ monocytic myeloid-derived suppressor cells in the tumors. Finally, human CAR-T cells pretreated with Met+Rap recapitulated the observations with murine CAR-T cells, demonstrating improved functions in vitro hypoxic conditions. These findings advocate for translational and clinical exploration of Met+Rap-pretreated CAR-T cells in human trials.
Language	English
Publishing date	2023-11-15
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.11.13.566775
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Article ; Online: Challenges in the discovery of tumor-specific alternative splicing-derived cell-surface antigens in glioma.

Scientific reports

2024 Volume 14, Issue 1, Page(s) 6362

Abstract: Despite advancements in cancer immunotherapy, solid tumors remain formidable challenges. In glioma, profound inter- and intra-tumoral heterogeneity of antigen landscape hampers therapeutic development. Therefore, it is critical to consider alternative ... ...

Abstract	Despite advancements in cancer immunotherapy, solid tumors remain formidable challenges. In glioma, profound inter- and intra-tumoral heterogeneity of antigen landscape hampers therapeutic development. Therefore, it is critical to consider alternative sources to expand the repertoire of targetable (neo-)antigens and improve therapeutic outcomes. Accumulating evidence suggests that tumor-specific alternative splicing (AS) could be an untapped reservoir of antigens. In this study, we investigated tumor-specific AS events in glioma, focusing on those predicted to generate major histocompatibility complex (MHC)-presentation-independent, cell-surface antigens that could be targeted by antibodies and chimeric antigen receptor-T cells. We systematically analyzed bulk RNA-sequencing datasets comparing 429 tumor samples (from The Cancer Genome Atlas) and 9166 normal tissue samples (from the Genotype-Tissue Expression project), and identified 13 AS events in 7 genes predicted to be expressed in more than 10% of the patients, including PTPRZ1 and BCAN, which were corroborated by an external RNA-sequencing dataset. Subsequently, we validated our predictions and elucidated the complexity of the isoforms using full-length transcript amplicon sequencing on patient-derived glioblastoma cells. However, analyses of the RNA-sequencing datasets of spatially mapped and longitudinally collected clinical tumor samples unveiled remarkable spatiotemporal heterogeneity of the candidate AS events. Furthermore, proteomics analysis did not reveal any peptide spectra matching the putative antigens. Our investigation illustrated the diverse characteristics of the tumor-specific AS events and the challenges of antigen exploration due to their notable spatiotemporal heterogeneity and elusive nature at the protein levels. Redirecting future efforts toward intracellular, MHC-presented antigens could offer a more viable avenue.
MeSH term(s)	Humans ; Alternative Splicing ; Antigens, Surface ; Glioma/genetics ; Glioblastoma ; Histocompatibility Antigens ; RNA ; Antigens, Neoplasm/genetics ; Receptor-Like Protein Tyrosine Phosphatases, Class 5
Chemical Substances	Antigens, Surface ; Histocompatibility Antigens ; RNA (63231-63-0) ; Antigens, Neoplasm ; PTPRZ1 protein, human (EC 3.1.3.48) ; Receptor-Like Protein Tyrosine Phosphatases, Class 5 (EC 3.1.3.48)
Language	English
Publishing date	2024-03-16
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-024-56684-0
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Article: Glioma-neuronal circuit remodeling induces regional immunosuppression.

Nejo, Takahide / Krishna, Saritha / Jimenez, Christian / Yamamichi, Akane / Young, Jacob S / Lakshmanachetty, Senthilnath / Chen, Tiffany / Phyu, Su Su Sabai / Ogino, Hirokazu / Watchmaker, Payal / Diebold, David / Choudhury, Abrar / Daniel, Andy G S / Raleigh, David R / Hervey-Jumper, Shawn L / Okada, Hideho

bioRxiv : the preprint server for biology

2023

Abstract: Neuronal activity-driven mechanisms impact glioblastoma cell proliferation and ... ...

Abstract	Neuronal activity-driven mechanisms impact glioblastoma cell proliferation and invasion
Language	English
Publishing date	2023-08-06
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.08.04.548295
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Article: Efficacy of cancer-specific anti-podoplanin CAR-T cells and oncolytic herpes virus G47Δ combination therapy against glioblastoma.

Chalise, Lushun / Kato, Akira / Ohno, Masasuke / Maeda, Sachi / Yamamichi, Akane / Kuramitsu, Shunichiro / Shiina, Satoshi / Takahashi, Hiromi / Ozone, Sachiko / Yamaguchi, Junya / Kato, Yukinari / Rockenbach, Yumi / Natsume, Atsushi / Todo, Tomoki

Molecular therapy oncolytics

2022 Volume 26, Page(s) 265–274

Abstract: Glioblastoma is a devastating malignant brain tumor with a poor prognosis despite standard therapy. Podoplanin (PDPN), a type I transmembrane mucin-like glycoprotein that is overexpressed in various cancers, is a potential therapeutic target for the ... ...

Abstract	Glioblastoma is a devastating malignant brain tumor with a poor prognosis despite standard therapy. Podoplanin (PDPN), a type I transmembrane mucin-like glycoprotein that is overexpressed in various cancers, is a potential therapeutic target for the treatment of glioblastoma. We previously reported the efficacy of chimeric antigen receptor (CAR)-T cells using an anti-pan-PDPN monoclonal antibody (mAb; NZ-1)-based third-generation CAR in a xenograft mouse model. However, NZ-1 also reacted with PDPN-expressing normal cells, such as lymphatic endothelial cells, pulmonary alveolar type I cells, and podocytes. To overcome possible on-target-off-tumor effects, we produced a cancer-specific mAb (CasMab, LpMab-2)-based CAR. LpMab-2 (Lp2) reacted with PDPN-expressing cancer cells but not with normal cells. In this study, Lp2-CAR-transduced T cells (Lp2-CAR-T) specifically targeted PDPN-expressing glioma cells while sparing the PDPN-expressing normal cells. Lp2-CAR-T also killed patient-derived glioma stem cells, demonstrating its clinical potential against glioblastoma. Systemic injection of Lp2-CAR-T cells inhibited the growth of a subcutaneous glioma xenograft model in immunodeficient mice. Combination therapy with Lp2-CAR-T and oncolytic virus G47Δ, a third-generation recombinant herpes simplex virus (HSV)-1, further inhibited the tumor growth and improved survival. These findings indicate that the combination therapy of Lp2-CAR-T cells and G47Δ may be a promising approach to treat glioblastoma.
Language	English
Publishing date	2022-07-20
Publishing country	United States
Document type	Journal Article
ISSN	2372-7705
ISSN	2372-7705
DOI	10.1016/j.omto.2022.07.006
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