Spectrum Of Pediatric Brain Tumors Research Articles

IMMU-51. THE LANDSCAPE OF TUMOR INFILTRATING T CELLS (TILS) OF CHILDHOOD BRAIN TUMORS

Abstract T lymphocytes have a unique ability to recognize a vast array of antigens prompt by an enormous T cell receptor (TCR) repertoire. Characterization of tumor-infiltrating T cells (TILs) and their TCRs is key to understand MHC-restricted anti-tumor immunity and for developing T cell centered immunotherapies such as adoptive cell therapy and tumor vaccines. In the current work, we investigated RNAseq data from nearly 1,000 pediatric brain tumor patients and performed the first large-scale comprehensive examination of the immunogenomic and TCR landscape of TILs across the spectrum of pediatric brain tumors. We show that the relative ratio between T cell diversity (clonality) and T cell abundance within each sample, represented by the clonal expansion index (CEI), is a strong predictor of prognosis across tumor types and molecular subtypes. Interestingly, we found that CEI was strongly associated with molecular subgroups of medulloblastoma but not with known genomic features of these subgroups. Analysis of single-cell (sc)RNAseq and scTCRseq data of TILs across several tumor types, validated clonal expansion of TILs which were frequently associated with effector-cytotoxic T cell phenotypes, whereas non-expanded TILs were associated mostly with CD4 T cell phenotypes. Investigation of T cell clones recognizing a common recurrent tumor-antigen across patients based on CDR3 homology and characteristics, reveals several T cell specificity groups which are tumor type restricted with defined HLA dominance. Using machine learning investigations of genomic profiles of the patients which contain these T cell specificity groups identified novel putative HLA-restricted tumor antigens shared across patients. Importantly, our framework grounded the foundations for developing a precision medicine approach of T cell centered immunotherapies. In all, our findings have major implications for understanding the interplay between T cell and tumor genomic, and for improving immunotherapy strategies for childhood brain tumors.

Abstract 1198: T cell receptor (TCR) landscape of childhood brain tumors

Abstract T lymphocytes have a unique ability to recognize a vast array of antigens prompt by an enormous T cell receptor (TCR) repertoire. Characterization of tumor-infiltrating T cells (TILs) is key to understand MHC-restricted anti-tumor immunity and for developing T cell-centered immunotherapies such as adoptive cell therapy and tumor vaccines. In the current work, we investigated RNA-Seq data from 997 pediatric brain tumor patients and performed a large-scale comprehensive examination of the immunogenomic and TCR landscape of TILs across the entire spectrum of pediatric brain tumors. We show that the relative ratio between T cell clonal diversity and T cell abundance within each sample, represented by the clonal expansion index (CEI), is a strong predictor of prognosis both within and between tumor types. Interestingly, we show that CEI is strongly associated with molecular subgroups of medulloblastoma but not with known genomic features of these subgroups. Investigation of TCR clonotypes recognizing a common recurrent tumor-antigen across patients based on CDR3 homology and characteristics, reveals 9 TCR clusters which are tumor-type restricted with defined prognoses and HLA dominance. Using computational immunogenomics and machine learning-based investigations of these clusters we identified novel putative HLA-restricted tumor antigens which could bind and activate the clusters’ specific TCRs. Importantly, our framework grounded the foundations for developing a precision medicine approach of T cell-centered immunotherapies. These findings have major implications for understanding the interplay between T cell and tumor genomics, and for developing new immunotherapies for children with brain tumors and other cancers. Citation Format: Itay Raphael, Michal Nisnboym, Rebecca A. Raphael, Shikhar Uttam, Ian F. Pollack, Maria Chikina, Dhivyaa Rajasundaram, Gary Kohanbash. T cell receptor (TCR) landscape of childhood brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1198.

IMMU-06. Landscape of adaptive immunity of childhood brain cancers

T lymphocytes have a unique ability to recognize a vast array of antigens prompted by an enormous T cell receptor (TCR) repertoire. Characterization of tumor-infiltrating T cells (TILs) is key to understand MHC-restricted anti-tumor immunity and for developing T cell-centered immunotherapies such as adoptive cell therapy and tumor vaccines. In the current work, we investigated RNA-Seq data from 997 pediatric brain tumor patients and performed a large-scale comprehensive examination of the immunogenomic and TCR landscape of TILs across the entire spectrum of pediatric brain tumors. We show that the relative ratio between T cell diversity (clonality) and T cell abundance within each sample, represented by the clonal expansion index (CEI), is a strong predictor of prognosis both within and between tumor types. Interestingly, we show that CEI was strongly associated with molecular subgroups of medulloblastoma but not with known tumor-genomic features of these subgroups. Investigation of TCR clones recognizing a common recurrent tumor-antigen across patients based on CDR3 homology and characteristics, reveals 9 TCR clusters which are tumor type restricted with defined prognoses and HLA dominance. Using computational immunogenomics and machine learning-based investigations of these clusters yielded novel putative HLA-restricted tumor antigens which could bind and activate the clusters’ specific TCRs. Importantly, our framework grounded the foundations for developing a precision medicine approach of T cell-centered immunotherapies. These findings have major implications for understanding the interplay between T cell and tumor genomic, and for developing new immunotherapies for children with brain tumors.

FREQUENCY OF PEDIATRIC BRAIN TUMORS IN TERTIARY CARE INSTITUTE OF PAKISTAN AND COMPARISON WITH INTERNATIONAL DATA

Objective: To analyze the histological spectrum of pediatric brain tumors (PBT) in Pakistani population and to compare the results with international data.
 Study Design: Retrospective observational study.
 Place and Duration of Study: Armed Forces Institute of Pathology, Rawalpindi, from Jan 2015 and Dec 2019.
 Methodology: This data was analyzed using the latest World Health Organization (WHO) classification of Tumors of Central Nervous System 2016. The cases were divided in 5 categories according to age (0-2, 3-5, 6-8, 9-11 & 12-14 years).
 Results: A total of 43 cases were included in the study. Of these cases, 26 (60.46%) were male and 17 (39.5%) were female. Male to female ratio was 1.5-1. The 6-8 year age group had the highest number of tumors while 0-2 year age group had the least. Mean age of diagnosis was 7.6 years. Ependymoma wasthe most common morphological type with 12 cases (28%) followed by pilocytic astrocytoma, diffuse glioma with 10 cases each (23%) and medulloblastoma with 9 cases (21%). Least common tumor subtype was Ewing sarcoma. Ependymoma were mostly of grade 3 (64%), pilocytic astrocytoma and medulloblastoma were of grade 1 and grade 4 respectively by definition, and diffuse gliomas were mainly of grade 2 (57%) type.
 Conclusion: Ependymoma and pilocytic astrocytomaare the most frequent types of pediatric brain tumors in our region which follows the same trend as mentioned in western and regional literature.

IMMU-16. TARGETING GLYPICAN 2 (GPC2) ON PEDIATRIC MALIGNANT BRAIN TUMORS WITH MRNA CAR T CELLS

Glypican 2 (GPC2) is a cell-surface oncoprotein initially identified in neuroblastoma, retinoblastoma, and medulloblastoma as an ideal target for immunotherapy (Cancer Cell, 2017). Here we evaluated GPC2 expression across the spectrum of pediatric brain tumors using RNA sequencing from specimens in the Children’s Brain Tumor Network (CBTN). High GPC2 expression, defined as >10 FPKM, was found in 100% of embryonal tumors with multilayered rosettes (ETMRs) (n=6), 95% of medulloblastomas (n=122), 86% of other embryonal tumors (n=21), 50% of choroid plexus carcinomas (n=4), 42% of high grade gliomas (HGG) (n=117), and 37% of diffuse midline gliomas (DMG) (n=65). Within medulloblastoma subtypes, group 4 tumors had the highest expression, and within the HGG tumor cohort H3.3 G34 mutated gliomas had the highest GPC2 expression. High GPC2 protein expression was validated with medulloblastoma and HGG/DMG primary tumors and cell lines using IHC, Western blot, and flow cytometry. We next developed two potent CAR T cell constructs using the D3 specific scFv directed against GPC2 for testing in brain tumor models. GPC2-directed CAR T cells were tested in vitro against medulloblastoma and HGG cells lines, and in vivo using two patient-derived medulloblastoma xenograft models: Rcmb28 (group 3) and 7316-4509 (group 4). GPC2-directed mRNA CAR T cells induced significant GPC2-specific cell death in medulloblastoma and HGG cellular models with concomitant T cell degranulation compared to CD19-directed mRNA CAR T cells. In vivo, GPC2-directed mRNA CAR T cells delivered locoregionally induced significant tumor regression measured by bioluminescence after 4–6 intratumoral infusions of 4 x 106 CAR T cells (p<0.0001 for Rcmb28, p<0.05 for 7316-4509). No GPC2-directed CAR T cell related toxicity was observed. GPC2 is a highly differentially expressed cell surface protein on multiple malignant pediatric brain tumors that can be targeted safely with local delivery of mRNA CAR T cells.

Cell-surface antigen profiling of pediatric brain tumors: B7-H3 is consistently expressed and can be targeted via local or systemic CAR T-cell delivery.

Immunotherapy with chimeric antigen receptor (CAR) T cells is actively being explored for pediatric brain tumors in preclinical models and early phase clinical studies. At present, it is unclear which CAR target antigens are consistently expressed across different pediatric brain tumor types. In addition, the extent of HLA class I expression is unknown, which is critical for tumor recognition by conventional αβTCR T cells. We profiled 49 low- and high-grade pediatric brain tumor patient-derived orthotopic xenografts (PDOX) by flow analysis for the expression of 5 CAR targets (B7-H3, GD2, IL-13Rα2, EphA2, and HER2), and HLA class I. In addition, we generated B7-H3-CAR T cells and evaluated their antitumor activity in vitro and in vivo. We established an expression hierarchy for the analyzed antigens (B7-H3 = GD2 >> IL-13Rα2 > HER2 = EphA2) and demonstrated that antigen expression is heterogenous. All high-grade gliomas expressed HLA class I, but only 57.1% of other tumor subtypes had detectable expression. We then selected B7-H3 as a target for CAR T-cell therapy. B7-H3-CAR T cells recognized tumor cells in an antigen-dependent fashion. Local or systemic administration of B7-H3-CAR T cells induced tumor regression in PDOX and immunocompetent murine glioma models resulting in a significant survival advantage. Our study highlights the importance of studying target antigen and HLA class I expression in PDOX samples for the future design of immunotherapies. In addition, our results support active preclinical and clinical exploration of B7-H3-targeted CAR T-cell therapies for a broad spectrum of pediatric brain tumors.

MODL-28. IMMUNE PRIMING WITH INTERFERON-Γ COMBINED WITH EPIGENETIC MODULATION IN PEDIATRIC BRAIN TUMORS

Systemic interferon-γ (IFNγ) has been shown to induce major histocompatibility complex class I (MHC-I) and T cell infiltration in solid tumors in adult patients, demonstrating a potential strategy to abrogate tumor-intrinsic mechanisms of immune escape. Pediatric brain tumors (PBT) may be particularly sensitive to this approach but have a paucity of immunogenic tumor antigens for presentation on MHC-I. Decitabine and other DNA methyltransferase (DNMT) inhibitors promote expression of oncofetal antigens and endogenous immune responses through epigenetic alterations. We tested the convergence of these immune priming mechanisms using a novel combination of IFNγ and decitabine across a spectrum of PBT. Primary human cell lines (Med-411FH, PBT-05FH, GBM-511FH, CCHMC-GBM-1, CCHMC-GBM-4, ATRT-310FH) and murine transgenic models were treated with IFNγ alone or in combination with decitabine and evaluated expression of cell surface MHC-I and PD-L1, interferon response genes (ISGs), and oncofetal antigens. PBT showed exquisite sensitivity to IFNγ, increasing expression of MHC-1/PD-L1 along with ISGs (TAP1, MX1, IRF1). Decitabine enhanced IFNγ-induced gene expression of oncofetal antigens NY-ESO-1 and MAGE-A1. In a medulloblastoma flank tumor model, MHC-I was increased by 40-fold following intraperitoneal IFNγ treatment (p=0.01), with a 3-fold increase in PD-L1 (p=0.005) compared to untreated controls. Effect on CD8+ T cell killing and validation in humanized models is ongoing. Immune priming of PBT with IFNγ is feasible and results in more substantial MHC-I upregulation compared to hypomethylating agents alone. These results provide a strong rationale for priming prior to checkpoint inhibition as a compelling therapeutic strategy in immunologically-quiescent PBT.

Clinical Utility of GlioSeq Next-Generation Sequencing Test in Pediatric and Young Adult Patients With Brain Tumors

Brain tumors are the leading cause of death in children. Establishing an accurate diagnosis and therapy is critical for patient management. This study evaluated the clinical utility of GlioSeq, a next-generation sequencing (NGS) assay, for the diagnosis and management of pediatric and young adult patients with brain tumors. Between May 2015 and March 2017, 142 consecutive brain tumors were tested using GlioSeq v1 and subset using GlioSeq v2. Out of 142 samples, 63% were resection specimens and 37% were small stereotactic biopsies. GlioSeq sequencing was successful in 100% and 98.6% of the cases for the detection of mutations and copy number changes, and gene fusions, respectively. Average turnaround time was 8.7 days. Clinically significant genetic alterations were detected in 95%, 66.6%, and 66.1% of high-grade gliomas, medulloblastomas, and low-grade gliomas, respectively. GlioSeq enabled molecular-based stratification in 92 (65%) cases by specific molecular subtype assignment (70, 76.1%), substantiating a neuropathologic diagnosis (18, 19.6%), and diagnostic recategorization (4, 4.3%). Fifty-seven percent of the cases harbored therapeutically actionable findings. GlioSeq NGS analysis offers rapid detection of a wide range of genetic alterations across a spectrum of pediatric brain tumors using formalin-fixed, paraffin-embedded specimens and facilitates integrated molecular-morphologic classification and personalized management of pediatric brain tumors.

Pediatric Brain Tumors: Innovative Genomic Information Is Transforming the Diagnostic and Clinical Landscape.

Pediatric neuro-oncology has undergone an exciting and dramatic transformation during the past 5 years. This article summarizes data from collaborative group and institutional trials that have advanced the science of pediatric brain tumors and survival of patients with these tumors. Advanced genomic analysis of the entire spectrum of pediatric brain tumors has heralded an era in which stakeholders in the pediatric neuro-oncology community are being challenged to reconsider their current research and diagnostic and treatment strategies. The incorporation of this new information into the next-generation treatment protocols will unleash new challenges. This review succinctly summarizes the key advances in our understanding of the common pediatric brain tumors (ie, medulloblastoma, low- and high-grade gliomas, diffuse intrinsic pontine glioma, and ependymoma) and some selected rare tumors (ie, atypical teratoid/rhabdoid tumor and CNS primitive neuroectodermal tumor). The potential impact of this new information on future clinical protocols also is discussed. Cutting-edge genomics technologies and the information gained from such studies are facilitating the identification of molecularly defined subgroups within patients with particular pediatric brain tumors. The number of evaluable patients in each subgroup is small, particularly in the subgroups of rare diseases. Therefore, international collaboration will be crucial to draw meaningful conclusions about novel approaches to treating pediatric brain tumors.

18F-FDG PET and MR imaging associations across a spectrum of pediatric brain tumors: a report from the pediatric brain tumor consortium.

The purpose of this study was to describe (18)F-FDG uptake across a spectrum of pediatric brain tumors and correlate (18)F-FDG PET with MR imaging variables, progression-free survival (PFS), and overall survival (OS). A retrospective analysis was conducted of children enrolled in phase I/II clinical trials through the Pediatric Brain Tumor Consortium from August 2000 to June 2010. PET variables were summarized within diagnostic categories using descriptive statistics. Associations of PET with MR imaging variables and PFS and OS by tumor types were evaluated. Baseline (18)F-FDG PET was available in 203 children; 66 had newly diagnosed brain tumors, and 137 had recurrent/refractory brain tumors before enrolling in a Pediatric Brain Tumor Consortium trial. MR imaging was performed within 2 wk of PET and before therapy in all cases. The (18)F-FDG uptake pattern and MR imaging contrast enhancement (CE) varied by tumor type. On average, glioblastoma multiforme and medulloblastoma had uniform, intense uptake throughout the tumor, whereas brain stem gliomas (BSGs) had low uptake in less than 50% of the tumor and ependymoma had low uptake throughout the tumor. For newly diagnosed BSG, correlation of (18)F-FDG uptake with CE portended reduced OS (P = 0.032); in refractory/recurrent BSG, lack of correlation between (18)F-FDG uptake and CE suggested decreased PFS (P = 0.023). In newly diagnosed BSG for which more than 50% of the tumor had (18)F-FDG uptake, there was a suggestion of lower apparent diffusion coefficient (P = 0.061) and decreased PFS (P = 0.065). (18)F-FDG PET and MR imaging showed a spectrum of patterns depending on tumor type. In newly diagnosed BSG, the correlation of (18)F-FDG uptake and CE suggested decreased OS, likely related to more aggressive disease. When more than 50% of the tumor had (18)F-FDG uptake, the apparent diffusion coefficient was lower, consistent with increased cellularity. In refractory/recurrent BSG, poor correlation between (18)F-FDG uptake and CE was associated with decreased PFS, which may reflect concurrent tissue breakdown at sites of treated disease and development of new sites of (18)F-FDG-avid malignancy.

Spectrum of pediatric brain tumors: a report of 341 cases from a tertiary cancer center in India.

Brain tumors are the second most common cancers after hematological malignancies accounting for approximate 21% of all childhood malignancies in children between ages of 0 and 14 y. The present study was undertaken to determine the spectrum of the brain tumors diagnosed in a tertiary cancer center in South India. A retrospective analysis of the data of pediatric brain tumors diagnosed between 2003 and 2009 was done and data was classified according to the age, gender and histology types. Out of 2,844 pediatric patients, 341 (11.99%) were diagnosed as having brain tumors. Most of the patients were in the age group of >5-14 y. Male to female ratio was 1.58:1. The most common pediatric brain tumor was medulloblastoma followed by astrocytoma and ependymoma. Glioblastoma multiforme was the most common subtype of astrocytoma. Other common tumors were glioma, oligodendroglioma, periphereral neuroectodermal tumor and germ cell tumor. As compared to western data, incidence of brain tumors in children was found to be less in the present study.

Exploratory Evaluation of MR Permeability with 18F-FDG PET Mapping in Pediatric Brain Tumors: A Report from the Pediatric Brain Tumor Consortium

The purpose of this study was to develop a method of registering (18)F-FDG PET with MR permeability images for investigating the correlation of (18)F-FDG uptake, permeability, and cerebral blood volume (CBV) in children with pediatric brain tumors and their relationship with outcome. Twenty-four children with brain tumors in a phase II study of bevacizumab and irinotecan underwent brain MR and (18)F-FDG PET within 2 wk. Tumor types included supratentorial high-grade astrocytoma (n = 7), low-grade glioma (n = 9), brain stem glioma (n = 4), medulloblastoma (n = 2), and ependymoma (n = 2). There were 33 cases (pretreatment only [n = 12], posttreatment only [n = 3], and both pretreatment [n = 9] and posttreatment [n = 9]). (18)F-FDG PET images were registered to MR images from the last time point of the T1 perfusion time series using mutual information. Three-dimensional regions of interest (ROIs) drawn on permeability images were automatically transferred to registered PET images. The quality of ROI registration was graded (1, excellent; 2, very good; 3, good; 4, fair; and 5, poor) by 3 independent experts. Spearman rank correlations were used to assess correlation of maximum tumor permeability (Kps(max)), maximum CBV (CBV(max)), and maximum (18)F-FDG uptake normalized to white matter (T/W(max)). Cox proportional hazards models were used to investigate associations of these parameters with progression-free survival (PFS). The quality of ROI registration between PET and MR was good to excellent in 31 of 33 cases. There was no correlation of baseline Kps(max) with CBV(max) (Spearman rank correlation = 0.018 [P = 0.94]) or T/W(max) (Spearman rank correlation = 0.07 [P = 0.76]). Baseline CBV(max) was correlated with T/W(max) (Spearman rank correlation = 0.47 [P = 0.036]). Baseline Kps(max), CBV(max), and T/W(max) were not significantly associated with PFS (P = 0.42, hazard ratio [HR] = 0.97, 95% confidence interval [CI] = 0.90-1.045, and number of events [n(events)] = 15 for Kps(max); P = 0.41, HR = 0.989, 95% CI = 0.963-1.015, and n(events) = 14 for CBV(max); and P = 0.17, HR = 1.49, 95% CI = 0.856-2.378, and n(events) = 15 for T/W(max)). (18)F-FDG PET and MR permeability images were successfully registered and compared across a spectrum of pediatric brain tumors. The lack of correlation between metabolism and permeability may be expected because these parameters characterize different molecular processes. The correlation of CBV and tumor metabolism may be related to an association with tumor grade. More patients are needed for a covariate analysis of these parameters and PFS by tumor histology.

Spectrum of pediatric brain tumors in India: A multi-institutional study

Till date there is no published multi-institutional data regarding the epidemiological profile of pediatric brain tumors in India. The present retrospective study analyses the histological spectrum of pediatric age group brain tumors in seven tertiary care hospitals in India. Data regarding frequencies of various primary brain tumors (diagnosed according to the World Health Organization (WHO) classification), in 3936 pediatric patients (<18 yrs of age), was collected from seven tertiary care hospitals in India. The most common primary pediatric brain tumors were astrocytic tumors (34.7%), followed by medulloblastoma and supratentorial primitive neuro-ectodermal tumors (22.4%), craniopharyngiomas (10.2%) and ependymal tumors (9.8%). The most common astrocytic tumor was pilocytic astrocytoma. In comparison to adults, oligodendrogliomas and lymphomas were rare in children. Our study is the first such report on the histological spectrum of brain tumors in children in India. Except for a slightly higher frequency of craniopharyngiomas, the histological profile of pediatric brain tumors in India is similar to that reported in the Western literature.

Spectrum of pediatric brain tumors in India

Spectrum of pediatric brain tumors in India

Current concepts in the molecular genetics of pediatric brain tumors: implications for emerging therapies

The revolution in molecular biology that has taken place over the past 2 decades has provided researchers with new and powerful tools for detailed study of the molecular mechanisms giving rise to the spectrum of pediatric brain tumors. Application of these tools has greatly advanced our understanding of the molecular pathogenesis of these lesions. After familiarizing readers with some promising new techniques in the field of oncogenomics, this review will present the current state of knowledge as it pertains to the molecular biology of pediatric brain neoplasms. Along the way, we hope to highlight specific instances where the detailed mechanistic knowledge acquired thus far may be exploited for therapeutic advantage.

A phase II study of carboplatin in children with recurrent or progressive solid tumors. A report from the childrens cancer group

Carboplatin is an analogue of cisplatin with less nonhematologic toxicity than the parent compound. It has been demonstrated previously to have activity against a spectrum of pediatric brain tumors. This Phase II study was undertaken to assess the activity of carboplatin in children with various solid tumors. Between October 1985 and March 1988, the Childrens Cancer Group entered 117 patients with drug-resistant, recurrent lymphomas and solid tumors, excluding primary central nervous system tumors, into a Phase II trial of carboplatin given intravenously at a dosage of 560 mg/m2 over 1 hour every 4 weeks. A complete response was seen in 1 of 15 evaluable patients with Ewing's sarcoma. Partial responses were seen in 2 of 17 evaluable patients with neuroblastoma, 1 of 16 with soft tissue sarcoma, 2 of 5 with Wilms' tumor, and 1 with an endodermal sinus tumor of the testis. Objective responses were not seen in patients with malignant lymphoma, osteosarcoma, or hepatoma. Four of 7 patients who responded to carboplatin had previously received cisplatin. Sixty-two percent of patients had a platelet count nadir of less than 50,000/mm3, and 41% had an absolute neutrophil count nadir of less than 1,000/mm3. Ototoxicity, nephrotoxicity, hypomagnesemia, hypertransaminasemia, and nausea and vomiting each were seen in fewer than 10% of patients. Carboplatin has some activity against Wilms' tumor, Ewing's sarcoma, neuroblastoma, soft tissue sarcoma, and endodermal sinus tumor of the testis. Activity was not demonstrated against osteosarcoma, malignant lymphoma, hepatoma, and miscellaneous other tumors. Myelosuppression was seen commonly, and nonhematologic toxicity was infrequent.

A phase II study of carboplatin in children with recurrent or progressive solid tumors. A report from the childrens cancer group

Carboplatin is an analogue of cisplatin with less nonhematologic toxicity than the parent compound. It has been demonstrated previously to have activity against a spectrum of pediatric brain tumors. This Phase II study was undertaken to assess the activity of carboplatin in children with various solid tumors.Between October 1985 and March 1988, the Childrens Cancer Group entered 117 patients with drug-resistant, recurrent lymphomas and solid tumors, excluding primary central nervous system tumors, into a Phase II trial of carboplatin given intravenously at a dosage of 560 mg/m2 over 1 hour every 4 weeks.A complete response was seen in 1 of 15 evaluable patients with Ewing's sarcoma. Partial responses were seen in 2 of 17 evaluable patients with neuroblastoma, 1 of 16 with soft tissue sarcoma, 2 of 5 with Wilms' tumor, and 1 with an endodermal sinus tumor of the testis. Objective responses were not seen in patients with malignant lymphoma, osteosarcoma, or hepatoma. Four of 7 patients who responded to carboplatin had previously received cisplatin. Sixty-two percent of patients had a platelet count nadir of less than 50,000/mm3, and 41% had an absolute neutrophil count nadir of less than 1,000/mm3. Ototoxicity, nephrotoxicity, hypomagnesemia, hypertransaminasemia, and nausea and vomiting each were seen in fewer than 10% of patients.Carboplatin has some activity against Wilms' tumor, Ewing's sarcoma, neuroblastoma, soft tissue sarcoma, and endodermal sinus tumor of the testis. Activity was not demonstrated against osteosarcoma, malignant lymphoma, hepatoma, and miscellaneous other tumors. Myelosuppression was seen commonly, and nonhematologic toxicity was infrequent.