&lt;p&gt;Immunotherapy for Medulloblastoma: Current Perspectives&lt;/p&gt;

Kabir, Tanvir; Kunos, Charles; Villanó, John L.; Chauhan, Aman

doi:10.2147/itt.s198162

Cited by 32 publications

(31 citation statements)

References 147 publications

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“…Given the fact that high SNV or indel mutational burdens are limited, especially in pediatric malignancies, the repertoire of tumor antigens needs to be broadened [ 12 ]. Several clinical studies are currently evaluating immunotherapy in medulloblastoma [ 44 ]. Cytotoxic T cells can infiltrate medulloblastoma [ 45 ] and checkpoint inhibitors against PD-1 are under investigation in clinical trials recruiting medulloblastoma patients and other CNS tumors.…”

Section: Discussionmentioning

confidence: 99%

“…Cytotoxic T cells can infiltrate medulloblastoma [ 45 ] and checkpoint inhibitors against PD-1 are under investigation in clinical trials recruiting medulloblastoma patients and other CNS tumors. Although immunotherapeutic approaches for medulloblastoma patients such as cancer vaccines, natural killer cells and CAR T cells are promising [ 44 ], one of the major limitations in treating medulloblastoma with immunotherapy is the low immunogenicity and mutational load. It is interesting to note that few reported medulloblastoma-specific fusion peptides, such as MLLT6–MRPL45, LCLAT1–ERBB4, ASAP1–WD4HV1 and PTEN–THAP9 [ 2 , 14 , 15 ] have similar immunogenic potential to the EPC2–GULP1 fusion peptide SAEEITLTI.…”

Section: Discussionmentioning

confidence: 99%

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Identification of an Immunogenic Medulloblastoma-Specific Fusion Involving EPC2 and GULP1

Paret

Lehmann

Bender

et al. 2021

Cancers

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Medulloblastoma is the most common malignant brain tumor in children. Immunotherapy is yet to demonstrate dramatic results in medulloblastoma, one reason being the low rate of mutations creating new antigens in this entity. In tumors with low mutational burden, gene fusions may represent a source of tumor-specific neoantigens. Here, we reviewed the landscape of fusions in medulloblastoma and analyzed their predicted immunogenicity. Furthermore, we described a new in-frame fusion protein identified by RNA-Seq. The fusion involved two genes on chromosome 2 coding for the enhancer of polycomb homolog 2 (EPC2) and GULP PTB domain containing engulfment adaptor 1 (GULP1) respectively. By qRT-PCR analysis, the fusion was detected in 3 out of 11 medulloblastoma samples, whereby 2 samples were from the same patients obtained at 2 different time points (initial diagnosis and relapse), but not in other pediatric brain tumor entities. Cloning of the full-length sequence indicated that the fusion protein contains the N-terminal enhancer of polycomb-like domain A (EPcA) of EPC2 and the coiled-coil domain of GULP1. In silico analyses predicted binding of the neoantigen-derived peptide to HLA-A*0201. A total of 50% of the fusions described in the literature were also predicted to produce an immunogenic peptide. The EPC2-GULP1 fusion peptide was able to induce a de novo T cell response characterized by interferon gamma release of CD8+ cytotoxic T cells in vitro. While the functional relevance of this fusion in medulloblastoma biology remains to be clarified, our data support an immunotherapeutic approach for pediatric medulloblastoma patients carrying the EPC2-GULP1 fusion and other immunogenic fusions.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Identification of an Immunogenic Medulloblastoma-Specific Fusion Involving EPC2 and GULP1

Paret

Lehmann

Bender

et al. 2021

Cancers

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“…Due to the heterogenic nature of MB tumors, immunotherapy has recently been the main focus of novel therapy development. Several immunotherapeutic approaches that aim to increase the immune cell recognition of brain tumors, such as MB, have reached clinical trials, including oncolytic viral therapy and cancer vaccines [44]. Oncolytic viral therapies in cancer, in general, aim to specifically infect and kill tumor cells, achieving this through two processes.…”

Section: Immunotherapy In Medulloblastomamentioning

confidence: 99%

Immunotherapy in Medulloblastoma: Current State of Research, Challenges, and Future Perspectives

Voskamp

Daalen

et al. 2021

Cancers

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Medulloblastoma (MB), a primary tumor of the central nervous system, is among the most prevalent pediatric neoplasms. The median age of diagnosis is six. Conventional therapies include surgical resection of the tumor with subsequent radiation and chemotherapy. However, these therapies often cause severe brain damage, and still, approximately 75% of pediatric patients relapse within a few years. Because the conventional therapies cause such severe damage, especially in the pediatric developing brain, there is an urgent need for better treatment strategies such as immunotherapy, which over the years has gained accumulating interest. Cancer immunotherapy aims to enhance the body’s own immune response to tumors and is already widely used in the clinic, e.g., in the treatment of melanoma and lung cancer. However, little is known about the possible application of immunotherapy in brain cancer. In this review, we will provide an overview of the current consensus on MB classification and the state of in vitro, in vivo, and clinical research concerning immunotherapy in MB. Based on existing evidence, we will especially focus on immune checkpoint inhibition and CAR T-cell therapy. Additionally, we will discuss challenges associated with these immunotherapies and relevant strategies to overcome those.

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“…These findings have suggested that the effectiveness of immunotherapy in MB depends on the immunologic differences in MB molecular subgroups. At present, several clinical trials using immunotherapy in MB are ongoing and most of them are at early stages [179]. The main immunebased strategies that are currently considered for treatment of this malignancy and here reviewed include: natural killer (NK) cells, CAR-T therapy, immune checkpoint inhibitors (ICIs), oncolytic viruses.…”

Section: Immunotherapy In Mbmentioning

confidence: 99%

The SHH/GLI signaling pathway: a therapeutic target for medulloblastoma

Severini

Ghirga

Bufalieri

et al. 2020

Expert Opinion on Therapeutic Targets

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Introduction: Medulloblastoma (MB) is a heterogeneous tumor of the cerebellum that is divided into four main subgroups with distinct molecular and clinical features. Sonic Hedgehog MB (SHH-MB) is the most genetically understood and occurs predominantly in childhood. Current therapies consist of aggressive and non-targeted multimodal approaches that are often ineffective and cause long-term complications. These problems intensify the need to develop molecularly targeted therapies to improve outcome and reduce treatment-related morbidities. In this scenario, Hedgehog (HH) signaling, a developmental pathway whose deregulation is involved in the pathogenesis of several malignancies, has emerged as an attractive druggable pathway for SHH-MB therapy. Areas covered: This review provides an overview of the advancements in the HH antagonist research field. We place an emphasis on Smoothened (SMO) and glioma-associated oncogene homolog (GLI) inhibitors and immunotherapy approaches that are validated in preclinical SHH-MB models and that have therapeutic potential for MB patients. Literature from Pubmed and data reported on ClinicalTrial. gov up to August 2020 were considered. Expert opinion: Extensive-omics analysis has enhanced our knowledge and has transformed the way that MB is studied and managed. The clinical use of SMO antagonists has yet to be determined, however, future GLI inhibitors and multitargeting approaches are promising.

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<p>Immunotherapy for Medulloblastoma: Current Perspectives</p>

Cited by 32 publications

References 147 publications

Identification of an Immunogenic Medulloblastoma-Specific Fusion Involving EPC2 and GULP1

Identification of an Immunogenic Medulloblastoma-Specific Fusion Involving EPC2 and GULP1

Immunotherapy in Medulloblastoma: Current State of Research, Challenges, and Future Perspectives

The SHH/GLI signaling pathway: a therapeutic target for medulloblastoma

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