RESUMO
Adoptively transferred T cells and agents designed to block the CD47-SIRPα axis are promising cancer therapeutics that activate distinct arms of the immune system1,2. Here we administered anti-CD47 antibodies in combination with adoptively transferred T cells with the goal of enhancing antitumour efficacy but observed abrogated therapeutic benefit due to rapid macrophage-mediated clearance of T cells expressing chimeric antigen receptors (CARs) or engineered T cell receptors. Anti-CD47-antibody-mediated CAR T cell clearance was potent and rapid enough to serve as an effective safety switch. To overcome this challenge, we engineered the CD47 variant CD47(Q31P) (47E), which engages SIRPα and provides a 'don't eat me' signal that is not blocked by anti-CD47 antibodies. TCR or CAR T cells expressing 47E are resistant to clearance by macrophages after treatment with anti-CD47 antibodies, and mediate substantial, sustained macrophage recruitment to the tumour microenvironment. Although many of the recruited macrophages manifested an M2-like profile3, the combined therapy synergistically enhanced antitumour efficacy. Our study identifies macrophages as major regulators of T cell persistence and illustrates the fundamental challenge of combining T-cell-directed therapeutics with those designed to activate macrophages. It delivers a therapeutic approach that is capable of simultaneously harnessing the antitumour effects of T cells and macrophages, offering enhanced potency against solid tumours.
Assuntos
Antígeno CD47 , Imunoterapia Adotiva , Neoplasias , Linfócitos T , Animais , Feminino , Humanos , Masculino , Camundongos , Antígenos de Diferenciação/imunologia , Antígenos de Diferenciação/metabolismo , Antígeno CD47/genética , Antígeno CD47/imunologia , Antígeno CD47/metabolismo , Linhagem Celular Tumoral , Imunoterapia Adotiva/métodos , Macrófagos/citologia , Macrófagos/imunologia , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Receptores Imunológicos/imunologia , Receptores Imunológicos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/transplante , Microambiente Tumoral/imunologia , Anticorpos/imunologia , Anticorpos/uso terapêutico , Ativação de MacrófagosRESUMO
OBJECTIVE: Adamantinomatous craniopharyngioma mainly affects children. Excessive weight gain is a major long-term complication. The primary objective of this study was to assess long-term weight changes in children treated for craniopharyngioma. The secondary objectives were to identify risk factors for excessive weight gain and to look for associations with hypothalamic damage by the tumour or treatment. DESIGN: Single-centre retrospective cohort study. METHOD: Children managed for craniopharyngioma at our centre between 1990 and 2019 were included. The body mass index (BMI) standard deviation scores (SDS) at baseline and at last follow-up were compared. Univariate and multivariate analyses were performed in order to identify variables associated with the long-term BMI-SDS variation. RESULTS: The 108 patients had a mean follow-up of 10.4 years. The mean BMI-SDS increase over time was 2.11 (P < .001) overall, 1.21 (P < .001) in the group without hypothalamic involvement by the tumour, and 1.95 (P < .001) in the group managed using intended hypothalamus-sparing surgery. The absence of hypothalamic involvement by the tumour or treatment was significantly associated with less weight gain (P = .046 and P < .01, respectively). After adjustment, factors associated with a BMI-SDS change greater than 2 were female sex (P = .023), tumour involving the hypothalamus (P = .04), and higher baseline BMI (P < .001). CONCLUSION: Clinically significant weight gain occurred in nearly all children treated for craniopharyngioma, including those whose hypothalamus was spared by the tumour and intentionally by treatment. However, hypothalamus integrity was associated with less weight gain. Despite hypothalamus-sparing strategies, hypothalamic obesity remains a major concern, indicating a need for novel treatment approaches.
Assuntos
Índice de Massa Corporal , Craniofaringioma , Neoplasias Hipofisárias , Aumento de Peso , Humanos , Craniofaringioma/epidemiologia , Craniofaringioma/complicações , Aumento de Peso/fisiologia , Masculino , Feminino , Criança , Estudos Retrospectivos , Neoplasias Hipofisárias/epidemiologia , Neoplasias Hipofisárias/patologia , Neoplasias Hipofisárias/complicações , Adolescente , Pré-Escolar , Seguimentos , Fatores de Risco , Hipotálamo , Estudos de CoortesRESUMO
Adenosine (Ado) mediates immune suppression in the tumor microenvironment and exhausted CD8+ CAR-T cells express CD39 and CD73, which mediate proximal steps in Ado generation. Here, we sought to enhance CAR-T cell potency by knocking out CD39, CD73, or adenosine receptor 2a (A2aR) but observed only modest effects. In contrast, overexpression of Ado deaminase (ADA-OE), which metabolizes Ado to inosine (INO), induced stemness and enhanced CAR-T functionality. Similarly, CAR-T cell exposure to INO augmented function and induced features of stemness. INO induced profound metabolic reprogramming, diminishing glycolysis, increasing mitochondrial and glycolytic capacity, glutaminolysis and polyamine synthesis, and reprogrammed the epigenome toward greater stemness. Clinical scale manufacturing using INO generated enhanced potency CAR-T cell products meeting criteria for clinical dosing. These results identify INO as a potent modulator of CAR-T cell metabolism and epigenetic stemness programming and deliver an enhanced potency platform for cell manufacturing.
Assuntos
Inosina , Linfócitos T , Humanos , Linfócitos T/metabolismoRESUMO
BACKGROUND: The French phase II AcSé-crizotinib trial aimed to evaluate the safety and efficacy of crizotinib in patients with ALK, ROS1, and MET-driven malignancies, including ALK-positive anaplastic large-cell lymphoma (ALK+ ALCL). METHODS: ALK+ ALCL patients 12 months or older with measurable disease and no standard care options available received crizotinib twice daily at 165 mg/m2 in children and adolescents and 250 mg in adults. The primary end-point was the response rate at 8 weeks. RESULTS: Twenty-eight patients were enroled between February 2014 and March 2018. Three patients who were not treated were excluded from the analysis. The median age was 19 years. The median previous line of chemotherapy was two. In the 24 patients with an evaluable response, the response rate at 8 weeks was 67% (95% CI: 47-82%). All patients discontinued crizotinib after a median treatment duration of 3.7 months: eight for progression, two for adverse events (AEs) related to prior treatments, and 15 by choice, including six for allogeneic stem-cell transplantation. The median follow-up was 45 months. Nine patients experienced an event: eight relapses (seven after crizotinib discontinuation and one after dose reduction), and one died in complete remission. The median duration of response was 43.3 months (95% CI: 8.3-not reached). The 3-year progression-free and overall survival rates were 40% (95% CI: 23-59%) and 63% (95% CI: 43-79%). Grade 3 or 4 treatment-related AEs occurred in 32% of patients. CONCLUSION: Crizotinib shows efficacy and an acceptable safety profile in ALK+ ALCL relapsed/refractory patients. However, a large proportion of patients experience a relapse after crizotinib discontinuation. Future studies will assess if prolonged ALK inhibitor exposure has curative potential without consolidation.
Assuntos
Neoplasias Pulmonares , Linfoma Anaplásico de Células Grandes , Humanos , Adulto , Criança , Adolescente , Adulto Jovem , Crizotinibe/uso terapêutico , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Proteínas Tirosina Quinases/uso terapêutico , Quinase do Linfoma Anaplásico , Recidiva Local de Neoplasia/tratamento farmacológico , Proteínas Proto-Oncogênicas , Receptores Proteína Tirosina Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológicoRESUMO
Importance: Innovative anticancer therapies for children, adolescents, and young adults are regularly prescribed outside their marketing authorization or through compassionate use programs. However, no clinical data of these prescriptions is systematically collected. Objectives: To measure the feasibility of the collection of clinical safety and efficacy data of compassionate and off-label innovative anticancer therapies, with adequate pharmacovigilance declaration to inform further use and development of these medicines. Design, Setting, and Participants: This cohort study included patients treated at French pediatric oncology centers from March 2020 to June 2022. Eligible patients were aged 25 years or younger with pediatric malignant neoplasms (solid tumors, brain tumors, or hematological malignant neoplasms) or related conditions who received compassionate use or off-label innovative anticancer therapies. Follow up was conducted through August 10, 2022. Exposures: All patients treated in a French Society of Pediatric Oncology (SFCE) center. Main Outcomes and Measures: Collection of adverse drug reactions and anticancer activity attributable to the treatment. Results: A total of 366 patients were included, with a median age of 11.1 years (range, 0.2-24.6 years); 203 of 351 patients (58%) in the final analysis were male. Fifty-five different drugs were prescribed, half of patients (179 of 351 [51%]) were prescribed these drugs within a compassionate use program, mainly as single agents (74%) and based on a molecular alteration (65%). Main therapies were MEK/BRAF inhibitors followed by multi-targeted tyrosine kinase inhibitors. In 34% of patients at least a grade 2 clinical and/or grade 3 laboratory adverse drug reaction was reported, leading to delayed therapy and permanent discontinuation of the innovative therapy in 13% and 5% of patients, respectively. Objective responses were reported in 57 of 230 patients (25%) with solid tumors, brain tumors, and lymphomas. Early identification of exceptional responses supported the development of specific clinical trials for this population. Conclusions and Relevance: This cohort study of the SACHA-France (Secured Access to Innovative Medicines for Children with Cancer) suggested the feasibility of prospective multicenter clinical safety and activity data collection for compassionate and off-label new anticancer medicines. This study allowed adequate pharmacovigilance reporting and early identification of exceptional responses allowing further pediatric drug development within clinical trials; based on this experience, this study will be enlarged to the international level.
Assuntos
Antineoplásicos , Neoplasias Encefálicas , Criança , Humanos , Masculino , Adolescente , Adulto Jovem , Lactente , Pré-Escolar , Adulto , Feminino , Uso Off-Label , Estudos Prospectivos , Estudos de Coortes , Antineoplásicos/efeitos adversos , Neoplasias Encefálicas/tratamento farmacológicoRESUMO
Adenosine (Ado) mediates immune suppression in the tumor microenvironment and exhausted CD8+ CAR T cells mediate Ado-induced immunosuppression through CD39/73-dependent Ado production. Knockout of CD39, CD73 or A2aR had modest effects on exhausted CAR T cells, whereas overexpression of Ado deaminase (ADA), which metabolizes Ado to inosine (INO), induced stemness features and potently enhanced functionality. Similarly, and to a greater extent, exposure of CAR T cells to INO augmented CAR T cell function and induced hallmark features of T cell stemness. INO induced a profound metabolic reprogramming, diminishing glycolysis and increasing oxidative phosphorylation, glutaminolysis and polyamine synthesis, and modulated the epigenome toward greater stemness. Clinical scale manufacturing using INO generated enhanced potency CAR T cell products meeting criteria for clinical dosing. These data identify INO as a potent modulator of T cell metabolism and epigenetic stemness programming and deliver a new enhanced potency platform for immune cell manufacturing.
RESUMO
The spectrum of somatic mutations in pediatric histiocytoses and their clinical implications are not fully characterized, especially for non-Langerhans cell histiocytosis (-LCH) subtypes. A cohort of 415 children with histiocytosis from the French histiocytosis registry was reviewed and analyzed for BRAFV600E . Most BRAFWT samples were analyzed by next-generation sequencing (NGS) with a custom panel of genes for histiocytosis and myeloid neoplasia. Of 415 case samples, there were 366 LCH, 1 Erdheim-Chester disease, 21 Rosai-Dorfman disease (RDD), 21 juvenile xanthogranuloma (JXG, mostly with severe presentation), and 6 malignant histiocytosis (MH). BRAFV600E was the most common mutation found in LCH (50.3%, n = 184). Among 105 non-BRAFV600E -mutated LCH case samples, NGS revealed mutations as follows: MAP2K1 (n = 44), BRAF exon 12 deletions (n = 26), and duplications (n = 8), other BRAF V600 codon mutation (n = 4), and non-MAP-kinase pathway genes (n = 5). Wild-type sequences were identified in 17.1% of samples. BRAFV600E was the only variant significantly correlated with critical presentations: organ-risk involvement and neurodegeneration. MAP-kinase pathway mutations were identified in seven RDD (mostly MAP2K1) and three JXG samples, but most samples were wild-type on NGS. Finally, two MH samples had KRAS mutations, and one had a novel BRAFG469R mutation. Rarely, we identified mutations unrelated to MAP-kinase pathway genes. In conclusion, we characterized the mutational spectrum of childhood LCH and clinical correlations of variants and subtypes. Variants responsible for JXG and RDD were not elucidated in more than half of the cases, calling for other sequencing approaches.
Assuntos
Doença de Erdheim-Chester , Histiocitose de Células de Langerhans , Humanos , Criança , Histiocitose de Células de Langerhans/genética , Proteínas Proto-Oncogênicas B-raf/genética , Doença de Erdheim-Chester/genética , Mutação , ÉxonsAssuntos
Antineoplásicos , Neoplasias Pulmonares , Linfoma Anaplásico de Células Grandes , Pediatria , Criança , Humanos , Crizotinibe/uso terapêutico , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Aprovação de Drogas , Receptores Proteína Tirosina Quinases , Inibidores de Proteínas Quinases/uso terapêutico , Antineoplásicos/uso terapêuticoRESUMO
CONTEXT: Craniopharyngioma is a benign brain tumor with frequent local recurrence or progression after treatment. GH replacement therapy (GHRT) is prescribed in children with GH deficiency resulting from childhood-onset craniopharyngioma. OBJECTIVE: To evaluate whether a shorter delay of GHRT initiation after childhood-onset craniopharyngioma completion therapy increased the risk of a new event (progression or recurrence). METHODS: Retrospective, observational, monocenter study. We compared a cohort of 71 childhood-onset patients with craniopharyngiomas treated with recombinant human GH (rhGH). Twenty-seven patients were treated with rhGH at least 12 months after craniopharyngioma treatment (>12-month group) and 44 patients before 12 months (<12-month group), among which 29 patients were treated between 6 and 12 months (6-12 month group). The main outcome was the risk of tumor new event (progression of residual tumor or tumor recurrence after complete resection) after primary treatment in the >12-month group and in the <12 month or in the 6- to 12-month group patients. RESULTS: In the >12-month group, the 2- and 5-year event-free survivals were respectively 81.5% (95% CI, 61.1-91.9) and 69.4% (95% CI, 47.9-83.4) compared with 72.2% (95% CI, 56.3-83.1) and 69.8% (95% CI, 53.8-81.2) in the <12-month group. The 2- and 5-year event-free survivals were the same in the 6- to 12-month group (72.4%; 95% CI, 52.4-85.1). By log-rank test, the event-free survival was not different between groups (P = .98 and P = .91).The median time for event was not statistically different.In univariate and multivariate analysis, the risk of craniopharyngioma new event was not associated with the GHRT time delay after craniopharyngioma treatment. CONCLUSIONS: No association was found between GHRT time delay after childhood-onset craniopharyngioma treatment and an increased risk of recurrence or tumor progression, suggesting GH replacement therapy can be initiated 6 months after last treatment for craniopharyngiomas.
Assuntos
Craniofaringioma , Hormônio do Crescimento Humano , Neoplasias Hipofisárias , Humanos , Criança , Craniofaringioma/patologia , Estudos Retrospectivos , Neoplasias Hipofisárias/tratamento farmacológico , Neoplasias Hipofisárias/epidemiologia , Neoplasias Hipofisárias/patologia , Recidiva Local de Neoplasia/etiologia , Hormônio do Crescimento Humano/efeitos adversos , Terapia de Reposição Hormonal/efeitos adversosRESUMO
The role of immune checkpoint inhibitors (ICIs) in the treatment of pediatric cancers continues to evolve. Such therapies function by augmenting existing antitumor T-cell responses that have been rendered ineffective by inhibitory pathways. Although ICIs have proven highly effective for adult cancers, initial phase I/II clinical trials using single-agent ICIs against unselected pediatric cancers have been overall disappointing. With the exception of pediatric classic Hodgkin lymphoma, responses to ICIs have been infrequent, likely stemming from an inherent difference in the immunogenicity of childhood cancers, which, on average, have far fewer neoantigens than adult cancers. Recently, however, hope has reemerged that certain subsets of children with cancer may benefit from ICI therapies. In preliminary studies, patients with both pediatric hypermutated and SMARCB1-deficient cancers have had impressive responses to ICI therapies, likely as a result of underlying biologies that enhance neoantigen expression and tumoral inflammation. Dedicated trials are ongoing to fully evaluate the efficacy of ICIs for patients with these subsets of pediatric cancer.
Assuntos
Doença de Hodgkin , Pediatria , Criança , Humanos , Inibidores de Checkpoint Imunológico , Fatores Imunológicos , ImunoterapiaRESUMO
Primary mediastinal large B-cell lymphoma (PMLBL) is a rare entity predominantly affecting adolescents and young adults. Recently, an international phase II trial in pediatric patients using dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine and prednisone plus rituximab (DA-EPOCH-R) failed to reproduce excellent survival reported in some adult studies. The optimal therapy regimen needs to be determined in this disease. The French prospective LMB2001 trial included all patients ≤18 years with mature B-cell lymphoma treated in French centers. For patients with PMLBL, treatment included four to eight courses of Lymphomes Malins B (LMB)-based chemotherapy without radiotherapy. From 2008, rituximab was added before each chemotherapy course. From 09/2001 to 03/2012, 42 patients with PMLBL were registered. The median age was 15 years (range, 8-18). Twenty-one patients were treated with chemotherapy plus rituximab. The median follow-up was 7.1 years (interquartile range, 5.8-11.1). Five-year event-free and overall survival were 88.1% (95% confidence interval (CI): 75.0-94.8) and 95.2% (95% CI: 84.0-98.7) for the whole population. The 5-year EFS was 81.0% (95% CI: 60.0-92.3) and 95.2% (95% CI: 77.3-99.2) (hazard ratio =0.24; 95% CI: 0.03- 2.2) and 5-year overall survival was 90.5% (95% CI: 71.1-97.3) and 100% for patients treated without and with rituximab, respectively. Only one of 21 patients treated with rituximab and LMB-based chemotherapy had local early treatment failure but achieved prolonged complete remission with second-line chemotherapy and radiotherapy. Intensive LMBbased chemotherapy with rituximab achieved excellent survival in children/adolescents with PMLBL. Further international prospective studies are required to confirm these results in this population.
Assuntos
Linfoma Difuso de Grandes Células B , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Ciclofosfamida , Doxorrubicina/efeitos adversos , Etoposídeo , Humanos , Linfoma Difuso de Grandes Células B/patologia , Prednisona/uso terapêutico , Estudos Prospectivos , Rituximab , Vincristina/efeitos adversos , Adulto JovemRESUMO
OBJECTIVE: The aim was to analyze the role of Epstein-Barr virus (EBV) in the bioclinical characteristics of patients treated for classic Hodgkin lymphoma (cHL) in France. METHODS: Biopathologic data of 301 patients treated for a cHL in/or according to the EuroNet PHL-C1 trial between November 2008 and February 2013 were centrally reviewed. RESULTS: Median age at diagnosis was 14 (3 to 18) years and the F/M ratio 0.86, 0.47 before 10 years and 0.9 from 11 to 18. CHL subtypes were nodular sclerosis for 266/301 (88%) patients, mixed cellularity for 22/301 (7%), lymphocyte rich for 2/301 (1%), and 11/301 were unclassified. EBV positivity by in situ hybridization was observed for 68/301 (23%) patients, significantly associated with mixed cellularity subtype and male sex, particularly overrepresented in boys below 10 years: 15/23 (65%) versus 28/139 among other male patients (20%). EBV viral load was detectable in 22 of 108 (22%) tested cases and was overrepresented in EBV cHL (13/28) versus non-EBV cHL (9/80) patients. Detailed semiquantitative histologic analysis showed a high number of B-cell residual follicles in EBV cHL relative to EBV-negative HL. CONCLUSION: Distribution of EBV cHL in children and adolescents is associated with young age and male sex, suggesting a specific physiopathology and may require a differential therapeutic approach.
Assuntos
Infecções por Vírus Epstein-Barr , Doença de Hodgkin , Linfoma não Hodgkin , Criança , Humanos , Adolescente , Masculino , Herpesvirus Humano 4/genética , Doença de Hodgkin/patologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/epidemiologia , Imuno-Histoquímica , Hibridização In Situ , Linfoma não Hodgkin/complicaçõesRESUMO
Chimeric Antigen Receptor T (CAR-T) cells are currently approved for B cell malignancies only, in children and adults. Despite a lack of robust evidence to approve such cellular immunotherapy for pediatric solid tumors, there is a growing interest for this approach in the treatment of pediatric brain tumors. Following the identification of tumor antigens as targets, the first clinical trials demonstrated some degree of clinical and biological responses to CAR-T cells for such tumor types. Additionaly, several preclinical studies have recently identified new attractive targets and antigen combination strategies, along with a superior tumor trafficking following locoregional administration. We review here the preclinical and clinical knowledge at the basis of the current clinical development of CAR-T cells for pediatric brain tumors.
Assuntos
Neoplasias Encefálicas/terapia , Imunoterapia Adotiva/métodos , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/transplante , Antígenos de Neoplasias/imunologia , Barreira Hematoencefálica , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/imunologia , Criança , Ensaios Clínicos como Assunto , Humanos , Memória Imunológica , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/tendências , Linfócitos T/imunologia , Microambiente Tumoral/imunologiaRESUMO
Extracranial rhabdoid tumours (ECRTs) are an aggressive malignancy of infancy and early childhood. The vast majority of cases demonstrate inactivation of SMARCB1 (ECRTSMARCB1 ) on a background of a remarkably stable genome, a low mutational burden, and no other recurrent mutations. Rarely, ECRTs can harbour the alternative inactivation of SMARCA4 (ECRTSMARCA4 ) instead of SMARCB1. However, very few ECRTSMARCA4 cases have been published to date, and a systematic characterization of ECRTSMARCA4 is missing from the literature. In this study, we report the clinical, pathological, and genomic features of additional cases of ECRTSMARCA4 and show that they are comparable to those of ECRTSMARCB1. We also assess whether ECRTSMARCB1 , ECRTSMARCA4 , and small cell carcinomas of the ovary, hypercalcaemic type (SCCOHT) represent distinct or overlapping entities at a molecular level. Using DNA methylation and transcriptomics-based tumour classification approaches, we demonstrate that ECRTSMARCA4 display molecular features intermediate between SCCOHT and ECRTSMARCB1 ; however, ECRTSMARCA4 appear to be more closely related to SCCOHT by DNA methylation. Conversely, both transcriptomics and DNA methylation show a larger gap between SCCOHT and ECRTSMARCB1 , potentially supporting their continuous separate classification. Lastly, we show that ECRTSMARCA4 display concomitant lack of SMARCA4 (BRG1) and SMARCA2 (BRM) expression at the protein level, similar to what is seen in SCCOHT. Overall, these results expand our knowledge on this rare tumour type and explore the similarities and differences among entities from the 'rhabdoid tumour' spectrum. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Assuntos
DNA Helicases/deficiência , Proteínas Nucleares/deficiência , Tumor Rabdoide/genética , Tumor Rabdoide/patologia , Fatores de Transcrição/deficiência , Carcinoma de Células Pequenas/genética , Carcinoma de Células Pequenas/patologia , Pré-Escolar , DNA Helicases/genética , Feminino , Humanos , Lactente , Masculino , Proteínas Nucleares/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Proteína SMARCB1/deficiência , Proteína SMARCB1/genética , Fatores de Transcrição/genéticaRESUMO
Pediatric cancers are not the equivalent of adult cancers occurring at a younger age and the prospect of immunotherapy in children has not been received with the same enthusiasm as in the adult setting. Although most pediatric malignancies are considered immunologically cold, we are learning more about PD-L1 expression, tumor mutational burden, and microsatellite instability in several pediatric cancers. The side effects of immunotherapy are an important consideration. Immune checkpoint inhibitors (ICIs) engender a unique constellation of inflammatory toxicities known as immune-related adverse events (irAEs). Three early-phase trials-KEYNOTE-051, iMATRIX, and ADVL1412-were the first to describe irAEs in pediatric patients and ICIs were well tolerated. There was concern about unknown late irAEs in pediatric patients, as they have much more time to develop than in adult or elderly patients. Academic clinicians, biopharmaceutical companies, and parents' advocates concluded that no benefit could be expected from further monotherapy trials employing other ICIs with the same mechanism of action until more scientific knowledge becomes available. On the other hand, ICIs could be useful in combination with other therapies to prevent the functional inactivation of several pathways in the hostile microenvironment. Future clinical studies on ICIs in children need to build on strong biological premises, taking into account the distinctive immunobiology of pediatric cancers vis-à-vis ICI-responsive adult cancers. We need to gain and share experiences of new therapies for managing pediatric patients with cancer, clarifying to what extent we can extrapolate the data obtained in adults.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Inibidores de Checkpoint Imunológico/efeitos adversos , Imunoterapia/efeitos adversos , Neoplasias/tratamento farmacológico , Criança , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Humanos , Neoplasias/imunologia , PrognósticoAssuntos
DNA Helicases/deficiência , DNA Helicases/genética , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Imunidade , Neoplasias/imunologia , Neoplasias/metabolismo , Proteínas Nucleares/deficiência , Proteínas Nucleares/genética , Proteína SMARCB1/deficiência , Proteína SMARCB1/genética , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética , Animais , Terapia Combinada/métodos , Modelos Animais de Doenças , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Camundongos , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Polimorfismo de Nucleotídeo Único , Resultado do TratamentoRESUMO
Atypical teratoid/rhabdoid tumors (ATRTs) typically arise in the central nervous system (CNS) of children under 3 years of age. Despite intensive multimodal therapy (surgery, chemotherapy and, if age permits, radiotherapy), median survival is 17 months1,2. We show that ATRTs robustly express B7-H3/CD276 that does not result from the inactivating mutations in SMARCB1 (refs. 3,4), which drive oncogenesis in ATRT, but requires residual SWItch/Sucrose Non-Fermentable (SWI/SNF) activity mediated by BRG1/SMARCA4. Consistent with the embryonic origin of ATRT5,6, B7-H3 is highly expressed on the prenatal, but not postnatal, brain. B7-H3.BB.z-chimeric antigen receptor (CAR) T cells administered intracerebroventricularly or intratumorally mediate potent antitumor effects against cerebral ATRT xenografts in mice, with faster kinetics, greater potency and reduced systemic levels of inflammatory cytokines compared to CAR T cells administered intravenously. CAR T cells administered ICV also traffic from the CNS into the periphery; following clearance of ATRT xenografts, B7-H3.BB.z-CAR T cells administered intracerebroventricularly or intravenously mediate antigen-specific protection from tumor rechallenge, both in the brain and periphery. These results identify B7-H3 as a compelling therapeutic target for this largely incurable pediatric tumor and demonstrate important advantages of locoregional compared to systemic delivery of CAR T cells for the treatment of CNS malignancies.
Assuntos
Antígenos B7/imunologia , Neoplasias Encefálicas/terapia , Vacinas Anticâncer/administração & dosagem , Imunoterapia Adotiva/métodos , Tumor Rabdoide/terapia , Teratoma/terapia , Adulto , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/imunologia , Encéfalo/patologia , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Células Cultivadas , Pré-Escolar , Feminino , Feto/patologia , Humanos , Lactente , Injeções Intraventriculares , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Receptores de Antígenos Quiméricos/administração & dosagem , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Tumor Rabdoide/imunologia , Tumor Rabdoide/patologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/transplante , Teratoma/imunologia , Teratoma/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Rhabdoid tumors (RTs) are genomically simple pediatric cancers driven by the biallelic inactivation of SMARCB1, leading to SWI/SNF chromatin remodeler complex deficiency. Comprehensive evaluation of the immune infiltrates of human and mice RTs, including immunohistochemistry, bulk RNA sequencing and DNA methylation profiling studies showed a high rate of tumors infiltrated by T and myeloid cells. Single-cell RNA (scRNA) and T cell receptor sequencing highlighted the heterogeneity of these cells and revealed therapeutically targetable exhausted effector and clonally expanded tissue resident memory CD8+ T subpopulations, likely representing tumor-specific cells. Checkpoint blockade therapy in an experimental RT model induced the regression of established tumors and durable immune responses. Finally, we show that one mechanism mediating RTs immunogenicity involves SMARCB1-dependent re-expression of endogenous retroviruses and interferon-signaling activation.