RARE DISEASE
Rhabdoid tumor
Rhabdoid tumor
Rhabdoid tumor
Synonyms: Malignant rhabdoid tumor
Synonyms: Malignant rhabdoid tumor
Synonyms: Malignant rhabdoid tumor
Drug discovery
3
drugs
With orphan designations
Overview
Rhabdoid tumor is a rare, highly aggressive malignancy primarily affecting infants and young children, with peak incidence under age 4 [1][4][12]. These tumors most commonly arise in the CNS (atypical teratoid rhabdoid tumors, ATRT), kidneys (malignant rhabdoid tumors, MRT), or soft tissues [1][6][17]. Over 90% involve biallelic SMARCB1 inactivation, disrupting chromatin remodeling and driving epigenetic dysregulation [1][8][19]. Prognosis remains poor despite multimodal therapy, with survival rates heavily influenced by age and primary site [4][12][16].
Burden
Therapies
Multimodal approach: Maximal safe resection + intensive chemotherapy (vincristine, cyclophosphamide, cisplatin/etoposide) + age-adjusted radiotherapy [1][3][13]
High-dose chemotherapy with autologous stem cell rescue for consolidation [1][3][5]
Protocols: COG ACNS0333 (surgery → chemo → HDCT) vs. Eu-Rhab (anthracycline-based regimens + early RT) [1][3][5]
Categories: rare neoplastic diseases
Research Papers
1,021 drug discovery papers about Rhabdoid tumor, with 8 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,021 drug discovery papers about Rhabdoid tumor, with 8 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-24 | Preclinical evaluation of ixazomib for high-risk pediatric brain tumors.
Many of the highest risk pediatric brain cancers continue to experience poor clinical outcomes despite intensification of current multimodal therapy. Proteasome inhibition has shown preclinical promise across a range of cancer models including diffuse midline glioma (DMG), medulloblastoma, and atypical teratoid / rhabdoid tumors (ATRT), though clinically viable agents have been limited. Recent studies in adults with glioblastoma suggest that ixazomib, a second-generation proteasome inhibitor, might achieve therapeutic concentrations in the CNS, presenting the opportunity that a CNS penetrant proteasome inhibitor might be similarly leveraged for benefit in childhood brain cancers. Ixazomib was tested against cell lines and orthotopic xenograft models of DMG, Myc-amplified medulloblastoma (Myc-MB), and ATRT. RNA sequencing and LC-MS based proteomics were utilized to define functional consequences of ixazomib treatment in these models. Proteasome activity readouts were used to assess ixazomib activity across brain regions and extracranial solid organs. Ixazomib demonstrates consistent cytotoxic effect across high-risk brain tumor models at low nanomolar concentrations. Ixazomib treatment activates proteostatic stress response and apoptosis. Treatment with ixazomib does not demonstrate survival benefit in orthotopic models, however, and pharmacodynamic testing suggests insufficient inhibition of proteasome activity within the CNS compared to extracranial tissues. While many pediatric brain tumor models demonstrate susceptibility to proteasome inhibition, ixazomib may lack sufficient blood-brain barrier penetration to be a translationally viable means of exploiting this vulnerability.
2026-09-24 | A PDGFRB-CD44-MIF crosstalk promotes cancer-associated cellular phenotypes in ATRT-TYR/MYC cell lines.
Atypical teratoid/rhabdoid tumor (ATRT) is the most common brain tumor in children less than one-year-old. Previous studies have identified three epigenetic subgroups of ATRT: ATRT-SHH, ATRT-TYR, and ATRT-MYC. Interestingly, it was found that ATRT-TYR/MYC (mesenchymal) subgroups are sensitive to receptor-tyrosine kinase inhibitors (RTKIs), particularly those that inhibit the platelet-derived growth factor receptor B (PDGFRB), highlighting the importance of PDGF signaling in ATRTs. In addition, the ATRT-TYR/MYC subgroups show upregulation of the macrophage migration inhibitory factor (MIF), with dysregulation of the MIF signaling pathway, which was found to have immunosuppressive effects in other cancers. While PDGF and MIF pathways have been found to promote tumorigenesis of other cancers including glioma, their roles in ATRTs remain unknown. We hypothesized that PDGF and MIF signaling pathways contribute to maintaining malignant phenotypes in ATRT-TYR/MYC subgroups. To test this hypothesis, our project aimed to characterize PDGF signaling and investigate PDGF-MIF crosstalk in ATRT-TYR/MYC subgroups, using CRISPR/Cas9 stable knockouts (KOs) of various PDGF receptor and ligands. We have shown that the PDGF pathway primarily promotes maintenance of malignant phenotypes in ATRT-TYR/MYC via modulation of the cell cycle. Furthermore, our studies reveal a plausible PDGFRB, MIF, and CD44 oncogenic signaling axis, that could modulate invasion and cellular phenotypic plasticity in ATRT-TYR/MYC, via regulation of neural stemness and epithelial-mesenchymal transition (EMT) marker expression. Our collective study findings point to an important role for PDGFRB-MIF-CD44 signaling in the maintenance of malignant cellular phenotypes in ATRT-TYR/MYC cell lines.
2026-09-16 | A Phase Ib Case Series Using Bortezomib With Chemotherapy in Atypical Teratoid/Rhabdoid Tumors.
Atypical teratoid/rhabdoid tumors (ATRTs) are aggressive pediatric brain tumors that are sensitive to proteasome inhibitors in preclinical models. We evaluated the feasibility of combining the proteasome inhibitor, bortezomib, with chemotherapy. Six patients aged 0.8-13 years with newly diagnosed ATRT were enrolled from January 2022 through December 2023. Bortezomib was given intravenously at the dose of 1.3 mg/m2/day on days 1, 4, 8, and 11 of a 21-day chemotherapy cycle for 6 cycles. Radiation therapy was given before initiation of chemotherapy in 4 patients or at the end of chemotherapy in one patient. The primary endpoint was grade 3 or higher non-hematologic toxicities. Thirty cycles of bortezomib with chemotherapy were evaluated. No grade 3 or higher toxicities were considered bortezomib-related. Four patients completed 6 cycles of bortezomib; 2 patients discontinued treatment due to progressive disease after 2 and 4 cycles, respectively. An additional 6 cycles of bortezomib were evaluated after high-dose chemotherapy in three patients without grade 4 bortezomib-related toxicity. Five patients had a near-total resection; one patient had a subtotal resection. Four patients were evaluable for response with 2 partial responses, 1 stable disease, and 1 progressive disease. Two patients without measurable tumor after surgery were not evaluable for response. Two patients remain alive without disease at 37 and 40 months, and one patient died without disease at 19 months after diagnosis. Three patients died with progressive disease. The toxicities were no more than expected with chemotherapy alone. Adding bortezomib to treatment of ATRT is feasible. NCT06853080.
2026-09-15 | Sometimes, More is Less in Atypical Teratoid Rhabdoid Tumor (ATRT): The Risks of Maintenance Intrathecal Chemotherapy.
Atypical Teratoid Rhabdoid Tumors (ATRT) are rare and aggressive pediatric brain tumors, and lack of consensus exists regarding optimal therapy. Some physicians recommend maintenance intrathecal chemotherapy, extrapolating from the salvage setting where it has been reported to promote remission. However, the risks of this therapy may be underappreciated. Here we present a case of a young patient with ATRT who received consolidation intrathecal chemotherapy following the ACNS 0333 regimen (resection, induction chemotherapy, high-dose chemotherapy with stem cell rescue, and radiotherapy) and developed life-altering neurologic sequelae. In the absence of clear benefit, we recommend against routine maintenance intrathecal chemotherapy.
2026-08-29 | Pediatrics supratentorial intraventricular atypical teratoid/rhabdoid tumors: a case report and a systematic review of the literature.
Atypical teratoid/rhabdoid tumors (AT/RTs) are rare, highly aggressive World Health Organization grade 4 brain tumors associated with early cerebrospinal fluid dissemination (CSF). AT/RTs typically occur in children under 4 years of age however, can also occur in adults and often carry a poor prognosis. These tumors are exceptionally uncommon, with evidence limited to isolated case reports. We illustrate a case of hemorrhagic left lateral ventricular AT/RT in a 5-year-old boy and systematically synthesize global literature evaluating clinical presentations, therapeutic interventions, and survival outcomes of primary supratentorial intraventricular AT/RT. Systematic searches were executed across PubMed, Embase, and Scopus databases up to 31 May 2026. Studies tracking histologically or immunohistochemically confirmed pediatric intraventricular AT/RT were included. Study quality was evaluated qualitatively via Joanna Briggs Institute tools; qualitative descriptive analysis synthesized outcomes, supplemented by post hoc stratified subgroup analysis. Twenty-four descriptive, uncontrolled studies comprising 28 pediatric patients (mean age: 3.9 years) were synthesized. The lateral ventricle was the primary epicenter (53.5%). Surgical resection margins were divided between gross total resection (GTR; 64.2%), subtotal resection (STR 17.8%), and biopsy (7.1%). The cohort demonstrated a 43.0% disease progression rate and a 69.6% (16/23) overall mortality rate among patients with follow up. Descriptive subgroup analysis demonstrated a comparable high mortality across age groups and tumor locations, whereas mortality was highest among patients with metastatic disease and appeared lower after GTR than STR 33.3% (6/18) vs. 80.0% (4/5). High risk of publication bias and inconsistent longitudinal tracking limit the evidence. Supratentorial intraventricular AT/RT exhibits high recurrence risks, but GTR combined with modern risk-adapted adjuvant protocols optimizes survival. Establishing international multi-institutional registries remains critical. • Atypical teratoid/rhabdoid tumors (AT/RTs) are rare, highly aggressive pediatric central nervous system tumors characterized by early cerebrospinal fluid dissemination (CSF) which carry a poor survival rate. While AT/RTs typically arise in the posterior fossa, primary supratentorial intraventricular tumors are rare, and current evidence is limited to isolated case reports and case series. • This study provides the largest qualitative synthesis of pediatric supratentorial intraventricular AT/RTs reported to date. The accompanying case is notable for its hemorrhagic lateral ventricular presentation causing obstructive hydrocephalus, diffuse leptomeningeal dissemination at diagnosis (M3 disease) with rapid clinical progression highlighting the aggressive behavior and surgical challenges associated with this rare tumor subtype.
gene therapies
2026-06-26 | Development of a Genetically Engineered Porcine Model of Rhabdoid Tumor Predisposition Syndrome Type 1 (RTPS-1).
Background and Objectives: Among CNS malignancies arising in infancy, ATRT stands out as the most frequently diagnosed in children younger than six months. Disruption of the SMARCB1 gene underlies the overwhelming majority of cases. Progress toward effective treatment has been hampered by two persistent challenges. Current mouse models, while informative, fall short of reproducing the full clinical and biological picture of human ATRT, and their ability to predict therapeutic outcomes in patients remains uncertain. Compounding this, the rarity of the disease makes it difficult to assemble patient cohorts of sufficient size for meaningful clinical trials. At the molecular level, germline loss of SMARCB1 exons 4 and 5 has emerged as a particularly penetrant predisposing event, with affected individuals presenting at an earlier age than those harboring other mutation types. The porcine SMARCB1 gene offers a compelling basis for translational modeling as its protein product is identical to the human ortholog at every amino acid position across isoforms, a degree of conservation that exceeds what is seen in the mouse. Methods: Thus, we hypothesized that germline deletion of exons 4 and 5 would predispose heterozygote swine to ATRT development. In this manuscript, we describe the creation of an ATRT porcine model through a CRISPR/Cas9 mediated gene-editing approach. Results: 15 piglets were produced, two of which had confirmed SMARCB1 targeted excisions. However, none developed tumors. To induce further tumorigenicity, one pig with confirmed exons 4 and 5 excision was crossed with a pig with TP53 exon 2 truncation. In total, 11 piglets were born, of which one contained the original excision without a TP53 mutation. This piglet developed a spinal mass at the T1 level. Conclusion: To our knowledge, this is the first ATRT porcine model ever developed and provides proof-of-concept feasibility for large animal modeling of SMARCB1-deficient rhabdoid tumors. These findings support the continued development of porcine RTPS-1 models toward preclinical application.
2026-06-23 | ID #753 ESTABLISHMENT OF A HIGH-FIDELITY SYNGENEIC MODEL FOR ATYPICAL TERATOID/RHABDOID TUMOR (AT/RT) RESEARCH
Abstract Atypical Teratoid/Rhabdoid Tumor (AT/RT) is the most common malignant brain tumor in infants <3 years, representing 10–15% of pediatric CNS malignancies. This lethal embryonic tumor is driven by biallelic inactivation of the chromatin-remodeling gene Smarcb1. Despite aggressive multimodal therapy (surgery, chemotherapy, radiotherapy), median overall survival remains <12 months. Current AT/RT research relies heavily on immunodeficient xenograft models, which fail to recapitulate the tumor microenvironment (TME) and cannot adequately evaluate immunotherapeutic strategies. Syngeneic immunocompetent models are essential for understanding TME composition and immune dynamics critical to developing next-generation treatments. Spontaneous AT/RT tumors were generated in an inducible Smarcb1fl/fl;Rosa26-CreERT2 mouse model (tamoxifen induction at E6–E7, Han et al., 2016) by Franck Bourdeaut’s laboratory at Institut Curie, Paris. Tumor explants were established as a stable syngeneic cell line and implanted orthotopically using the guide screw method into immunocompetent C57BL/6 hosts. Tumors were characterized by: (i) immunohistochemistry and western confirming biallelic SMARCB1 loss; (ii) in vivo growth kinetics and survival curves; and (iii) single-cell RNA sequencing (scRNA-seq) of tumor and immune compartments. The established cell line demonstrated 100% penetrance with aggressive growth kinetics. ScRNA-seq analysis revealed a macrophage-dominant tumor microenvironment (72% of immune infiltrate), with T-cell exhaustion markers (PD1+, TIM3+) and minimal lymphocyte infiltration. Notably, this immune phenotype closely mirrors observations in human AT/RT patient samples, establishing our model as a high-fidelity platform. This immunocompetent syngeneic AT/RT model recapitulates human disease immune architecture and provides a robust platform for studying tumor-immune interactions and evaluating immunotherapeutic strategies, including oncolytic virotherapy, checkpoint modulation, and adoptive cell therapies. This model will accelerate clinical translation of promising approaches for this uniformly fatal pediatric malignancy.
2025-10-01 | Figure S3 from A Novel Conditionally Replicative Oncolytic Adenovirus under the Control of the <i>SALL4</i> Promoter Inhibits the Growth of Rhabdoid Tumors
<p>Figure S3 shows expression of <i>CLDN6</i> and <i>USP44</i> mRNA in RT cell lines</p>
2025-10-01 | Figure S1 from A Novel Conditionally Replicative Oncolytic Adenovirus under the Control of the <i>SALL4</i> Promoter Inhibits the Growth of Rhabdoid Tumors
<p>Figure S1 shows Map of the <i>SALL4 </i>promoter (pSALL4) region in human and structure of pSALL4-OAd.</p>
2025-10-01 | Data from A Novel Conditionally Replicative Oncolytic Adenovirus under the Control of the <i>SALL4</i> Promoter Inhibits the Growth of Rhabdoid Tumors
<div>Abstract<p>Rhabdoid tumors (RT) are highly aggressive pediatric malignancies with limited treatment options. <i>SALL4</i>, a gene essential for embryonic stem cell pluripotency and self-renewal, is frequently overexpressed in RTs. To exploit this, we developed a conditionally replicating oncolytic adenovirus (pSALL4-OAd) by placing the E1 region under the control of the <i>SALL4</i> promoter, restricting viral replication to SALL4-positive cells. SALL4 protein expression was analyzed in 10 clinical RT specimens via IHC, whereas <i>SALL4</i> mRNA levels and promoter activity were assessed in eight RT cell lines using qPCR and dual-luciferase assays. The replication selectivity and cytopathic effects of pSALL4-OAd were tested <i>in vitro</i> at doses of 0 to 1,000 viral particles/cell. <i>In vivo</i>, 1.0 × 10<sup>7</sup> G401 cells were implanted subcutaneously into immunodeficient mice, followed by intratumoral administration of pSALL4-OAd (3 × 10<sup>10</sup> viral particles) or PBS. Tumor growth was monitored over the treatment period. SALL4 protein was detected in 40% of clinical RT specimens, and RT cell lines exhibited four- to 400-fold higher <i>SALL4</i> mRNA levels compared with normal tissues. Elevated <i>SALL4</i> promoter activity was confirmed in three of five RT cell lines. pSALL4-OAd selectively replicated in SALL4-positive cells and induced significant cytopathic effects proportional to promoter activity <i>in vitro</i>. <i>In vivo</i>, pSALL4-OAd administration caused tumor necrosis, reduced SALL4-positive cells, and suppressed tumor proliferation. These results demonstrate the potential of pSALL4-OAd as a targeted and effective therapeutic strategy for SALL4-expressing RTs.</p></div>
antibodies
2026-06-03 | Spatial dissection of ADC/RPT targets defines heterogeneous expression landscapes and therapeutic implications in rhabdoid tumors.
Rhabdoid tumors (RT) are among the most aggressive pediatric malignancies, characterized by early onset in life, loss of SWI/SNF complex members (SMARCB1 or SMARCA4), and dismal outcomes despite multimodal therapy. Refractory and relapsing RT remain almost uniformly fatal, and targeted or immune-based approaches have yet to demonstrate clinical benefit. To explore novel therapeutic vulnerabilities, we systematically investigated the expression of clinically actionable surface proteins that could serve as targets for antibody-drug conjugates (ADCs), radiopharmaceutical therapy (RPT), or cellular immunotherapies. Based on large-scale transcriptomic analyses, we prioritized FAP (fibroblast activation protein), CXCR4 (chemokine receptor 4), and IL13RA2 (interleukin receptor 13 RA2) and performed comprehensive protein-level validation by immunohistochemistry in an unprecedented cohort of 60 rhabdoid tumors spanning all molecular subgroups (ATRT-TYR, ATRT-SHH, ATRT-MYC and eMRT). Integrating these data with spatial and single-nucleus transcriptomic profiling, we identified subgroup- and cell-type-specific expression patterns, including heterogeneous FAP distribution between stromal and tumor compartments and a distinct IL13RA2-positive rhabdoid cell population with melanosomal and stem-like features: Overall 51/60 tumors demonstrated positivity, defined as immunohistochemical H-score above or at least equal to 10, for FAP in the stroma and 34/60 tumors for CXCR4, indicating that a substantial fraction of rhabdoid tumors may be amenable to targeted therapies directed against these epitopes. These findings define a set of biologically and clinically relevant surface targets in RT and provide a translational blueprint for rational ADC and RPT target development in pediatric cancer.
2026-05-27 | Spatial multiomic profiling to identify de-differentiated tumor phenotypes and exhausted T cell niches in rhabdoid and sarcomatoid RCC.
4557 Background: Rhabdoid and sarcomatoid (S/R) differentiation are high-grade dedifferentiated states that can arise across renal cell carcinoma (RCC) subtypes. Although associated with poor patient prognosis, S/R RCC paradoxically exhibits increased sensitivity to immune checkpoint blockade. The mechanisms underlying this aggressive, yet immunotherapy-responsive phenotype remain unclear. Spatial multi-omic profiling offers a powerful framework to interrogate tumor-intrinsic and microenvironmental programs that account for this phenotype. Here, we applied spatial multi-omic analyses to treatment-naïve clear cell RCC specimens from seven patients, enabling direct comparison of sarcomatoid, rhabdoid, and clear cell regions captured within the same tissue sections. Methods: Hematoxylin and eosin (H&E)–stained sections from seven FFPE patient samples were reviewed and annotated by a genitourinary pathologist to identify discrete regions of sarcomatoid, rhabdoid, or clear cell morphology. Annotated FFPE samples were processed by Singular Genomics using the G4X spatial multi-omic platform, which enables quantification of 315 RNA transcripts, 14 protein targets, and fluorescent H&E imaging. Results: Initial spatial multi-omic profiling resolved distinct tumor regions with clear cell biology alongside areas exhibiting rhabdoid or sarcomatoid features. Comparative analysis of immune infiltrates across these regions revealed enrichment of both T cells and B cells within rhabdoid regions. In addition, T cells localized to rhabdoid and sarcomatoid regions displayed distinct phenotypic states compared with those in clear cell regions. Differential gene expression (DGE) analysis of T cells from rhabdoid and sarcomatoid regions relative to clear cell RCC demonstrated upregulation of activation markers ( CD69 , IL2RA ), exhaustion markers ( LAG3 , PDCD1 ), and cytotoxic genes ( GZMA , GZMK , NKG7 ). Parallel analysis of tumor cell transcriptional programs further highlighted distinct tumor biology across histologic regions. Sarcomatoid tumor cells exhibited increased expression of genes associated with cellular stress, inflammation, and epithelial–mesenchymal transition (EMT), including IGFBP7 and FOS . In contrast, rhabdoid tumor cells showed upregulation of antigen-presentation machinery ( HLA-A , TAP1/2 ) along with elevated expression of EMT-associated genes ( MET , VCAM1 , and CD44) . Conclusions: Spatial multi-omic analysis of S/R RCC revealed distinct immune and transcriptional programs across sarcomatoid, rhabdoid and clear cell regions. T cells within S/R regions exhibited activated and exhausted phenotypes, while tumor cell characterization of S/R cells reveals upregulation of stress, inflammatory and antigen-presentation machinery, features that may underlie the sensitivity of S/R RCC to immune checkpoint inhibitors.
2026-05-18 | Claudin-6 Protein Expression in Atypical Teratoid/Rhabdoid Tumors Is Strongly Enriched in the Molecular Subgroup AT/RT-TYR.
Claudin-6 has emerged as a promising immunotherapeutic target, yet protein-level data in atypical teratoid/rhabdoid tumors (AT/RTs) have been inconsistent. We analyzed 36 well-characterized AT/RT samples and found membranous claudin-6 protein expression in 58% of cases, with striking enrichment in the molecular subgroup AT/RT-TYR (100%) and significantly higher staining scores compared with AT/RT-SHH and AT/RT-MYC. Correspondingly, AT/RT-TYR showed lower CLDN6 promoter methylation. Pilot spatial transcriptomic experiments in AT/RT-TYR confirmed heterogeneous CLDN6 transcription, and co-expression analyses linked CLDN6 to epithelial-mesenchymal transition-related genes. These findings clarify subgroup-specific expression patterns and support claudin-6 as a biologically and therapeutically relevant target in AT/RT-TYR.
2026-04-27 | Atypical Teratoid/Rhabdoid Tumor of the Lateral Ventricle: A Case Series and Experience with Molecular Subtyping-Guided Immunotherapy.
Atypical teratoid/rhabdoid tumors (AT/RT) are rare, highly aggressive pediatric central nervous system (CNS) malignancies. AT/RT of the lateral ventricle is an exceptionally rare subgroup, with only 11 reported cases. SMARCB1 inactivation is the primary molecular feature of AT/RT. Current consensus is to classify AT/RT based on methylation and molecular profiles into the following subgroups: AT/RT-TYR, AT/RT-SHH, AT/RT-MYC, and a potentially distinct SMARCA4-deficient subtype. AT/RT-MYC exhibits high levels of CD8+ tumor-infiltrating lymphocytes, indicating immunogenic potential. We report three pediatric cases presenting with intracranial hypertension and seizures. Diagnosis was confirmed via histopathology and molecular profiling. Interventions included gross total resection, chemotherapy, radiotherapy, and combined immune checkpoint inhibitors (pembrolizumab and ipilimumab). Outcomes varied from rapid progression to 3-year recurrence-free survival. A cohort of 14 pediatric patients with lateral ventricle AT/RT, comprising 3 institutional cases and 11 cases identified from the PubMed database, was evaluated through a narrative synthesis. These advancements highlight the crucial role of molecular subtyping in tailoring personalized treatments, including epigenetic modifiers and immune-based regimens. However, clinical validation is essential to establish standardized protocols. Integrating genomic, epigenetic, and immune microenvironment profiling may enhance risk assessment and treatment precision, ultimately improving survival and quality of life in pediatric patients.
2026-04-22 | Compartment-specific immune and tumor markers associated with clinical outcomes in patients with and without sarcomatoid/rhabdoid renal cell carcinoma treated with ipilimumab and nivolumab.
Immune checkpoint inhibition with ipilimumab and nivolumab prolongs survival in renal cell carcinoma (RCC). Tumors with sarcomatoid and/or rhabdoid features are considered responsive to immune checkpoint inhibitors (ICIs), despite their aggressive nature. Although sarcomatoid/rhabdoid dedifferentiation is not considered a distinct subtype of RCC, these tumors differ clinically and molecularly from nonsarcomatoid/rhabdoid RCC tumors. We sought to identify biomarkers underlying responsiveness to ICIs and compare the immune microenvironments of tumors with or without sarcomatoid/rhabdoid components. We constructed a tissue microarray from archived RCC tumors collected from patients treated with first-line ipilimumab and nivolumab. Digital spatial profiling was carried out using NanoString's GeoMx platform with a panel of 58 proteins. Regions of interest were segmented into immune [cluster of differentiation (CD)68+ and CD45+] and tumor [positive for both cytokeratin and carbonic anhydrase 9 (CAIX+ CK+)] compartments. To investigate marker expression in tumors with and without sarcomatoid/rhabdoid dedifferentiation, two additional tissue microarrays were analyzed, comprising cohorts of patients treated with heterogeneous first-line therapies. Key findings were validated by immunohistochemistry. After quality control, 44 pretreatment tumors from 44 patients were analyzed. Tumor programmed death-ligand 1 (PD-L1) expression was higher in responders (P = 0.03) and associated with improved progression-free survival [PFS; hazard ratio (HR) 0.4, 95% confidence interval (CI) 0.2-0.8, P = 0.01] and overall survival (OS; HR 0.2, 95% CI 0.06-0.5, P < 0.005) on multivariable analysis. This finding was confirmed by immunohistochemistry. In the CD45+ compartment of sarcomatoid/rhabdoid tumors, CD25 expression was associated with worse PFS (HR 58.8, 95% CI 2.8-1250, P = 0.01). Differential expression analysis showed higher CD66b in sarcomatoid/rhabdoid tumors (log2 fold change = 2.2, P < 0.001), validated by immunohistochemistry with significantly higher myeloperoxidase (MPO) staining (χ2 = 15.7, df = 3, P < 0.001). Tumor PD-L1 is associated with better PFS and OS after ipilimumab + nivolumab. In the sarcomatoid/rhabdoid subset, lower CD25 (a marker of regulatory T cells) was associated with improved PFS, while increased neutrophil infiltration (CD66b+/MPO+) emerged as a novel feature of sarcomatoid/rhabdoid tumors, which may be harnessed for therapeutic benefit in this population.
cell therapies
2026-09-22 | Abstract A002: Epigenetic Regulation of the GDF15 Immune Checkpoint Determines Sensitivity of Atypical Teratoid/Rhabdoid Tumors to Natural Killer Cell Immunotherapy
Abstract Atypical teratoid/rhabdoid tumors (ATRTs) are highly aggressive pediatric central nervous system malignancies characterized by poor clinical outcomes despite intensive multimodal therapy, including surgery, chemotherapy, and radiation. Although molecular classification has improved our understanding of ATRT biology, these advances have not yet translated into effective therapies for patients. Here, we investigated natural killer (NK) cell-based immunotherapy as a novel therapeutic strategy for ATRTs and identified subgroup-specific differences in tumor sensitivity to NK cell-mediated cytotoxicity driven by variable expression of the immunomodulatory cytokine - growth and differentiation factor 15 (GDF15). ATRTs are almost universally defined by loss of SMARCB1, a core component of the ATP-dependent SWI/SNF chromatin-remodeling complex, resulting in widespread dysregulation of lineage-specific enhancers. Through integrated multi-omic analyses of patient tumors and ATRT cell lines, including RNA-seq, ATAC-seq, DNA methylation profiling, ChIP-seq, and chromatin conformation capture (3C) assays, we identified subgroup-specific differences in the epigenetic regulation of the GDF15 locus. Differential DNA methylation at the GDF15 promoter, distinct histone modification patterns at both the promoter and a previously unrecognized upstream enhancer, and long-range promoter-enhancer interactions collectively contributed to subgroup-dependent variability in GDF15 expression. Mechanistically, DNA methylation-dependent chromatin occupancy by two antagonistic regulatory proteins, RE1-silencing transcription factor (REST) and CCCTC-binding factor (CTCF), governed the epigenetic architecture of the GDF15 locus. REST-mediated displacement of CTCF silenced GDF15 expression and overcame tumor-mediated suppression of NK cell function. Genetic disruption of this regulatory axis, as well as blockade of GDF15 with neutralizing antibodies, reversed NK cell suppression in vitro and significantly enhanced NK cell-mediated antitumor activity in orthotopic intracranial ATRT models. Collectively, these findings reveal a novel epigenetic mechanism regulating immune evasion in ATRTs. GDF15 represents a therapeutically actionable immune checkpoint and its combination with NK cell-based immunotherapy could offer a promising treatment strategy for subsets of patients with ATRTs and other GDF15-expressing brain tumors. Citation Format: Vidya Gopalakrishnan, Jyothishmathi Swaminathan, Ben Ho, Donghang Cheng, Lei Guo, Shu Feng, Ashutosh Singh, Yanwen Yang, Swarnalatha Manickavinayaham, Arianna Anjier, Xiaolian Fan, Alvaro Laureano, William Brugmann, Shinji Maegawa, Javiera Bravo Alegria, Bridget Kennis, Tara Dobson, David Sandberg, Laurence Cooper, Soumen Khatua, Lucia Silla, Wafik Zaky, Richard Gorlick, Dean Lee, Marcos Estecio, Abhinav Jain, Nancy Gordon, Najat C. Daw, Lin Xu, Annie Huang. Epigenetic Regulation of the GDF15 Immune Checkpoint Determines Sensitivity of Atypical Teratoid/Rhabdoid Tumors to Natural Killer Cell Immunotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Bridging Discovery and Clinical Impact in Pediatric Cancer; 2026 Sep 22-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_1):Abstract nr A002.
2026-08-11 | Fingerroot-derived nanovesicles attenuate atypical teratoid rhabdoid tumor progression via modulation of Wnt signaling
Atypical teratoid rhabdoid tumor (ATRT) is an aggressive central nervous system tumor that primarily affects young children and has poor prognosis, highlighting the need for new treatment options. In this study, we examined how fingerroot exosome-like nanovesicles (FELNs) derived from Boesenbergia rotunda (L.) Mansf. affect ATRT and investigated their mechanisms of action. FELNs are round vesicles approximately 100 nm in diameter. Fluorescently labeled FELNs were taken up by cells and induced dose- and time-dependent cytotoxicity via apoptosis in ATRT cell lines BT12 and cisplatin-resistant BT16, with minimal effect in normal brain cells. Moreover, non-toxic concentrations of FELNs significantly decreased ATRT cell migration and invasion. Proteomic analysis revealed that FELNs disrupt multiple signaling pathways involved in ATRT development, including the Wnt/β-catenin pathway. FELN treatment reduced β-catenin protein levels and increased GSK-3β activity. It also decreased the expression of target genes, including c-myc, cyclin D1, axin2, and survivin . Overall, our findings demonstrate that FELNs exert anti-cancer effects in ATRT cells by inducing apoptosis and decreasing migration and invasion. These effects are partially mediated through the GSK-3β-dependent β-catenin pathway. The low toxicity in normal cells suggests that FELNs could be promising new therapeutic agents for cancer treatment.
2026-07-27 | Intracerebroventricular B7-H3-targeting CAR T cells for non-pontine DMG and recurrent/refractory pediatric CNS tumors: a phase 1 trial.
High-grade central nervous system (CNS) tumors carry a poor prognosis with limited curative options if first-line therapy fails. B7-H3 is expressed in many of these tumors, and chimeric antigen receptor (CAR) T cell therapy is an emerging immunotherapeutic strategy. BrainChild-03 (NCT04185038) is a single-center, dose-escalation phase 1 study of repeated intracerebroventricular (ICV) B7-H3 CAR T cells in children and young adults with recurrent/refractory CNS tumors (Arms A, B) and diffuse intrinsic pontine glioma (DIPG, Arm C). Here, we report results from Arm B, in which patients with refractory/relapsed CNS tumors or pre- or post-progression non-pontine diffuse midline glioma (DMG) received repeated ICV infusions. Primary objectives were feasibility and safety/tolerability; secondary objectives included CAR T cell detection, disease response, and survival. Of 36 enrolled patients (atypical teratoid rhabdoid tumor n = 5, DMG n = 8, embryonal tumor with multilayer rosettes n = 2, ependymoma n = 4, high-grade glioma n = 6, medulloblastoma n = 8, pineoblastoma n = 3), manufacturing was successful for 35 patients, 26 of whom received therapy. Median age was 10 years (range 1-26). Dose escalation from 1 × 107 to 10 × 107 CAR T cells/dose identified this dose as the maximally tolerated dose regimen, with no dose-limiting toxicities observed. Across 181 total doses (median 7/patient), common adverse events included headache (n = 26), fever (n = 15), and nausea (n = 14). Median survival from first infusion was 11.5 months, ranging from 3.2 months (pineoblastoma, HGG) to 21.4 months (ependymoma); two patients achieved a partial response. Repeated ICV B7-H3 CAR T cell dosing is feasible and tolerable across a spectrum of pediatric CNS tumors, supporting continued investigation in future trials.
2026-04-03 | Abstract 1528: AZD5851, a TGF-β-resistant GPC3 CAR-T cell product, prolongs animal survival times in patient derived orthotopic xenograft models of medulloblastoma and atypical teratoid rhabdoid tumor
Abstract BACKGROUND: Glypican-3 (GPC3) is uniquely expressed and has been associated with the development of several pediatric solid embryonal tumors, making it a prime target for GPC3 CAR-T cell killing. TGF-β, a cytokine associated with immunosuppression, has also been shown to be highly expressed in the microenvironment of these tumors, potentially hindering CAR-T cell antitumor activity. In this study, we examined the therapeutic efficacy of AZD5851, an autologous CAR-T product that expresses a CAR specific for GPC3 and a dominant negative (dn)TGFβRII as an armoring strategy. METHODOLOGY: To assess the drug’s in vivo efficacy, 5 established patient-derived orthotopic xenograft (PDOX) models of pediatric medulloblastoma (ICb-2123MB, -1299MB, -S1129MB), atypical teratoid rhabdoid tumor (IC-L1115ATRT) and a high grade glioma (IC-2664HGG), with confirmed expression of GPC3 and TGF-β through immunohistochemical staining, were treated with untransduced T cells [dosed at 12x106 cells/mouse, intravenously (IV) once] or GPC3 CAR-T cells (dosed at 5x106 cells/mouse, IV once). 20 eight-week-old SCID mice per model received intra-cerebral (IC) or intra-cerebellar (ICb) tumor cell implantation and were divided into 2 treatment groups (n=10 per group): Untransduced T cells and GPC3 CAR-T cells. Animal survival times were analyzed using Gehan-Breslow-Wilcoxon analysis. RESULTS: GPC3 CAR-T cell treatment was well tolerated in mice with no loss of body weight or other toxicities. GPC3 CAR-T cell treatment significantly improved the median survival time in 2/5 models, including ICb-2123MB from 90.5 days in the untransduced T cell group to 162.5 days (P=0.02) and IC-L1115ATRT from 136 days to 174 days (P=0.02). CONCLUSION: Our data identifies single agent antitumor activity for GPC3 CAR-T cells for PDOX models of pediatric medulloblastoma and atypical teratoid rhabdoid tumor. The results support further clinical translational efforts involving the use of AZD5851 alone or in combination with other therapies for the treatment of these tumors. Citation Format: Milagros Suarez, Aalaa Abdallah, Xin Zhai, Zilu Huang, Yuchen Du, Nitin Wadhwani, Alicia Lenzen, Jee Young Kwon, Steven B. Neuhauser, Timothy Stearns, Jeffrey H. Chuang, Emily L. Jocoy, Carol J. Bult, Beverly Teicher, Malcolm A. Smith, Xiao Nan Li. AZD5851, a TGF-β-resistant GPC3 CAR-T cell product, prolongs animal survival times in patient derived orthotopic xenograft models of medulloblastoma and atypical teratoid rhabdoid tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1528.
2026-02-06 | B7-H3-targeted natural killer cells effectively kill atypical teratoid / rhabdoid tumors and extend survival in orthotopic xenografts.
Atypical teratoid/rhabdoid tumors (AT/RTs) are the most common malignant CNS tumor in infants, and patients suffer from low survival rates and treatment-related morbidities. These tumors frequently overexpress the pan-cancer antigen B7-H3 (CD276), which can be targeted with immunotherapy. We hypothesized that adding a B7-H3-targeting cytotoxic chimeric antigen receptor (CAR) to NK cells can enhance killing against AT/RTs. We designed a library of variable affinity B7-H3-targeted CARs, which were transduced into primary healthy donor-derived NK cells. We verified B7-H3 expression in a panel of AT/RT cell lines and further engineered luciferase and nuclear GFP-expressing AT/RT (CHLA-04, CHLA-06, BT12, BT37) as well as a CHLA-06-derived B7-H3 knockout. We tested CAR-NK cell functionality using in vitro co-culture cytotoxicity assays. We delivered anti-B7-H3 CAR-NK cells intratumorally or intracerebroventricularly (ICV) to AT/RT orthotopic xenografts and monitored for tumor growth and animal survival. B7-H3-targeted CAR-NK cells demonstrated target-specific cytotoxicity when compared to unmodified NK cells. Knockout of B7-H3 in target cells abolished the increased CAR-mediated target killing. When delivered intratumorally to CHLA-06 orthotopic xenograft-bearing mice, anti-B7-H3 CAR-NK cells eliminated tumor cells and prolonged survival. When CAR-NK cells were delivered ICV against a CNS disseminated tumor model of BT12, treated mice had significantly improved survival. Anti-B7-H3 CAR-NK cells effectively kill AT/RTs in multiple pre-clinical in vitro and in vivo models in an antigen-specific manner. Evidence of efficacy in translationally relevant models provides support for using B7-H3-targeting CAR-NK cells in high-risk AT/RT patients.
other
2026-05-27 | Immunogenicity profiles in pediatric extra-cranial rhabdoid tumors: A framework for future risk stratification.
10026 Background: Malignant rhabdoid tumors (MRTs) are highly aggressive pediatric cancers driven by SMARCB1 loss. Emerging evidence suggests that the tumor immune microenvironment may influence the biological behavior of tumors. However, data on immune patterns in extra-cranial MRTs remain extremely limited, particularly in low- and middle-income settings. This study characterizes immune marker expression and immune phenotypes in a large single-center cohort to explore their potential relevance for future risk stratification. Methods: Formalin-fixed paraffin-embedded specimens from pediatric extra-cranial MRTs were evaluated for CD4⁺, CD8⁺, and CD68⁺ immune infiltrates using immunohistochemistry. Marker expression was categorized as high or low. Tumor immune phenotypes were subsequently classified based on the balance of infiltrating populations into: (immune-cold (uniformly low), mixed (variable across markers), and inflamed (uniformly high). Associations between immune phenotypes, clinicopathologic features, and survival trends were explored to determine whether immune architecture could serve as a biologically meaningful correlate of clinical behavior. Results: Individually, none of the immune markers (CD4, CD8, CD68) showed statistically significant correlation with overall survival. However, higher CD4⁺ and CD8⁺ T-cell infiltration demonstrated a consistent trend toward improved clinical outcomes. The most informative observation emerged at the phenotype level: tumors with a mixed immune profile exhibited more favorable survival trends and delayed progression compared with immune-cold tumors, whereas fully inflamed tumors were rare. These findings suggest that the equilibrium and interaction of immune infiltrates—rather than absolute immune cell density—may shape clinical behavior. Conclusions: Pediatric extra-cranial MRTs demonstrate distinct immune microenvironment patterns that are readily identifiable using routine immunohistochemistry. Although individual immune markers did not independently predict survival, immune-cold versus mixed phenotypes reflected meaningful biological divergence and aligned with clinical outcomes. Integrating immune phenotyping into diagnostic workflows may provide a pragmatic foundation for future risk stratification and help identify patients most likely to benefit from emerging immuno-epigenetic treatment strategies. Statement of Clinical Significance: Immune profiling using routine immunohistochemistry can classify pediatric extra-cranial rhabdoid tumors into clinically relevant immune phenotypes. Identifying immune-cold versus mixed tumors may support future risk stratification and guide biologically informed treatment selection.
2026-04-30 | Transformation of Pleomorphic Xanthoastrocytoma with Germline ATM Mutation into a SMARCB1-Deficient Rhabdoid Tumor: A Case Report
Hyeonseung Lee, Hyun Jin Park, Bo Kyung Kim, Kyung Taek Hong, Hyoung Jin Kang, Sung-Hye Park, Ji Hoon Phi, June-Young Koh and Jung Yoon Choi. CPHO 2026;33:34-8. https://doi.org/10.15264/cpho.2026.33.1.34
2026-02-06 | Atypical Teratoid Rhabdoid Tumor With TTF-1 Expression: A Case Report and Possible Insight Into Its Embryologic Origin.
Atypical teratoid rhabdoid tumor (AT/RT) of the brain is a highly malignant (CNS WHO grade 4) embryonal neoplasm. Majority of AT/RTs occur in the posterior fossa although supratentorial examples may also be observed. Pathologically, the tumor typically consists of cells with rhabdoid morphology that are immunoreactive for synaptophysin, EMA, and variably for GFAP. Diagnosis is typically confirmed by observing loss of INI-1 or BRG-1 expression from the nucleus of the tumor cells. Little is known regarding the embryogenesis of AT/RT. We therefore present here a case of supratentorial AT/RT in a 3-year-old male who presented with fatigue, irritability, left facial drop, left sided weakness of arm and leg, headaches, and vomiting. Neuroimaging revealed a large tumor involving the basal ganglia and foramen of Monro. Neuropathologic examination of the resected tumor revealed morphologic, immunohistochemical, and molecular evidence of an AT/RT (Group 1, SHH subtype). The tumor cells additionally exhibited immunoreactivity for TTF-1 (also known as NKX2.1), which has been reported to be expressed in GABAergic precursor cells in the medial ganglionic eminence. This example may provide at least a small insight into embryonic origins of supratentorial AT/RT.
2026-01-29 | Beyond Aqueductal Stenosis: A Case of an Atypical Teratoid/Rhabdoid Tumor Presenting With Neonatal Hydrocephalus.
An atypical teratoid/rhabdoid tumor (ATRT) is a rare and highly aggressive embryonal tumor in the central nervous system, with the highest incidence in infants. Neonatal cases frequently experience delayed diagnosis due to nonspecific symptoms, with imaging findings that may mimic more prevalent congenital anomalies such as aqueductal stenosis. We report a case of a full-term male neonate with prenatal findings of severe lateral and third ventriculomegaly, initially misdiagnosed to be due to an obstructive etiology due to hemorrhage in the fourth ventricle/aqueduct. Later, on a postnatal MRI, a non-enhancing hemorrhagic mass was suspected to be arising from the tectum, which on histopathology was confirmed to be an ATRT with loss of SMARCB1 (INI1) expression.
2025-12-29 | Sellar atypical teratoid/rhabdoid tumor in an adult mimicking a pituitary macroadenoma: an illustrative case and literature review
Background: Atypical teratoid/rhabdoid tumors (ATRTs) are rare, aggressive tumors of the central nervous system. In the sellar region, they can clinically and radiologically mimic pituitary macroadenomas, which may delay accurate diagnosis and appropriate treatment. Case Description: A 42-year-old woman presented with visual disturbances and hyperprolactinemia. Brain MRI revealed a sellar mass compressing the optic chiasm, initially suggestive of a pituitary macroadenoma. Within days, she developed cranial nerve palsies and signs of brainstem compression. Repeat imaging showed intratumoral necrosis, hemorrhage, and rapid tumor enlargement. She underwent urgent endonasal transsphenoidal resection. Postoperatively, MRI revealed aggressive tumor regrowth with worsening brainstem compression. Histopathological analysis confirmed an ATRT based on rhabdoid morphology, high mitotic index, and SMARCB1 (INI1) loss. The patient died before any adjuvant therapy could be initiated. Conclusion: Sellar ATRTs should be considered in rapidly progressing or radiologically atypical sellar lesions. Early biopsy and prompt multidisciplinary management are crucial, although the prognosis remains poor in aggressive presentations.
small molecules
2026-09-24 | Preclinical evaluation of ixazomib for high-risk pediatric brain tumors.
Many of the highest risk pediatric brain cancers continue to experience poor clinical outcomes despite intensification of current multimodal therapy. Proteasome inhibition has shown preclinical promise across a range of cancer models including diffuse midline glioma (DMG), medulloblastoma, and atypical teratoid / rhabdoid tumors (ATRT), though clinically viable agents have been limited. Recent studies in adults with glioblastoma suggest that ixazomib, a second-generation proteasome inhibitor, might achieve therapeutic concentrations in the CNS, presenting the opportunity that a CNS penetrant proteasome inhibitor might be similarly leveraged for benefit in childhood brain cancers. Ixazomib was tested against cell lines and orthotopic xenograft models of DMG, Myc-amplified medulloblastoma (Myc-MB), and ATRT. RNA sequencing and LC-MS based proteomics were utilized to define functional consequences of ixazomib treatment in these models. Proteasome activity readouts were used to assess ixazomib activity across brain regions and extracranial solid organs. Ixazomib demonstrates consistent cytotoxic effect across high-risk brain tumor models at low nanomolar concentrations. Ixazomib treatment activates proteostatic stress response and apoptosis. Treatment with ixazomib does not demonstrate survival benefit in orthotopic models, however, and pharmacodynamic testing suggests insufficient inhibition of proteasome activity within the CNS compared to extracranial tissues. While many pediatric brain tumor models demonstrate susceptibility to proteasome inhibition, ixazomib may lack sufficient blood-brain barrier penetration to be a translationally viable means of exploiting this vulnerability.
2026-09-24 | A PDGFRB-CD44-MIF crosstalk promotes cancer-associated cellular phenotypes in ATRT-TYR/MYC cell lines.
Atypical teratoid/rhabdoid tumor (ATRT) is the most common brain tumor in children less than one-year-old. Previous studies have identified three epigenetic subgroups of ATRT: ATRT-SHH, ATRT-TYR, and ATRT-MYC. Interestingly, it was found that ATRT-TYR/MYC (mesenchymal) subgroups are sensitive to receptor-tyrosine kinase inhibitors (RTKIs), particularly those that inhibit the platelet-derived growth factor receptor B (PDGFRB), highlighting the importance of PDGF signaling in ATRTs. In addition, the ATRT-TYR/MYC subgroups show upregulation of the macrophage migration inhibitory factor (MIF), with dysregulation of the MIF signaling pathway, which was found to have immunosuppressive effects in other cancers. While PDGF and MIF pathways have been found to promote tumorigenesis of other cancers including glioma, their roles in ATRTs remain unknown. We hypothesized that PDGF and MIF signaling pathways contribute to maintaining malignant phenotypes in ATRT-TYR/MYC subgroups. To test this hypothesis, our project aimed to characterize PDGF signaling and investigate PDGF-MIF crosstalk in ATRT-TYR/MYC subgroups, using CRISPR/Cas9 stable knockouts (KOs) of various PDGF receptor and ligands. We have shown that the PDGF pathway primarily promotes maintenance of malignant phenotypes in ATRT-TYR/MYC via modulation of the cell cycle. Furthermore, our studies reveal a plausible PDGFRB, MIF, and CD44 oncogenic signaling axis, that could modulate invasion and cellular phenotypic plasticity in ATRT-TYR/MYC, via regulation of neural stemness and epithelial-mesenchymal transition (EMT) marker expression. Our collective study findings point to an important role for PDGFRB-MIF-CD44 signaling in the maintenance of malignant cellular phenotypes in ATRT-TYR/MYC cell lines.
2026-09-16 | A Phase Ib Case Series Using Bortezomib With Chemotherapy in Atypical Teratoid/Rhabdoid Tumors.
Atypical teratoid/rhabdoid tumors (ATRTs) are aggressive pediatric brain tumors that are sensitive to proteasome inhibitors in preclinical models. We evaluated the feasibility of combining the proteasome inhibitor, bortezomib, with chemotherapy. Six patients aged 0.8-13 years with newly diagnosed ATRT were enrolled from January 2022 through December 2023. Bortezomib was given intravenously at the dose of 1.3 mg/m2/day on days 1, 4, 8, and 11 of a 21-day chemotherapy cycle for 6 cycles. Radiation therapy was given before initiation of chemotherapy in 4 patients or at the end of chemotherapy in one patient. The primary endpoint was grade 3 or higher non-hematologic toxicities. Thirty cycles of bortezomib with chemotherapy were evaluated. No grade 3 or higher toxicities were considered bortezomib-related. Four patients completed 6 cycles of bortezomib; 2 patients discontinued treatment due to progressive disease after 2 and 4 cycles, respectively. An additional 6 cycles of bortezomib were evaluated after high-dose chemotherapy in three patients without grade 4 bortezomib-related toxicity. Five patients had a near-total resection; one patient had a subtotal resection. Four patients were evaluable for response with 2 partial responses, 1 stable disease, and 1 progressive disease. Two patients without measurable tumor after surgery were not evaluable for response. Two patients remain alive without disease at 37 and 40 months, and one patient died without disease at 19 months after diagnosis. Three patients died with progressive disease. The toxicities were no more than expected with chemotherapy alone. Adding bortezomib to treatment of ATRT is feasible. NCT06853080.
2026-09-15 | Sometimes, More is Less in Atypical Teratoid Rhabdoid Tumor (ATRT): The Risks of Maintenance Intrathecal Chemotherapy.
Atypical Teratoid Rhabdoid Tumors (ATRT) are rare and aggressive pediatric brain tumors, and lack of consensus exists regarding optimal therapy. Some physicians recommend maintenance intrathecal chemotherapy, extrapolating from the salvage setting where it has been reported to promote remission. However, the risks of this therapy may be underappreciated. Here we present a case of a young patient with ATRT who received consolidation intrathecal chemotherapy following the ACNS 0333 regimen (resection, induction chemotherapy, high-dose chemotherapy with stem cell rescue, and radiotherapy) and developed life-altering neurologic sequelae. In the absence of clear benefit, we recommend against routine maintenance intrathecal chemotherapy.
2026-08-29 | Pediatrics supratentorial intraventricular atypical teratoid/rhabdoid tumors: a case report and a systematic review of the literature.
Atypical teratoid/rhabdoid tumors (AT/RTs) are rare, highly aggressive World Health Organization grade 4 brain tumors associated with early cerebrospinal fluid dissemination (CSF). AT/RTs typically occur in children under 4 years of age however, can also occur in adults and often carry a poor prognosis. These tumors are exceptionally uncommon, with evidence limited to isolated case reports. We illustrate a case of hemorrhagic left lateral ventricular AT/RT in a 5-year-old boy and systematically synthesize global literature evaluating clinical presentations, therapeutic interventions, and survival outcomes of primary supratentorial intraventricular AT/RT. Systematic searches were executed across PubMed, Embase, and Scopus databases up to 31 May 2026. Studies tracking histologically or immunohistochemically confirmed pediatric intraventricular AT/RT were included. Study quality was evaluated qualitatively via Joanna Briggs Institute tools; qualitative descriptive analysis synthesized outcomes, supplemented by post hoc stratified subgroup analysis. Twenty-four descriptive, uncontrolled studies comprising 28 pediatric patients (mean age: 3.9 years) were synthesized. The lateral ventricle was the primary epicenter (53.5%). Surgical resection margins were divided between gross total resection (GTR; 64.2%), subtotal resection (STR 17.8%), and biopsy (7.1%). The cohort demonstrated a 43.0% disease progression rate and a 69.6% (16/23) overall mortality rate among patients with follow up. Descriptive subgroup analysis demonstrated a comparable high mortality across age groups and tumor locations, whereas mortality was highest among patients with metastatic disease and appeared lower after GTR than STR 33.3% (6/18) vs. 80.0% (4/5). High risk of publication bias and inconsistent longitudinal tracking limit the evidence. Supratentorial intraventricular AT/RT exhibits high recurrence risks, but GTR combined with modern risk-adapted adjuvant protocols optimizes survival. Establishing international multi-institutional registries remains critical. • Atypical teratoid/rhabdoid tumors (AT/RTs) are rare, highly aggressive pediatric central nervous system tumors characterized by early cerebrospinal fluid dissemination (CSF) which carry a poor survival rate. While AT/RTs typically arise in the posterior fossa, primary supratentorial intraventricular tumors are rare, and current evidence is limited to isolated case reports and case series. • This study provides the largest qualitative synthesis of pediatric supratentorial intraventricular AT/RTs reported to date. The accompanying case is notable for its hemorrhagic lateral ventricular presentation causing obstructive hydrocephalus, diffuse leptomeningeal dissemination at diagnosis (M3 disease) with rapid clinical progression highlighting the aggressive behavior and surgical challenges associated with this rare tumor subtype.
gene therapies
2026-06-26 | Development of a Genetically Engineered Porcine Model of Rhabdoid Tumor Predisposition Syndrome Type 1 (RTPS-1).
Background and Objectives: Among CNS malignancies arising in infancy, ATRT stands out as the most frequently diagnosed in children younger than six months. Disruption of the SMARCB1 gene underlies the overwhelming majority of cases. Progress toward effective treatment has been hampered by two persistent challenges. Current mouse models, while informative, fall short of reproducing the full clinical and biological picture of human ATRT, and their ability to predict therapeutic outcomes in patients remains uncertain. Compounding this, the rarity of the disease makes it difficult to assemble patient cohorts of sufficient size for meaningful clinical trials. At the molecular level, germline loss of SMARCB1 exons 4 and 5 has emerged as a particularly penetrant predisposing event, with affected individuals presenting at an earlier age than those harboring other mutation types. The porcine SMARCB1 gene offers a compelling basis for translational modeling as its protein product is identical to the human ortholog at every amino acid position across isoforms, a degree of conservation that exceeds what is seen in the mouse. Methods: Thus, we hypothesized that germline deletion of exons 4 and 5 would predispose heterozygote swine to ATRT development. In this manuscript, we describe the creation of an ATRT porcine model through a CRISPR/Cas9 mediated gene-editing approach. Results: 15 piglets were produced, two of which had confirmed SMARCB1 targeted excisions. However, none developed tumors. To induce further tumorigenicity, one pig with confirmed exons 4 and 5 excision was crossed with a pig with TP53 exon 2 truncation. In total, 11 piglets were born, of which one contained the original excision without a TP53 mutation. This piglet developed a spinal mass at the T1 level. Conclusion: To our knowledge, this is the first ATRT porcine model ever developed and provides proof-of-concept feasibility for large animal modeling of SMARCB1-deficient rhabdoid tumors. These findings support the continued development of porcine RTPS-1 models toward preclinical application.
2026-06-23 | ID #753 ESTABLISHMENT OF A HIGH-FIDELITY SYNGENEIC MODEL FOR ATYPICAL TERATOID/RHABDOID TUMOR (AT/RT) RESEARCH
Abstract Atypical Teratoid/Rhabdoid Tumor (AT/RT) is the most common malignant brain tumor in infants <3 years, representing 10–15% of pediatric CNS malignancies. This lethal embryonic tumor is driven by biallelic inactivation of the chromatin-remodeling gene Smarcb1. Despite aggressive multimodal therapy (surgery, chemotherapy, radiotherapy), median overall survival remains <12 months. Current AT/RT research relies heavily on immunodeficient xenograft models, which fail to recapitulate the tumor microenvironment (TME) and cannot adequately evaluate immunotherapeutic strategies. Syngeneic immunocompetent models are essential for understanding TME composition and immune dynamics critical to developing next-generation treatments. Spontaneous AT/RT tumors were generated in an inducible Smarcb1fl/fl;Rosa26-CreERT2 mouse model (tamoxifen induction at E6–E7, Han et al., 2016) by Franck Bourdeaut’s laboratory at Institut Curie, Paris. Tumor explants were established as a stable syngeneic cell line and implanted orthotopically using the guide screw method into immunocompetent C57BL/6 hosts. Tumors were characterized by: (i) immunohistochemistry and western confirming biallelic SMARCB1 loss; (ii) in vivo growth kinetics and survival curves; and (iii) single-cell RNA sequencing (scRNA-seq) of tumor and immune compartments. The established cell line demonstrated 100% penetrance with aggressive growth kinetics. ScRNA-seq analysis revealed a macrophage-dominant tumor microenvironment (72% of immune infiltrate), with T-cell exhaustion markers (PD1+, TIM3+) and minimal lymphocyte infiltration. Notably, this immune phenotype closely mirrors observations in human AT/RT patient samples, establishing our model as a high-fidelity platform. This immunocompetent syngeneic AT/RT model recapitulates human disease immune architecture and provides a robust platform for studying tumor-immune interactions and evaluating immunotherapeutic strategies, including oncolytic virotherapy, checkpoint modulation, and adoptive cell therapies. This model will accelerate clinical translation of promising approaches for this uniformly fatal pediatric malignancy.
2025-10-01 | Figure S3 from A Novel Conditionally Replicative Oncolytic Adenovirus under the Control of the <i>SALL4</i> Promoter Inhibits the Growth of Rhabdoid Tumors
<p>Figure S3 shows expression of <i>CLDN6</i> and <i>USP44</i> mRNA in RT cell lines</p>
2025-10-01 | Figure S1 from A Novel Conditionally Replicative Oncolytic Adenovirus under the Control of the <i>SALL4</i> Promoter Inhibits the Growth of Rhabdoid Tumors
<p>Figure S1 shows Map of the <i>SALL4 </i>promoter (pSALL4) region in human and structure of pSALL4-OAd.</p>
2025-10-01 | Data from A Novel Conditionally Replicative Oncolytic Adenovirus under the Control of the <i>SALL4</i> Promoter Inhibits the Growth of Rhabdoid Tumors
<div>Abstract<p>Rhabdoid tumors (RT) are highly aggressive pediatric malignancies with limited treatment options. <i>SALL4</i>, a gene essential for embryonic stem cell pluripotency and self-renewal, is frequently overexpressed in RTs. To exploit this, we developed a conditionally replicating oncolytic adenovirus (pSALL4-OAd) by placing the E1 region under the control of the <i>SALL4</i> promoter, restricting viral replication to SALL4-positive cells. SALL4 protein expression was analyzed in 10 clinical RT specimens via IHC, whereas <i>SALL4</i> mRNA levels and promoter activity were assessed in eight RT cell lines using qPCR and dual-luciferase assays. The replication selectivity and cytopathic effects of pSALL4-OAd were tested <i>in vitro</i> at doses of 0 to 1,000 viral particles/cell. <i>In vivo</i>, 1.0 × 10<sup>7</sup> G401 cells were implanted subcutaneously into immunodeficient mice, followed by intratumoral administration of pSALL4-OAd (3 × 10<sup>10</sup> viral particles) or PBS. Tumor growth was monitored over the treatment period. SALL4 protein was detected in 40% of clinical RT specimens, and RT cell lines exhibited four- to 400-fold higher <i>SALL4</i> mRNA levels compared with normal tissues. Elevated <i>SALL4</i> promoter activity was confirmed in three of five RT cell lines. pSALL4-OAd selectively replicated in SALL4-positive cells and induced significant cytopathic effects proportional to promoter activity <i>in vitro</i>. <i>In vivo</i>, pSALL4-OAd administration caused tumor necrosis, reduced SALL4-positive cells, and suppressed tumor proliferation. These results demonstrate the potential of pSALL4-OAd as a targeted and effective therapeutic strategy for SALL4-expressing RTs.</p></div>
antibodies
2026-06-03 | Spatial dissection of ADC/RPT targets defines heterogeneous expression landscapes and therapeutic implications in rhabdoid tumors.
Rhabdoid tumors (RT) are among the most aggressive pediatric malignancies, characterized by early onset in life, loss of SWI/SNF complex members (SMARCB1 or SMARCA4), and dismal outcomes despite multimodal therapy. Refractory and relapsing RT remain almost uniformly fatal, and targeted or immune-based approaches have yet to demonstrate clinical benefit. To explore novel therapeutic vulnerabilities, we systematically investigated the expression of clinically actionable surface proteins that could serve as targets for antibody-drug conjugates (ADCs), radiopharmaceutical therapy (RPT), or cellular immunotherapies. Based on large-scale transcriptomic analyses, we prioritized FAP (fibroblast activation protein), CXCR4 (chemokine receptor 4), and IL13RA2 (interleukin receptor 13 RA2) and performed comprehensive protein-level validation by immunohistochemistry in an unprecedented cohort of 60 rhabdoid tumors spanning all molecular subgroups (ATRT-TYR, ATRT-SHH, ATRT-MYC and eMRT). Integrating these data with spatial and single-nucleus transcriptomic profiling, we identified subgroup- and cell-type-specific expression patterns, including heterogeneous FAP distribution between stromal and tumor compartments and a distinct IL13RA2-positive rhabdoid cell population with melanosomal and stem-like features: Overall 51/60 tumors demonstrated positivity, defined as immunohistochemical H-score above or at least equal to 10, for FAP in the stroma and 34/60 tumors for CXCR4, indicating that a substantial fraction of rhabdoid tumors may be amenable to targeted therapies directed against these epitopes. These findings define a set of biologically and clinically relevant surface targets in RT and provide a translational blueprint for rational ADC and RPT target development in pediatric cancer.
2026-05-27 | Spatial multiomic profiling to identify de-differentiated tumor phenotypes and exhausted T cell niches in rhabdoid and sarcomatoid RCC.
4557 Background: Rhabdoid and sarcomatoid (S/R) differentiation are high-grade dedifferentiated states that can arise across renal cell carcinoma (RCC) subtypes. Although associated with poor patient prognosis, S/R RCC paradoxically exhibits increased sensitivity to immune checkpoint blockade. The mechanisms underlying this aggressive, yet immunotherapy-responsive phenotype remain unclear. Spatial multi-omic profiling offers a powerful framework to interrogate tumor-intrinsic and microenvironmental programs that account for this phenotype. Here, we applied spatial multi-omic analyses to treatment-naïve clear cell RCC specimens from seven patients, enabling direct comparison of sarcomatoid, rhabdoid, and clear cell regions captured within the same tissue sections. Methods: Hematoxylin and eosin (H&E)–stained sections from seven FFPE patient samples were reviewed and annotated by a genitourinary pathologist to identify discrete regions of sarcomatoid, rhabdoid, or clear cell morphology. Annotated FFPE samples were processed by Singular Genomics using the G4X spatial multi-omic platform, which enables quantification of 315 RNA transcripts, 14 protein targets, and fluorescent H&E imaging. Results: Initial spatial multi-omic profiling resolved distinct tumor regions with clear cell biology alongside areas exhibiting rhabdoid or sarcomatoid features. Comparative analysis of immune infiltrates across these regions revealed enrichment of both T cells and B cells within rhabdoid regions. In addition, T cells localized to rhabdoid and sarcomatoid regions displayed distinct phenotypic states compared with those in clear cell regions. Differential gene expression (DGE) analysis of T cells from rhabdoid and sarcomatoid regions relative to clear cell RCC demonstrated upregulation of activation markers ( CD69 , IL2RA ), exhaustion markers ( LAG3 , PDCD1 ), and cytotoxic genes ( GZMA , GZMK , NKG7 ). Parallel analysis of tumor cell transcriptional programs further highlighted distinct tumor biology across histologic regions. Sarcomatoid tumor cells exhibited increased expression of genes associated with cellular stress, inflammation, and epithelial–mesenchymal transition (EMT), including IGFBP7 and FOS . In contrast, rhabdoid tumor cells showed upregulation of antigen-presentation machinery ( HLA-A , TAP1/2 ) along with elevated expression of EMT-associated genes ( MET , VCAM1 , and CD44) . Conclusions: Spatial multi-omic analysis of S/R RCC revealed distinct immune and transcriptional programs across sarcomatoid, rhabdoid and clear cell regions. T cells within S/R regions exhibited activated and exhausted phenotypes, while tumor cell characterization of S/R cells reveals upregulation of stress, inflammatory and antigen-presentation machinery, features that may underlie the sensitivity of S/R RCC to immune checkpoint inhibitors.
2026-05-18 | Claudin-6 Protein Expression in Atypical Teratoid/Rhabdoid Tumors Is Strongly Enriched in the Molecular Subgroup AT/RT-TYR.
Claudin-6 has emerged as a promising immunotherapeutic target, yet protein-level data in atypical teratoid/rhabdoid tumors (AT/RTs) have been inconsistent. We analyzed 36 well-characterized AT/RT samples and found membranous claudin-6 protein expression in 58% of cases, with striking enrichment in the molecular subgroup AT/RT-TYR (100%) and significantly higher staining scores compared with AT/RT-SHH and AT/RT-MYC. Correspondingly, AT/RT-TYR showed lower CLDN6 promoter methylation. Pilot spatial transcriptomic experiments in AT/RT-TYR confirmed heterogeneous CLDN6 transcription, and co-expression analyses linked CLDN6 to epithelial-mesenchymal transition-related genes. These findings clarify subgroup-specific expression patterns and support claudin-6 as a biologically and therapeutically relevant target in AT/RT-TYR.
2026-04-27 | Atypical Teratoid/Rhabdoid Tumor of the Lateral Ventricle: A Case Series and Experience with Molecular Subtyping-Guided Immunotherapy.
Atypical teratoid/rhabdoid tumors (AT/RT) are rare, highly aggressive pediatric central nervous system (CNS) malignancies. AT/RT of the lateral ventricle is an exceptionally rare subgroup, with only 11 reported cases. SMARCB1 inactivation is the primary molecular feature of AT/RT. Current consensus is to classify AT/RT based on methylation and molecular profiles into the following subgroups: AT/RT-TYR, AT/RT-SHH, AT/RT-MYC, and a potentially distinct SMARCA4-deficient subtype. AT/RT-MYC exhibits high levels of CD8+ tumor-infiltrating lymphocytes, indicating immunogenic potential. We report three pediatric cases presenting with intracranial hypertension and seizures. Diagnosis was confirmed via histopathology and molecular profiling. Interventions included gross total resection, chemotherapy, radiotherapy, and combined immune checkpoint inhibitors (pembrolizumab and ipilimumab). Outcomes varied from rapid progression to 3-year recurrence-free survival. A cohort of 14 pediatric patients with lateral ventricle AT/RT, comprising 3 institutional cases and 11 cases identified from the PubMed database, was evaluated through a narrative synthesis. These advancements highlight the crucial role of molecular subtyping in tailoring personalized treatments, including epigenetic modifiers and immune-based regimens. However, clinical validation is essential to establish standardized protocols. Integrating genomic, epigenetic, and immune microenvironment profiling may enhance risk assessment and treatment precision, ultimately improving survival and quality of life in pediatric patients.
2026-04-22 | Compartment-specific immune and tumor markers associated with clinical outcomes in patients with and without sarcomatoid/rhabdoid renal cell carcinoma treated with ipilimumab and nivolumab.
Immune checkpoint inhibition with ipilimumab and nivolumab prolongs survival in renal cell carcinoma (RCC). Tumors with sarcomatoid and/or rhabdoid features are considered responsive to immune checkpoint inhibitors (ICIs), despite their aggressive nature. Although sarcomatoid/rhabdoid dedifferentiation is not considered a distinct subtype of RCC, these tumors differ clinically and molecularly from nonsarcomatoid/rhabdoid RCC tumors. We sought to identify biomarkers underlying responsiveness to ICIs and compare the immune microenvironments of tumors with or without sarcomatoid/rhabdoid components. We constructed a tissue microarray from archived RCC tumors collected from patients treated with first-line ipilimumab and nivolumab. Digital spatial profiling was carried out using NanoString's GeoMx platform with a panel of 58 proteins. Regions of interest were segmented into immune [cluster of differentiation (CD)68+ and CD45+] and tumor [positive for both cytokeratin and carbonic anhydrase 9 (CAIX+ CK+)] compartments. To investigate marker expression in tumors with and without sarcomatoid/rhabdoid dedifferentiation, two additional tissue microarrays were analyzed, comprising cohorts of patients treated with heterogeneous first-line therapies. Key findings were validated by immunohistochemistry. After quality control, 44 pretreatment tumors from 44 patients were analyzed. Tumor programmed death-ligand 1 (PD-L1) expression was higher in responders (P = 0.03) and associated with improved progression-free survival [PFS; hazard ratio (HR) 0.4, 95% confidence interval (CI) 0.2-0.8, P = 0.01] and overall survival (OS; HR 0.2, 95% CI 0.06-0.5, P < 0.005) on multivariable analysis. This finding was confirmed by immunohistochemistry. In the CD45+ compartment of sarcomatoid/rhabdoid tumors, CD25 expression was associated with worse PFS (HR 58.8, 95% CI 2.8-1250, P = 0.01). Differential expression analysis showed higher CD66b in sarcomatoid/rhabdoid tumors (log2 fold change = 2.2, P < 0.001), validated by immunohistochemistry with significantly higher myeloperoxidase (MPO) staining (χ2 = 15.7, df = 3, P < 0.001). Tumor PD-L1 is associated with better PFS and OS after ipilimumab + nivolumab. In the sarcomatoid/rhabdoid subset, lower CD25 (a marker of regulatory T cells) was associated with improved PFS, while increased neutrophil infiltration (CD66b+/MPO+) emerged as a novel feature of sarcomatoid/rhabdoid tumors, which may be harnessed for therapeutic benefit in this population.
cell therapies
2026-09-22 | Abstract A002: Epigenetic Regulation of the GDF15 Immune Checkpoint Determines Sensitivity of Atypical Teratoid/Rhabdoid Tumors to Natural Killer Cell Immunotherapy
Abstract Atypical teratoid/rhabdoid tumors (ATRTs) are highly aggressive pediatric central nervous system malignancies characterized by poor clinical outcomes despite intensive multimodal therapy, including surgery, chemotherapy, and radiation. Although molecular classification has improved our understanding of ATRT biology, these advances have not yet translated into effective therapies for patients. Here, we investigated natural killer (NK) cell-based immunotherapy as a novel therapeutic strategy for ATRTs and identified subgroup-specific differences in tumor sensitivity to NK cell-mediated cytotoxicity driven by variable expression of the immunomodulatory cytokine - growth and differentiation factor 15 (GDF15). ATRTs are almost universally defined by loss of SMARCB1, a core component of the ATP-dependent SWI/SNF chromatin-remodeling complex, resulting in widespread dysregulation of lineage-specific enhancers. Through integrated multi-omic analyses of patient tumors and ATRT cell lines, including RNA-seq, ATAC-seq, DNA methylation profiling, ChIP-seq, and chromatin conformation capture (3C) assays, we identified subgroup-specific differences in the epigenetic regulation of the GDF15 locus. Differential DNA methylation at the GDF15 promoter, distinct histone modification patterns at both the promoter and a previously unrecognized upstream enhancer, and long-range promoter-enhancer interactions collectively contributed to subgroup-dependent variability in GDF15 expression. Mechanistically, DNA methylation-dependent chromatin occupancy by two antagonistic regulatory proteins, RE1-silencing transcription factor (REST) and CCCTC-binding factor (CTCF), governed the epigenetic architecture of the GDF15 locus. REST-mediated displacement of CTCF silenced GDF15 expression and overcame tumor-mediated suppression of NK cell function. Genetic disruption of this regulatory axis, as well as blockade of GDF15 with neutralizing antibodies, reversed NK cell suppression in vitro and significantly enhanced NK cell-mediated antitumor activity in orthotopic intracranial ATRT models. Collectively, these findings reveal a novel epigenetic mechanism regulating immune evasion in ATRTs. GDF15 represents a therapeutically actionable immune checkpoint and its combination with NK cell-based immunotherapy could offer a promising treatment strategy for subsets of patients with ATRTs and other GDF15-expressing brain tumors. Citation Format: Vidya Gopalakrishnan, Jyothishmathi Swaminathan, Ben Ho, Donghang Cheng, Lei Guo, Shu Feng, Ashutosh Singh, Yanwen Yang, Swarnalatha Manickavinayaham, Arianna Anjier, Xiaolian Fan, Alvaro Laureano, William Brugmann, Shinji Maegawa, Javiera Bravo Alegria, Bridget Kennis, Tara Dobson, David Sandberg, Laurence Cooper, Soumen Khatua, Lucia Silla, Wafik Zaky, Richard Gorlick, Dean Lee, Marcos Estecio, Abhinav Jain, Nancy Gordon, Najat C. Daw, Lin Xu, Annie Huang. Epigenetic Regulation of the GDF15 Immune Checkpoint Determines Sensitivity of Atypical Teratoid/Rhabdoid Tumors to Natural Killer Cell Immunotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Bridging Discovery and Clinical Impact in Pediatric Cancer; 2026 Sep 22-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_1):Abstract nr A002.
2026-08-11 | Fingerroot-derived nanovesicles attenuate atypical teratoid rhabdoid tumor progression via modulation of Wnt signaling
Atypical teratoid rhabdoid tumor (ATRT) is an aggressive central nervous system tumor that primarily affects young children and has poor prognosis, highlighting the need for new treatment options. In this study, we examined how fingerroot exosome-like nanovesicles (FELNs) derived from Boesenbergia rotunda (L.) Mansf. affect ATRT and investigated their mechanisms of action. FELNs are round vesicles approximately 100 nm in diameter. Fluorescently labeled FELNs were taken up by cells and induced dose- and time-dependent cytotoxicity via apoptosis in ATRT cell lines BT12 and cisplatin-resistant BT16, with minimal effect in normal brain cells. Moreover, non-toxic concentrations of FELNs significantly decreased ATRT cell migration and invasion. Proteomic analysis revealed that FELNs disrupt multiple signaling pathways involved in ATRT development, including the Wnt/β-catenin pathway. FELN treatment reduced β-catenin protein levels and increased GSK-3β activity. It also decreased the expression of target genes, including c-myc, cyclin D1, axin2, and survivin . Overall, our findings demonstrate that FELNs exert anti-cancer effects in ATRT cells by inducing apoptosis and decreasing migration and invasion. These effects are partially mediated through the GSK-3β-dependent β-catenin pathway. The low toxicity in normal cells suggests that FELNs could be promising new therapeutic agents for cancer treatment.
2026-07-27 | Intracerebroventricular B7-H3-targeting CAR T cells for non-pontine DMG and recurrent/refractory pediatric CNS tumors: a phase 1 trial.
High-grade central nervous system (CNS) tumors carry a poor prognosis with limited curative options if first-line therapy fails. B7-H3 is expressed in many of these tumors, and chimeric antigen receptor (CAR) T cell therapy is an emerging immunotherapeutic strategy. BrainChild-03 (NCT04185038) is a single-center, dose-escalation phase 1 study of repeated intracerebroventricular (ICV) B7-H3 CAR T cells in children and young adults with recurrent/refractory CNS tumors (Arms A, B) and diffuse intrinsic pontine glioma (DIPG, Arm C). Here, we report results from Arm B, in which patients with refractory/relapsed CNS tumors or pre- or post-progression non-pontine diffuse midline glioma (DMG) received repeated ICV infusions. Primary objectives were feasibility and safety/tolerability; secondary objectives included CAR T cell detection, disease response, and survival. Of 36 enrolled patients (atypical teratoid rhabdoid tumor n = 5, DMG n = 8, embryonal tumor with multilayer rosettes n = 2, ependymoma n = 4, high-grade glioma n = 6, medulloblastoma n = 8, pineoblastoma n = 3), manufacturing was successful for 35 patients, 26 of whom received therapy. Median age was 10 years (range 1-26). Dose escalation from 1 × 107 to 10 × 107 CAR T cells/dose identified this dose as the maximally tolerated dose regimen, with no dose-limiting toxicities observed. Across 181 total doses (median 7/patient), common adverse events included headache (n = 26), fever (n = 15), and nausea (n = 14). Median survival from first infusion was 11.5 months, ranging from 3.2 months (pineoblastoma, HGG) to 21.4 months (ependymoma); two patients achieved a partial response. Repeated ICV B7-H3 CAR T cell dosing is feasible and tolerable across a spectrum of pediatric CNS tumors, supporting continued investigation in future trials.
2026-04-03 | Abstract 1528: AZD5851, a TGF-β-resistant GPC3 CAR-T cell product, prolongs animal survival times in patient derived orthotopic xenograft models of medulloblastoma and atypical teratoid rhabdoid tumor
Abstract BACKGROUND: Glypican-3 (GPC3) is uniquely expressed and has been associated with the development of several pediatric solid embryonal tumors, making it a prime target for GPC3 CAR-T cell killing. TGF-β, a cytokine associated with immunosuppression, has also been shown to be highly expressed in the microenvironment of these tumors, potentially hindering CAR-T cell antitumor activity. In this study, we examined the therapeutic efficacy of AZD5851, an autologous CAR-T product that expresses a CAR specific for GPC3 and a dominant negative (dn)TGFβRII as an armoring strategy. METHODOLOGY: To assess the drug’s in vivo efficacy, 5 established patient-derived orthotopic xenograft (PDOX) models of pediatric medulloblastoma (ICb-2123MB, -1299MB, -S1129MB), atypical teratoid rhabdoid tumor (IC-L1115ATRT) and a high grade glioma (IC-2664HGG), with confirmed expression of GPC3 and TGF-β through immunohistochemical staining, were treated with untransduced T cells [dosed at 12x106 cells/mouse, intravenously (IV) once] or GPC3 CAR-T cells (dosed at 5x106 cells/mouse, IV once). 20 eight-week-old SCID mice per model received intra-cerebral (IC) or intra-cerebellar (ICb) tumor cell implantation and were divided into 2 treatment groups (n=10 per group): Untransduced T cells and GPC3 CAR-T cells. Animal survival times were analyzed using Gehan-Breslow-Wilcoxon analysis. RESULTS: GPC3 CAR-T cell treatment was well tolerated in mice with no loss of body weight or other toxicities. GPC3 CAR-T cell treatment significantly improved the median survival time in 2/5 models, including ICb-2123MB from 90.5 days in the untransduced T cell group to 162.5 days (P=0.02) and IC-L1115ATRT from 136 days to 174 days (P=0.02). CONCLUSION: Our data identifies single agent antitumor activity for GPC3 CAR-T cells for PDOX models of pediatric medulloblastoma and atypical teratoid rhabdoid tumor. The results support further clinical translational efforts involving the use of AZD5851 alone or in combination with other therapies for the treatment of these tumors. Citation Format: Milagros Suarez, Aalaa Abdallah, Xin Zhai, Zilu Huang, Yuchen Du, Nitin Wadhwani, Alicia Lenzen, Jee Young Kwon, Steven B. Neuhauser, Timothy Stearns, Jeffrey H. Chuang, Emily L. Jocoy, Carol J. Bult, Beverly Teicher, Malcolm A. Smith, Xiao Nan Li. AZD5851, a TGF-β-resistant GPC3 CAR-T cell product, prolongs animal survival times in patient derived orthotopic xenograft models of medulloblastoma and atypical teratoid rhabdoid tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1528.
2026-02-06 | B7-H3-targeted natural killer cells effectively kill atypical teratoid / rhabdoid tumors and extend survival in orthotopic xenografts.
Atypical teratoid/rhabdoid tumors (AT/RTs) are the most common malignant CNS tumor in infants, and patients suffer from low survival rates and treatment-related morbidities. These tumors frequently overexpress the pan-cancer antigen B7-H3 (CD276), which can be targeted with immunotherapy. We hypothesized that adding a B7-H3-targeting cytotoxic chimeric antigen receptor (CAR) to NK cells can enhance killing against AT/RTs. We designed a library of variable affinity B7-H3-targeted CARs, which were transduced into primary healthy donor-derived NK cells. We verified B7-H3 expression in a panel of AT/RT cell lines and further engineered luciferase and nuclear GFP-expressing AT/RT (CHLA-04, CHLA-06, BT12, BT37) as well as a CHLA-06-derived B7-H3 knockout. We tested CAR-NK cell functionality using in vitro co-culture cytotoxicity assays. We delivered anti-B7-H3 CAR-NK cells intratumorally or intracerebroventricularly (ICV) to AT/RT orthotopic xenografts and monitored for tumor growth and animal survival. B7-H3-targeted CAR-NK cells demonstrated target-specific cytotoxicity when compared to unmodified NK cells. Knockout of B7-H3 in target cells abolished the increased CAR-mediated target killing. When delivered intratumorally to CHLA-06 orthotopic xenograft-bearing mice, anti-B7-H3 CAR-NK cells eliminated tumor cells and prolonged survival. When CAR-NK cells were delivered ICV against a CNS disseminated tumor model of BT12, treated mice had significantly improved survival. Anti-B7-H3 CAR-NK cells effectively kill AT/RTs in multiple pre-clinical in vitro and in vivo models in an antigen-specific manner. Evidence of efficacy in translationally relevant models provides support for using B7-H3-targeting CAR-NK cells in high-risk AT/RT patients.
other
2026-05-27 | Immunogenicity profiles in pediatric extra-cranial rhabdoid tumors: A framework for future risk stratification.
10026 Background: Malignant rhabdoid tumors (MRTs) are highly aggressive pediatric cancers driven by SMARCB1 loss. Emerging evidence suggests that the tumor immune microenvironment may influence the biological behavior of tumors. However, data on immune patterns in extra-cranial MRTs remain extremely limited, particularly in low- and middle-income settings. This study characterizes immune marker expression and immune phenotypes in a large single-center cohort to explore their potential relevance for future risk stratification. Methods: Formalin-fixed paraffin-embedded specimens from pediatric extra-cranial MRTs were evaluated for CD4⁺, CD8⁺, and CD68⁺ immune infiltrates using immunohistochemistry. Marker expression was categorized as high or low. Tumor immune phenotypes were subsequently classified based on the balance of infiltrating populations into: (immune-cold (uniformly low), mixed (variable across markers), and inflamed (uniformly high). Associations between immune phenotypes, clinicopathologic features, and survival trends were explored to determine whether immune architecture could serve as a biologically meaningful correlate of clinical behavior. Results: Individually, none of the immune markers (CD4, CD8, CD68) showed statistically significant correlation with overall survival. However, higher CD4⁺ and CD8⁺ T-cell infiltration demonstrated a consistent trend toward improved clinical outcomes. The most informative observation emerged at the phenotype level: tumors with a mixed immune profile exhibited more favorable survival trends and delayed progression compared with immune-cold tumors, whereas fully inflamed tumors were rare. These findings suggest that the equilibrium and interaction of immune infiltrates—rather than absolute immune cell density—may shape clinical behavior. Conclusions: Pediatric extra-cranial MRTs demonstrate distinct immune microenvironment patterns that are readily identifiable using routine immunohistochemistry. Although individual immune markers did not independently predict survival, immune-cold versus mixed phenotypes reflected meaningful biological divergence and aligned with clinical outcomes. Integrating immune phenotyping into diagnostic workflows may provide a pragmatic foundation for future risk stratification and help identify patients most likely to benefit from emerging immuno-epigenetic treatment strategies. Statement of Clinical Significance: Immune profiling using routine immunohistochemistry can classify pediatric extra-cranial rhabdoid tumors into clinically relevant immune phenotypes. Identifying immune-cold versus mixed tumors may support future risk stratification and guide biologically informed treatment selection.
2026-04-30 | Transformation of Pleomorphic Xanthoastrocytoma with Germline ATM Mutation into a SMARCB1-Deficient Rhabdoid Tumor: A Case Report
Hyeonseung Lee, Hyun Jin Park, Bo Kyung Kim, Kyung Taek Hong, Hyoung Jin Kang, Sung-Hye Park, Ji Hoon Phi, June-Young Koh and Jung Yoon Choi. CPHO 2026;33:34-8. https://doi.org/10.15264/cpho.2026.33.1.34
2026-02-06 | Atypical Teratoid Rhabdoid Tumor With TTF-1 Expression: A Case Report and Possible Insight Into Its Embryologic Origin.
Atypical teratoid rhabdoid tumor (AT/RT) of the brain is a highly malignant (CNS WHO grade 4) embryonal neoplasm. Majority of AT/RTs occur in the posterior fossa although supratentorial examples may also be observed. Pathologically, the tumor typically consists of cells with rhabdoid morphology that are immunoreactive for synaptophysin, EMA, and variably for GFAP. Diagnosis is typically confirmed by observing loss of INI-1 or BRG-1 expression from the nucleus of the tumor cells. Little is known regarding the embryogenesis of AT/RT. We therefore present here a case of supratentorial AT/RT in a 3-year-old male who presented with fatigue, irritability, left facial drop, left sided weakness of arm and leg, headaches, and vomiting. Neuroimaging revealed a large tumor involving the basal ganglia and foramen of Monro. Neuropathologic examination of the resected tumor revealed morphologic, immunohistochemical, and molecular evidence of an AT/RT (Group 1, SHH subtype). The tumor cells additionally exhibited immunoreactivity for TTF-1 (also known as NKX2.1), which has been reported to be expressed in GABAergic precursor cells in the medial ganglionic eminence. This example may provide at least a small insight into embryonic origins of supratentorial AT/RT.
2026-01-29 | Beyond Aqueductal Stenosis: A Case of an Atypical Teratoid/Rhabdoid Tumor Presenting With Neonatal Hydrocephalus.
An atypical teratoid/rhabdoid tumor (ATRT) is a rare and highly aggressive embryonal tumor in the central nervous system, with the highest incidence in infants. Neonatal cases frequently experience delayed diagnosis due to nonspecific symptoms, with imaging findings that may mimic more prevalent congenital anomalies such as aqueductal stenosis. We report a case of a full-term male neonate with prenatal findings of severe lateral and third ventriculomegaly, initially misdiagnosed to be due to an obstructive etiology due to hemorrhage in the fourth ventricle/aqueduct. Later, on a postnatal MRI, a non-enhancing hemorrhagic mass was suspected to be arising from the tectum, which on histopathology was confirmed to be an ATRT with loss of SMARCB1 (INI1) expression.
2025-12-29 | Sellar atypical teratoid/rhabdoid tumor in an adult mimicking a pituitary macroadenoma: an illustrative case and literature review
Background: Atypical teratoid/rhabdoid tumors (ATRTs) are rare, aggressive tumors of the central nervous system. In the sellar region, they can clinically and radiologically mimic pituitary macroadenomas, which may delay accurate diagnosis and appropriate treatment. Case Description: A 42-year-old woman presented with visual disturbances and hyperprolactinemia. Brain MRI revealed a sellar mass compressing the optic chiasm, initially suggestive of a pituitary macroadenoma. Within days, she developed cranial nerve palsies and signs of brainstem compression. Repeat imaging showed intratumoral necrosis, hemorrhage, and rapid tumor enlargement. She underwent urgent endonasal transsphenoidal resection. Postoperatively, MRI revealed aggressive tumor regrowth with worsening brainstem compression. Histopathological analysis confirmed an ATRT based on rhabdoid morphology, high mitotic index, and SMARCB1 (INI1) loss. The patient died before any adjuvant therapy could be initiated. Conclusion: Sellar ATRTs should be considered in rapidly progressing or radiologically atypical sellar lesions. Early biopsy and prompt multidisciplinary management are crucial, although the prognosis remains poor in aggressive presentations.
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Drug Discovery Landscape
3 orphan drug designations for Rhabdoid tumor.
3 orphan drug designations for Rhabdoid tumor.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
N-hydroxy-N-(methylacylfulvene)urea | small molecules | FDA | — | Lantern Pharma Inc. |
O-18F-fluoroethyl-L-tyrosine | small molecules | FDA | — | Advanced Imaging Projects, LLC |
tazemetostat | small molecules | FDA | Epizyme Inc. |
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