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Current advances in immunotherapy for atypical teratoid rhabdoid tumor (ATRT).

ABSTRACT: Atypical teratoid rhabdoid tumors (ATRT) are rare and aggressive embryonal tumors of central nervous system that typically affect children younger than 3 years of age. Given the generally poor outcomes of patients with ATRT and the significant toxicities associated with conventional multi-modal therapies, there is an urgent need for more novel approaches to treat ATRT, one such approach being immunotherapy. The recent rise of large-scale, multicenter interdisciplinary studies has delineated several molecular and genetic characteristics unique to ATRT. This review aims to describe currently available data on the tumor immune microenvironment of ATRT and its specific subtypes and to summarize the emerging clinical and preclinical results of immunotherapy-based approaches. It will also highlight the evolving knowledge of epigenetics on immunomodulation in this epigenetically influenced tumor, which may help guide the development of effective immunotherapeutic approaches in the future.

SUBMITTER: Tran S

PROVIDER: S-EPMC10346396 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Current advances in immunotherapy for atypical teratoid rhabdoid tumor (ATRT).

Tran Son S Plant-Fox Ashley S AS Chi Susan N SN Narendran Aru A

Neuro-oncology practice 20230128 4

Atypical teratoid rhabdoid tumors (ATRT) are rare and aggressive embryonal tumors of central nervous system that typically affect children younger than 3 years of age. Given the generally poor outcomes of patients with ATRT and the significant toxicities associated with conventional multi-modal therapies, there is an urgent need for more novel approaches to treat ATRT, one such approach being immunotherapy. The recent rise of large-scale, multicenter interdisciplinary studies has delineated seve ...[more]

PMID: 37457224

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Project description:Abstract Brain tumor diagnostics is achieved by combining morphology assessment and biomarker identification. However, the inter-observer variability of the histopathological diagnosis and lack of distinctive biomarkers makes these diagnoses particularly challenging. Recently, the potential for methylation-based characterization has been developed for brain tumors. To provide accurate and efficient brain tumor diagnostics, The Jackson Laboratory developed a DNA methylation array (Illumina Infinium HD Methylation EPIC), combining the “Classifier” established by the German Cancer Research Center (DKFZ), which can identify 82 distinct central nervous system tumors. Here we present a pediatric patient referred to us for medulloblastoma subtype classification by the methylation profile. Surprisingly, the array classified the tumor type as atypical teratoid/rhabdoid tumor (ATRT), subclass SHH. Also, the CNV profile indicated the SMARCB1/INI1 heterozygous deletion as part of the chromosome 22q deletion typically seen in ATRT, and absent was the isochromosome 17q commonly associated with medulloblastoma. Immunohistochemistry confirmed the loss of SMARCB1/INI1 expression leading to ATRT. Additionally, our NGS panel found a novel SMARCB1/INI1 frameshift variant c.1150delG (p.Ala384fs) in the last exon (exon 9). Although this variant is not expected to induce nonsense-mediated mRNA decay, it is located in the ATP-dependent nucleosome-remodeling complex domain Sfh1/SNF5 (IPR017393), which is associated with cell proliferation and differentiation. In addition, ClinVar reported several pathogenic/likely pathogenic variants in this domain, further supporting SMARCB1/INI1 c.1150delG which, together with the SMARCB1/INI1 deletion, may contribute to the loss of SMARCB1/INI1 expression, resulting in ATRT. We have identified the ATRT misclassification by the methylation profile and characterized a novel SMARCB1/INI1 variant c.1150delG most likely contributing to ATRT. We further propose that the DNA methylation profile will significantly improve the brain tumor diagnostics for cases with ambiguous, or contradictory histology and molecular profiles.

Project description:BACKGROUND: To describe therapeutic approaches in children with atypical Teratoid Rhabdoid Tumours (ATRT) in France. METHODS: Observational study including all children less than 18 years old diagnosed with ATRT in France between 2009 and 2011. RESULTS: Forty seven children were included in this retrospective study. Six patients received no curative treatment while forty-one patients had a curative project. Median age was 1.5 years (range 0-16). The disease was disseminated in 10 patients. Surgical resection was complete in 21 cases. Chemotherapy was administered in 41 children. Twenty-six patients received upfront Vincristine-Methotrexate (5g/m2 x 3) with intra-thecal Methotrexate, which was stopped in eleven patients: in four cases the disease progressed and in seven cases the toxicities were manageable. Fifteen children received different chemotherapy courses and in four of them the diseases progressed. Eight patients underwent second-look surgery. Radiotherapy was administered in 17 patients at a median time of 19 weeks (13-44) after diagnosis. High-dose chemotherapy (HDCT) was given in 9 children and maintenance therapy in 5 children, starting at respectively 35 and 42 weeks after diagnosis. Median follow-up was 26 months (0.6-47). Median time for progression was 5 months. Two-years overall survival was 32% + /-8%. Median survival was 8 months. DISCUSSION: The survival rate of children with ATRT remains poor, the addition of VM is easily manageable but its benefit remains uncertain. The disease progressed mostly before radiotherapy. Future trials should focus on the delay of radiotherapy and the benefit of HDCT. Because ATRT is a rare disease of infancy carrying grim prognosis, focus on long term outcome, especially neurocognitive remain very limited. With the new era of multimodality therapy, some patients are now long term survivors. We reviewed the neuropsychological (NP) status of the survivors from the Canadian ATRT registry. Among patients diagnosed between 1995-2012, 16/72 were survivors (22%). Formal NP assessments were available in 7 patients. Four patients could not be tested (3 too young, 1 blind significantly impaired, 1 lost to follow up). Additionally 1 patient was in special education class (grade 12), one received educational assistance (grade 8), one meet academic expectation (grade 4). Data on last survivor is pending. For the 7 patients with comprehensive NP, the median age at diagnosis was 28.2 months (11.2-60.7). Four tumors were infratentorial and 3 were metastatic. Four patients underwent complete resection. All patients received post operative sequential high dose chemotherapy (Carpoplatin/Thiotepa). Five patients received intrathecal chemotherapy. Two patients underwent radiation (1focal, 1CSI). Median age at time of NP was 7.3 years (3.9-9.28). Full Scale Intellectual Quotient (FSIQ) ranged from 60 to 119 (median = 71). Simple expressive and receptive language appeared relatively preserved (low average to superior). Three most recently diagnosed patients assessed at a median time of 2.6 years (2.6-4.7) from diagnosis had average to high average scores for FSIQ, academic and visual spatial skills, visual and verbal memory. Four other diagnosed earlier tested at a median time of 5.1 years (3.3-8.3) post-diagnosis had a FSIQ ranging from 60 to 71 (median = 68). Approximately 50% of their scores were in the impaired range. Whether these findings suggest further decline overtime or reflect improvement in overall management of these recently diagnosed patients remain unclear. Nevertheless this cohort of infants appears significantly impaired at school age despite the absence of systematic radiotherapy. Larger series focusing on neurocognition are definitely needed before embracing adjuvant radiotherapy as standard of care.

Project description:Abstract Novel therapies are needed to for the treatment of atypical teratoid/rhabdoid tumor (ATRT), an aggressive brain tumor that predominantly affects young children and has an average 5-year survival under 50%. Claudin-6 (CLDN6) is a tight junction protein present during development and is expressed in up to 70% of ATRT specimens but not in normal tissue, making it a promising immunotherapeutic target. CLDN6-targeted chimeric antigen receptor (CAR) T cells in combination with a CAR T cell-amplifying mRNA vaccine have demonstrated antitumor activity against other CLDN6-expressing cancers in pre-clinical and a phase I adult trial (NCT04503278; Haanen J et al AACR, 2022). To assess the effectiveness of CLDN6-targeted CAR T cells against ATRT, we utilized a second-generation mRNA CAR with a 4-1BB costimulatory domain and single-chain variable fragment against CLDN6 (Reinhard et al, 2020). CLDN6 expression in patient-derived ATRT specimens was profiled by RNAseq (mean FPKM 11.4) and immunohistochemistry (positive staining in 53% of specimens). Tumor-derived cell lines were assessed for CLDN6 expression by flow cytometry. Co-culture of CLDN6-directed mRNA CAR T cells resulted in tumor-specific cytotoxicity compared to CD19-directed control CAR T cells in CLDN6-positive ATRT cell lines 7316-2187 (92% versus 15% at 10:1, p < 0.0001; 86% versus 0% at 5:1, p<0.0001) and 7316-2141 (75% versus 7% at 10:1, p<0.0001; 53% versus 0% at 5:1, p< 0.0001). Patient-derived, orthotopic xenograft ATRT models were created through intracranial injection of tumor cells into the cerebellum of NSG mice. Following engraftment with 7316-2141, repeated intratumoral administration of mRNA CLDN6 CAR T cells resulted in significant tumor regression (-1.9x108 vs. +2.4x109 p/sec/cm2/sr, p<0.001) and improved survival compared to mRNA CD19 CAR T cells (median OS not reached vs. 13 days, p=0.002). This work highlights the potential for targeting CLDN6 via CAR T cell therapy in patients with ATRT as a novel therapeutic strategy.

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Current advances in immunotherapy for atypical teratoid rhabdoid tumor (ATRT).

Publications

Current advances in immunotherapy for atypical teratoid rhabdoid tumor (ATRT).

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