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1.
Cell ; 184(8): 2033-2052.e21, 2021 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-33765443

RESUMEN

Metastasis is the leading cause of cancer-related deaths, and greater knowledge of the metastatic microenvironment is necessary to effectively target this process. Microenvironmental changes occur at distant sites prior to clinically detectable metastatic disease; however, the key niche regulatory signals during metastatic progression remain poorly characterized. Here, we identify a core immune suppression gene signature in pre-metastatic niche formation that is expressed predominantly by myeloid cells. We target this immune suppression program by utilizing genetically engineered myeloid cells (GEMys) to deliver IL-12 to modulate the metastatic microenvironment. Our data demonstrate that IL12-GEMy treatment reverses immune suppression in the pre-metastatic niche by activating antigen presentation and T cell activation, resulting in reduced metastatic and primary tumor burden and improved survival of tumor-bearing mice. We demonstrate that IL12-GEMys can functionally modulate the core program of immune suppression in the pre-metastatic niche to successfully rebalance the dysregulated metastatic microenvironment in cancer.


Asunto(s)
Terapia de Inmunosupresión , Células Mieloides/metabolismo , Inmunidad Adaptativa , Animales , Línea Celular Tumoral , Ingeniería Genética , Humanos , Interleucina-12/genética , Interleucina-12/metabolismo , Pulmón/metabolismo , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Activación de Linfocitos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Células Mieloides/citología , Células Mieloides/inmunología , Metástasis de la Neoplasia , Rabdomiosarcoma/metabolismo , Rabdomiosarcoma/patología , Tasa de Supervivencia , Linfocitos T/inmunología , Linfocitos T/metabolismo , Microambiente Tumoral
2.
Mol Ther ; 31(3): 801-809, 2023 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-36518078

RESUMEN

The clinical impact of any therapy requires the product be safe and effective. Gammaretroviral vectors pose several unique risks, including inadvertent exposure to replication competent retrovirus (RCR) that can arise during vector manufacture. The US FDA has required patient monitoring for RCR, and the National Gene Vector Biorepository is an NIH resource that has assisted eligible investigators in meeting this requirement. To date, we have found no evidence of RCR in 338 pre-treatment and 1,595 post-treatment blood samples from 737 patients associated with 60 clinical trials. Most samples (75%) were obtained within 1 year of treatment, and samples as far out as 9 years after treatment were analyzed. The majority of trials (93%) were cancer immunotherapy, and 90% of the trials used vector products produced with the PG13 packaging cell line. The data presented here provide further evidence that current manufacturing methods generate RCR-free products and support the overall safety profile of retroviral gene therapy.


Asunto(s)
Retroviridae , Replicación Viral , Humanos , Retroviridae/genética , Vectores Genéticos/genética , Línea Celular , Terapia Genética/efectos adversos
3.
Curr Opin Pediatr ; 34(1): 53-60, 2022 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-34812775

RESUMEN

PURPOSE OF REVIEW: The prognosis of pediatric patients with metastatic solid tumors remains poor, necessitating development of novel therapeutic strategies. The biology of the pediatric tumor microenvironment (TME) presents obstacles for the efficacy of current therapeutic approaches including immunotherapies. Targeting various aspects of the TME in pediatric patients with solid tumors represents a therapeutic opportunity that may improve outcomes. Here we will discuss recent advances in characterization of the TME, and clinical advances in targeting the immune, vascular, and stromal aspects of the TME. RECENT FINDINGS: Although immunotherapies have shown limited success in the treatment of pediatric solid tumor patients thus far, optimization of these approaches to overcome the TME shows promise. In addition, there is increasing focus on the myeloid compartment as a therapeutic target. Vascular endothelial growth factor (VEGF) targeting has resulted in responses in some refractory pediatric solid tumors. There has been relatively little focus on stromal targeting; however, emerging preclinical data are improving our understanding of underlying biology, paving the way for future therapies. SUMMARY: Although translation of TME-targeting therapies for pediatric solid tumors is in the early stages, we are optimistic that continued exploration of approaches aimed at rebalancing the TME will lead to improved outcomes for this population.


Asunto(s)
Neoplasias , Microambiente Tumoral , Niño , Humanos , Inmunoterapia/métodos , Neoplasias/tratamiento farmacológico , Pronóstico , Factor A de Crecimiento Endotelial Vascular/uso terapéutico
4.
J Transl Med ; 15(1): 59, 2017 03 16.
Artículo en Inglés | MEDLINE | ID: mdl-28298232

RESUMEN

BACKGROUND: Clinical trials of Chimeric Antigen Receptor (CAR) T cells manufactured from autologous peripheral blood mononuclear cell (PBMC) concentrates for the treatment of hematologic malignancies have been promising, but CAR T cell yields have been variable. This variability is due in part to the contamination of the PBMC concentrates with monocytes and granulocytes. METHODS: Counter-flow elutriation allows for the closed system separation of lymphocytes from monocytes and granulocytes. We investigated the use of PBMC concentrates enriched for lymphocytes using elutriation for manufacturing 8 CD19- and 5 GD2-CAR T cell products. RESULTS: When compared to PBMC concentrates, lymphocyte-enriched elutriation fractions contained greater proportions of CD3+ and CD56+ cells and reduced proportions of CD14+ and CD15+ cells. All 13 CAR T cell products manufactured using the elutriated lymphocytes yielded sufficient quantities of transduced CAR T cells to meet clinical dose criteria. The GD2-CAR T cell products contained significantly more T cells and transduced T cells than the CD19-CAR T cell products. A comparison of the yields of CAR T cells produced from elutriated lymphocytes with the yields of CAR T cells previous produced from cells isolated from PBMC concentrates by anti-CD3/CD28 bead selection or by anti-CD3/CD28 bead selection plus plastic adherence found that greater quantities of GD2-CAR T cells were produced from elutriated lymphocytes, but not CD19-CAR T cells. CONCLUSIONS: Enrichment of PBMC concentrates for lymphocytes using elutriation increased the quantity of GD2-CAR T cells produced. These results provide further evidence that CAR T cell expansion is inhibited by monocytes and granulocytes.


Asunto(s)
Receptores de Antígenos de Linfocitos T/metabolismo , Linfocitos T/inmunología , Antígenos CD/metabolismo , Adhesión Celular , Niño , Humanos , Recuento de Linfocitos , Transducción Genética , Adulto Joven
5.
J Digit Imaging ; 30(3): 275-286, 2017 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-28074302

RESUMEN

Oncologists evaluate therapeutic response in cancer trials based on tumor quantification following selected "target" lesions over time. At our cancer center, a majority of oncologists use Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 quantifying tumor progression based on lesion measurements on imaging. Currently, our oncologists handwrite tumor measurements, followed by multiple manual data transfers; however, our Picture Archiving Communication System (PACS) (Carestream Health, Rochester, NY) has the ability to export tumor measurements, making it possible to manage tumor metadata digitally. We developed an interface, "Exportable Notation and Bookmark List Engine" (ENABLE), which produces prepopulated RECIST v1.1 worksheets and compiles cohort data and data models from PACS measurement data, thus eliminating handwriting and manual data transcription. We compared RECIST v1.1 data from eight patients (16 computed tomography exams) enrolled in an IRB-approved therapeutic trial with ENABLE outputs: 10 data fields with a total of 194 data points. All data in ENABLE's output matched with the existing data. Seven staff were taught how to use the interface with a 5-min explanatory instructional video. All were able to use ENABLE successfully without additional guidance. We additionally assessed 42 metastatic genitourinary cancer patients with available RECIST data within PACS to produce a best response waterfall plot. ENABLE manages tumor measurements and associated metadata exported from PACS, producing forms and data models compatible with cancer databases, obviating handwriting and the manual re-entry of data. Automation should reduce transcription errors and improve efficiency and the auditing process.


Asunto(s)
Bases de Datos Factuales , Neoplasias/patología , Sistemas de Información Radiológica , Carga Tumoral , Instituciones Oncológicas , Progresión de la Enfermedad , Humanos , Registros Médicos , Neoplasias/diagnóstico por imagen , Criterios de Evaluación de Respuesta en Tumores Sólidos , Tomografía Computarizada por Rayos X , Neoplasias Urogenitales/diagnóstico por imagen , Neoplasias Urogenitales/patología
6.
Blood ; 122(7): 1105-13, 2013 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-23757729

RESUMEN

Fibrocytes are hematopoietic stem cell-derived fibroblast precursors that are implicated in chronic inflammation, fibrosis, and wound healing. Myeloid-derived suppressor cells (MDSCs) expand in cancer-bearing hosts and contribute to tumor immune evasion. They are typically described as CD11b⁺HLA-DR⁻ in humans. We report abnormal expansions of CD11b⁺HLA-DR⁺ myeloid cells in peripheral blood mononuclear fractions of subjects with metastatic pediatric sarcomas. Like classical fibrocytes, they display cell surface α smooth muscle actin, collagen I/V, and mediate angiogenesis. However, classical fibrocytes serve as antigen presenters and augment immune reactivity, whereas fibrocytes from cancer subjects suppressed anti-CD3-mediated T-cell proliferation, primarily via indoleamine oxidase (IDO). The degree of fibrocyte expansion observed in individual subjects directly correlated with the frequency of circulating GATA3⁺CD4⁺ cells (R = 0.80) and monocytes from healthy donors cultured with IL-4 differentiated into fibrocytes with the same phenotypic profile and immunosuppressive properties as those observed in patients with cancer. We thus describe a novel subset of cancer-induced myeloid-derived suppressor cells, which bear the phenotypic and functional hallmarks of fibrocytes but mediate immune suppression. These cells are likely expanded in response to Th2 immune deviation and may contribute to tumor progression via both immune evasion and angiogenesis.


Asunto(s)
Fibroblastos/patología , Linfocitos/patología , Células Mieloides/patología , Rabdomiosarcoma/patología , Sarcoma de Ewing/secundario , Escape del Tumor/inmunología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Western Blotting , Diferenciación Celular , Proliferación Celular , Células Cultivadas , Niño , Fibroblastos/inmunología , Citometría de Flujo , Factor de Transcripción GATA3 , Perfilación de la Expresión Génica , Células Endoteliales de la Vena Umbilical Humana , Humanos , Inmunofenotipificación , Terapia de Inmunosupresión , Interleucina-4/farmacología , Receptores de Lipopolisacáridos , Activación de Linfocitos , Linfocitos/inmunología , Monocitos/inmunología , Monocitos/patología , Células Mieloides/inmunología , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Rabdomiosarcoma/sangre , Rabdomiosarcoma/inmunología , Sarcoma de Ewing/sangre , Sarcoma de Ewing/inmunología , Células Th2
7.
Cancer Cell ; 42(1): 35-51.e8, 2024 01 08.
Artículo en Inglés | MEDLINE | ID: mdl-38134936

RESUMEN

Chimeric antigen receptor T cells (CAR-Ts) have remarkable efficacy in liquid tumors, but limited responses in solid tumors. We conducted a Phase I trial (NCT02107963) of GD2 CAR-Ts (GD2-CAR.OX40.28.z.iC9), demonstrating feasibility and safety of administration in children and young adults with osteosarcoma and neuroblastoma. Since CAR-T efficacy requires adequate CAR-T expansion, patients were grouped into good or poor expanders across dose levels. Patient samples were evaluated by multi-dimensional proteomic, transcriptomic, and epigenetic analyses. T cell assessments identified naive T cells in pre-treatment apheresis associated with good expansion, and exhausted T cells in CAR-T products with poor expansion. Myeloid cell assessment identified CXCR3+ monocytes in pre-treatment apheresis associated with good expansion. Longitudinal analysis of post-treatment samples identified increased CXCR3- classical monocytes in all groups as CAR-T numbers waned. Together, our data uncover mediators of CAR-T biology and correlates of expansion that could be utilized to advance immunotherapies for solid tumor patients.


Asunto(s)
Neuroblastoma , Receptores Quiméricos de Antígenos , Niño , Adulto Joven , Humanos , Receptores Quiméricos de Antígenos/genética , Receptores de Antígenos de Linfocitos T/genética , Proteómica , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Linfocitos T , Neuroblastoma/patología , Tratamiento Basado en Trasplante de Células y Tejidos
8.
Blood ; 117(8): 2484-93, 2011 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-21163925

RESUMEN

Joint arthropathy secondary to recurrent hemarthroses remains a debilitating complication of hemophilia despite the use of prophylactic factor concentrates. Increased vascularity and neoangiogenesis have been implicated in the progression of musculoskeletal disorders and tumor growth. We hypothesized that de novo blood vessel formation could play a major role in the pathogenesis of hemophilic joint disease (HJD). We observed a 4-fold elevation in proangiogenic factors (vascular endothelial growth factor-A [VEGF-A], stromal cell-derived factor-1, and matrix metalloprotease-9) and proangiogenic macrophage/monocyte cells (VEGF(+)/CD68(+) and VEGFR1(+)/CD11b(+)) in the synovium and peripheral blood of HJD subjects along with significantly increased numbers of VEGFR2(+)/AC133(+) endothelial progenitor cells and CD34(+)/VEGFR1(+) hematopoietic progenitor cells. Sera from HJD subjects induced an angiogenic response in endothelial cells that was abrogated by blocking VEGF, whereas peripheral blood mononuclear cells from HJD subjects stimulated synovial cell proliferation, which was blocked by a humanized anti-VEGF antibody (bevacizumab). Human synovial cells, when incubated with HJD sera, could elicit up-regulation of HIF-1α mRNA with HIF-1α expression in the synovium of HJD subjects, implicating hypoxia in the neoangiogenesis process. Our results provide evidence of local and systemic angiogenic response in hemophilic subjects with recurrent hemarthroses suggesting a potential to develop surrogate biologic markers to identify the onset and progression of hemophilic synovitis.


Asunto(s)
Hemartrosis/etiología , Hemofilia A/complicaciones , Neovascularización Patológica/complicaciones , Sinovitis/etiología , Células Cultivadas , Fibroblastos/citología , Hemartrosis/fisiopatología , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Neovascularización Patológica/patología , ARN Mensajero/análisis , Recurrencia , Estudios Retrospectivos , Membrana Sinovial/química , Sinovitis/fisiopatología , Regulación hacia Arriba/genética , Factores de Crecimiento Endotelial Vascular/análisis , Factores de Crecimiento Endotelial Vascular/sangre
9.
Cell Biosci ; 13(1): 136, 2023 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-37491298

RESUMEN

BACKGROUND: The absence of prominent, actionable genetic alternations in osteosarcomas (OS) implies that transcriptional and epigenetic mechanisms significantly contribute to the progression of this life-threatening form of cancer. Therefore, the identification of potential transcriptional events that promote the survival of OS cells could be key in devising targeted therapeutic approaches for OS. We have previously shown that RUNX2 is a transcription factor (TF) essential for OS cell survival. Unfortunately, the transcriptional network or circuitry regulated by RUNX2 in OS cells is still largely unknown. METHODS: The TFs that are in the RUNX2 transcriptional circuitry were identified by analyzing RNAseq and ChIPseq datasets of RUNX2. To evaluate the effect of SOX9 knockdown on the survival of osteosarcoma cells in vitro, we employed cleaved caspase-3 immunoblotting and propidium iodide staining techniques. The impact of SOX9 and JMJD1C depletion on OS tumor growth was examined in vivo using xenografts and immunohistochemistry. Downstream targets of SOX9 were identified and dissected using RNAseq, pathway analysis, and gene set enrichment analysis. Furthermore, the interactome of SOX9 was identified using BioID and validated by PLA. RESULT: Our findings demonstrate that SOX9 is a critical TF that is induced by RUNX2. Both in vitro and in vivo experiments revealed that SOX9 plays a pivotal role in the survival of OS. RNAseq analysis revealed that SOX9 activates the transcription of MYC, a downstream target of RUNX2. Mechanistically, our results suggest a transcriptional network involving SOX9, RUNX2, and MYC, with SOX9 binding to RUNX2. Moreover, we discovered that JMJD1C, a chromatin factor, is a novel binding partner of SOX9, and depletion of JMJD1C impairs OS tumor growth. CONCLUSION: The findings of this study represent a significant advancement in our understanding of the transcriptional network present in OS cells, providing valuable insights that may contribute to the development of targeted therapies for OS.

10.
JAMA Dermatol ; 159(10): 1112-1118, 2023 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-37585199

RESUMEN

Importance: Knowledge about the prevalence and tumor types of CDKN2A-related melanoma-astrocytoma syndrome (MAS) is limited and could improve disease recognition. Objective: To estimate the prevalence and describe the tumor types of MAS. Design, Setting, and Participants: This retrospective cohort study analyzed all available MAS cases from medical centers in the US (2 sites) and Europe (2 sites) and from biomedical population genomic databases (UK Biobank [United Kingdom], Geisinger MyCode [US]) between January 1, 1976, and December 31, 2020. Patients with MAS with CDKN2A germline pathogenic variants and 1 or more neural tumors were included. Data were analyzed from June 1, 2022, to January 31, 2023. Main Outcomes and Measures: Disease prevalence and tumor frequency. Results: Prevalence of MAS ranged from 1 in 170 503 (n = 1 case; 95% CI, 1:30 098-1:965 887) in Geisinger MyCode (n = 170 503; mean [SD] age, 58.9 [19.1] years; 60.6% women; 96.2% White) to 1 in 39 149 (n = 12 cases; 95% CI, 1:22 396-1:68 434) in UK Biobank (n = 469 789; mean [SD] age, 70.0 [8.0] years; 54.2% women; 94.8% White). Among UK Biobank patients with MAS (n = 12) identified using an unbiased genomic ascertainment approach, brain neoplasms (4 of 12, 33%; 1 glioblastoma, 1 gliosarcoma, 1 astrocytoma, 1 unspecified type) and schwannomas (3 of 12, 25%) were the most common malignant and benign neural tumors, while cutaneous melanoma (2 of 12, 17%) and head and neck squamous cell carcinoma (2 of 12, 17%) were the most common nonneural malignant neoplasms. In a separate case series of 14 patients with MAS from the US and Europe, brain neoplasms (4 of 14, 29%; 2 glioblastomas, 2 unspecified type) and malignant peripheral nerve sheath tumor (2 of 14, 14%) were the most common neural cancers, while cutaneous melanoma (4 of 14, 29%) and sarcomas (2 of 14, 14%; 1 liposarcoma, 1 unspecified type) were the most common nonneural cancers. Cutaneous neurofibromas (7 of 14, 50%) and schwannomas (2 of 14, 14%) were also common. In 1 US family, a father and son with MAS had clinical diagnoses of neurofibromatosis type 1 (NF1). Genetic testing of the son detected a pathogenic CDKN2A splicing variant (c.151-1G>C) and was negative for NF1 genetic alterations. In UK Biobank, 2 in 150 (1.3%) individuals with clinical NF1 diagnoses had likely pathogenic variants in CDKN2A, including 1 individual with no detected variants in the NF1 gene. Conclusions and Relevance: This cohort study estimates the prevalence and describes the tumors of MAS. Additional studies are needed in genetically diverse populations to further define population prevalence and disease phenotypes.


Asunto(s)
Astrocitoma , Neoplasias Encefálicas , Melanoma , Neurilemoma , Neurofibromatosis 1 , Neoplasias Cutáneas , Humanos , Femenino , Persona de Mediana Edad , Anciano , Masculino , Melanoma/epidemiología , Melanoma/genética , Neurofibromatosis 1/diagnóstico , Estudios Retrospectivos , Estudios de Cohortes , Prevalencia , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/genética , Astrocitoma/epidemiología , Astrocitoma/genética , Fenotipo , Neoplasias Encefálicas/epidemiología , Neoplasias Encefálicas/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Melanoma Cutáneo Maligno
11.
Clin Cancer Res ; 29(17): 3329-3339, 2023 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-37398992

RESUMEN

PURPOSE: Antibodies against insulin-like growth factor (IGF) type 1 receptor have shown meaningful but transient tumor responses in patients with rhabdomyosarcoma (RMS). The SRC family member YES has been shown to mediate IGF type 1 receptor (IGF-1R) antibody acquired resistance, and cotargeting IGF-1R and YES resulted in sustained responses in murine RMS models. We conducted a phase I trial of the anti-IGF-1R antibody ganitumab combined with dasatinib, a multi-kinase inhibitor targeting YES, in patients with RMS (NCT03041701). PATIENTS AND METHODS: Patients with relapsed/refractory alveolar or embryonal RMS and measurable disease were eligible. All patients received ganitumab 18 mg/kg intravenously every 2 weeks. Dasatinib dose was 60 mg/m2/dose (max 100 mg) oral once daily [dose level (DL)1] or 60 mg/m2/dose (max 70 mg) twice daily (DL2). A 3+3 dose escalation design was used, and maximum tolerated dose (MTD) was determined on the basis of cycle 1 dose-limiting toxicities (DLT). RESULTS: Thirteen eligible patients, median age 18 years (range 8-29) enrolled. Median number of prior systemic therapies was 3; all had received prior radiation. Of 11 toxicity-evaluable patients, 1/6 had a DLT at DL1 (diarrhea) and 2/5 had a DLT at DL2 (pneumonitis, hematuria) confirming DL1 as MTD. Of nine response-evaluable patients, one had a confirmed partial response for four cycles, and one had stable disease for six cycles. Genomic studies from cell-free DNA correlated with disease response. CONCLUSIONS: The combination of dasatinib 60 mg/m2/dose daily and ganitumab 18 mg/kg every 2 weeks was safe and tolerable. This combination had a disease control rate of 22% at 5 months.


Asunto(s)
Rabdomiosarcoma , Familia-src Quinasas , Humanos , Animales , Ratones , Niño , Adolescente , Adulto Joven , Adulto , Dasatinib/efectos adversos , Factor I del Crecimiento Similar a la Insulina , Receptor IGF Tipo 1 , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Dosis Máxima Tolerada
12.
Cancer Res Commun ; 3(12): 2468-2482, 2023 12 06.
Artículo en Inglés | MEDLINE | ID: mdl-37966258

RESUMEN

Understanding of tumor biology and identification of effective therapies is lacking for many rare tumors. My Pediatric and Adult Rare Tumor (MyPART) network was established to engage patients, advocates, and researchers and conduct a comprehensive longitudinal Natural History Study of Rare Solid Tumors. Through remote or in-person enrollment at the NIH Clinical Center, participants with rare solid tumors ≥4 weeks old complete standardized medical and family history forms, patient reported outcomes, and provide tumor, blood and/or saliva samples. Medical records are extracted for clinical status and treatment history, and tumors undergo genomic analysis. A total of 200 participants (65% female, 35% male, median age at diagnosis 43 years, range = 2-77) enrolled from 46 U.S. states and nine other countries (46% remote, 55% in-person). Frequent diagnoses were neuroendocrine neoplasms (NEN), adrenocortical carcinomas (ACC), medullary thyroid carcinomas (MTC), succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumors (sdGIST), and chordomas. At enrollment, median years since diagnosis was 3.5 (range = 0-36.6), 63% participants had metastatic disease and 20% had no evidence of disease. Pathogenic germline and tumor mutations included SDHA/B/C (sdGIST), RET (MTC), TP53 and CTNNB1 (ACC), MEN1 (NEN), and SMARCB1 (poorly-differentiated chordoma). Clinically significant anxiety was observed in 20%-35% of adults. Enrollment of participants and comprehensive data collection were feasible. Remote enrollment was critical during the COVID-19 pandemic. Over 30 patients were enrolled with ACC, NEN, and sdGIST, allowing for clinical/genomic analyses across tumors. Longitudinal follow-up and expansion of cohorts are ongoing to advance understanding of disease course and establish external controls for interventional trials. SIGNIFICANCE: This study demonstrates that comprehensive, tumor-agnostic data and biospecimen collection is feasible to characterize different rare tumors, and speed progress in research. The findings will be foundational to developing external controls groups for single-arm interventional trials, where randomized control trials cannot be conducted because of small patient populations.


Asunto(s)
Tumores del Estroma Gastrointestinal , Tumores Neuroendocrinos , Adulto , Niño , Humanos , Masculino , Femenino , Preescolar , Adolescente , Adulto Joven , Persona de Mediana Edad , Anciano , Pandemias , Tumores del Estroma Gastrointestinal/diagnóstico , Mutación , Progresión de la Enfermedad
13.
Front Endocrinol (Lausanne) ; 13: 961650, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36387865

RESUMEN

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy of the adrenal gland with an unfavorable prognosis. It is rare in the pediatric population, with an incidence of 0.2-0.3 patients per million in patients under 20 years old. It is primarily associated with Li-Fraumeni and Beckwith-Wiedemann tumor predisposition syndromes in children. The incidence of pediatric ACC is 10-15fold higher in southern Brazil due to a higher prevalence of TP53 mutation associated with Li-Fraumeni syndrome in that population. Current treatment protocols are derived from adult ACC and consist of surgery and/or chemotherapy with etoposide, doxorubicin, and cisplatin (EDP) with mitotane. Limited research has been reported on other treatment modalities for pediatric ACC, including mitotane, pembrolizumab, cabozantinib, and chimeric antigen receptor autologous cell (CAR-T) therapy.


Asunto(s)
Neoplasias de la Corteza Suprarrenal , Carcinoma Corticosuprarrenal , Síndrome de Li-Fraumeni , Adulto , Humanos , Niño , Adulto Joven , Carcinoma Corticosuprarrenal/diagnóstico , Carcinoma Corticosuprarrenal/terapia , Carcinoma Corticosuprarrenal/genética , Mitotano/uso terapéutico , Neoplasias de la Corteza Suprarrenal/genética , Neoplasias de la Corteza Suprarrenal/terapia , Neoplasias de la Corteza Suprarrenal/patología , Síndrome de Li-Fraumeni/genética
14.
Nat Commun ; 13(1): 5296, 2022 09 08.
Artículo en Inglés | MEDLINE | ID: mdl-36075914

RESUMEN

Autologous T cells transduced to express a high affinity T-cell receptor specific to NY-ESO-1 (letetresgene autoleucel, lete-cel) show promise in the treatment of metastatic synovial sarcoma, with 50% overall response rate. The efficacy of lete-cel treatment in 45 synovial sarcoma patients (NCT01343043) has been previously reported, however, biomarkers predictive of response and resistance remain to be better defined. This post-hoc analysis identifies associations of response to lete-cel with lymphodepleting chemotherapy regimen (LDR), product attributes, cell expansion, cytokines, and tumor gene expression. Responders have higher IL-15 levels pre-infusion (p = 0.011) and receive a higher number of transduced effector memory (CD45RA- CCR7-) CD8 + cells per kg (p = 0.039). Post-infusion, responders have increased IFNγ, IL-6, and peak cell expansion (p < 0.01, p < 0.01, and p = 0.016, respectively). Analysis of tumor samples post-treatment illustrates lete-cel infiltration and a decrease in expression of macrophage genes, suggesting remodeling of the tumor microenvironment. Here we report potential predictive and pharmacodynamic markers of lete-cel response that may inform LDR, cell dose, and strategies to enhance anticancer efficacy.


Asunto(s)
Sarcoma Sinovial , Antígenos de Neoplasias/metabolismo , Biomarcadores/metabolismo , Linfocitos T CD8-positivos/metabolismo , Humanos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Sarcoma Sinovial/genética , Sarcoma Sinovial/patología , Sarcoma Sinovial/terapia , Microambiente Tumoral
15.
Nature ; 438(7069): 820-7, 2005 Dec 08.
Artículo en Inglés | MEDLINE | ID: mdl-16341007

RESUMEN

The cellular and molecular mechanisms by which a tumour cell undergoes metastasis to a predetermined location are largely unknown. Here we demonstrate that bone marrow-derived haematopoietic progenitor cells that express vascular endothelial growth factor receptor 1 (VEGFR1; also known as Flt1) home to tumour-specific pre-metastatic sites and form cellular clusters before the arrival of tumour cells. Preventing VEGFR1 function using antibodies or by the removal of VEGFR1(+) cells from the bone marrow of wild-type mice abrogates the formation of these pre-metastatic clusters and prevents tumour metastasis, whereas reconstitution with selected Id3 (inhibitor of differentiation 3)-competent VEGFR1+ cells establishes cluster formation and tumour metastasis in Id3 knockout mice. We also show that VEGFR1+ cells express VLA-4 (also known as integrin alpha4beta1), and that tumour-specific growth factors upregulate fibronectin--a VLA-4 ligand--in resident fibroblasts, providing a permissive niche for incoming tumour cells. Conditioned media obtained from distinct tumour types with unique patterns of metastatic spread redirected fibronectin expression and cluster formation, thereby transforming the metastatic profile. These findings demonstrate a requirement for VEGFR1+ haematopoietic progenitors in the regulation of metastasis, and suggest that expression patterns of fibronectin and VEGFR1+VLA-4+ clusters dictate organ-specific tumour spread.


Asunto(s)
Movimiento Celular , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Metástasis de la Neoplasia/patología , Metástasis de la Neoplasia/fisiopatología , Neoplasias/metabolismo , Neoplasias/patología , Receptor 1 de Factores de Crecimiento Endotelial Vascular/metabolismo , Animales , Adhesión Celular , Movimiento Celular/efectos de los fármacos , Proliferación Celular , Medios de Cultivo Condicionados/farmacología , Fibronectinas/metabolismo , Células Madre Hematopoyéticas/efectos de los fármacos , Humanos , Proteínas Inhibidoras de la Diferenciación/metabolismo , Integrina alfa4beta1/metabolismo , Metaloproteinasa 9 de la Matriz , Metaloproteinasas de la Matriz/metabolismo , Ratones , Ratones Transgénicos , Especificidad de Órganos , Especificidad por Sustrato , Regulación hacia Arriba , Receptor 1 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores
16.
Cancers (Basel) ; 13(11)2021 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-34071333

RESUMEN

Adrenocortical carcinoma (ACC) is a rare cancer of the adrenal gland that is frequently associated with excess production of adrenal hormones. Although surgical resection may be curative in early-stage disease, few effective therapeutic options exist in the inoperable advanced or metastatic setting. Immunotherapies, inclusive of a broad array of immune-activating and immune-modulating antineoplastic agents, have demonstrated clinical benefit in a wide range of solid and hematologic malignancies. Due to the broad activity across multiple cancer types, there is significant interest in testing these agents in rare tumors, including ACC. Multiple clinical trials evaluating immunotherapies for the treatment of ACC have been conducted, and many more are ongoing or planned. Immunotherapies that have been evaluated in clinical trials for ACC include the immune checkpoint inhibitors pembrolizumab, nivolumab, and avelumab. Other immunotherapies that have been evaluated include the monoclonal antibodies figitumumab and cixutumumab directed against the ACC-expressed insulin-like growth factor 1 (IGF-1) receptor, the recombinant cytotoxin interleukin-13-pseudomonas exotoxin A, and autologous tumor lysate dendritic cell vaccine. These agents have shown modest clinical activity, although nonzero in the case of the immune checkpoint inhibitors. Clinical trials are ongoing to evaluate whether this clinical activity may be augmented through combinations with other immune-acting agents or targeted therapies.

17.
Cancer Genet ; 256-257: 21-25, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-33836455

RESUMEN

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare malignancy arising from the adrenal cortex. ACC carries a dismal prognosis and surgery offers the only chance for a cure. Germline pathogenic variants among certain oncogenes have been implicated in ACC. Here, we report the first case of ACC in a patient with a pathogenic variant in the Ataxia Telangiectasia Mutated (ATM) gene. PATIENTS AND METHODS: A 56-year-old Caucasian woman with biopsy proven ACC deemed unresectable and treated with etoposide, doxorubicin and cisplatin (EDP), and mitotane presented to our institution for evaluation. The tumor specimen was examined pathologically, and genetic analyses were performed on the tumor and germline using next-generation sequencing. RESULTS: Pathologic evaluation revealed an 18.0 × 14.0 × 9.0 cm low-grade ACC with tumor free resection margins. Immunohistochemistry stained for inhibin, melan-A, and chromogranin. ClinOmics analysis revealed a germline pathogenic deletion mutation of one nucleotide in ATM is denoted as c.1215delT at the cDNA level and p.Asn405LysfsX15 (N405KfsX15) at the protein level. Genomic analysis of the tumor showed loss of heterozygosity (LOH) of chromosome 11 on which the ATM resides. CONCLUSION: ACC is an aggressive malignancy for which surgical resection currently offers the only curative option. Here we report a heterozygous loss-of-function mutation in germline DNA and LOH of ATM in tumor in an ACC patient, a classic two-hit scenario in a well-known cancer suppresser gene, suggesting a pathogenic role of the ATM gene in certain ACC cases.


Asunto(s)
Neoplasias de la Corteza Suprarrenal/genética , Proteínas de la Ataxia Telangiectasia Mutada/genética , Mutación de Línea Germinal/genética , Neoplasias de la Corteza Suprarrenal/diagnóstico por imagen , Neoplasias de la Corteza Suprarrenal/patología , Femenino , Genómica , Humanos , Persona de Mediana Edad , Imagen Multimodal
18.
Cancer Cell ; 39(6): 725-729, 2021 06 14.
Artículo en Inglés | MEDLINE | ID: mdl-34129817

RESUMEN

The tumor immune microenvironment (TIME) is a complex ecosystem that contains adaptive and innate immune cells that have tumor-promoting and anti-tumor effects. There is still much to learn about the diversity, plasticity, and functions of innate immune cells in the TIME and their roles in determining the response to immunotherapies. Experts discuss recent advances in our understanding of their biology in cancer as well as outstanding questions and potential therapeutic avenues.


Asunto(s)
Inmunidad Innata , Inmunoterapia/métodos , Linfocitos/inmunología , Neoplasias/terapia , Microambiente Tumoral/inmunología , Vacunas contra el Cáncer/farmacología , Células Dendríticas/inmunología , Humanos , Células Asesinas Naturales/inmunología , Linfocitos/patología , Mastocitos/inmunología , Mastocitos/patología , Células Supresoras de Origen Mieloide/inmunología , Neoplasias/inmunología , Neoplasias/patología , Neutrófilos/inmunología , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/patología
19.
Blood Adv ; 5(23): 5312-5322, 2021 12 14.
Artículo en Inglés | MEDLINE | ID: mdl-34619768

RESUMEN

Infections are a known complication of chimeric antigen receptor (CAR) T-cell therapy with data largely emerging from CD19 CAR T-cell targeting. As CAR T-cell therapy continues to evolve, infection risks and management thereof will become increasingly important to optimize outcomes across the spectrum of antigens and disease targeted. We retrospectively characterized infectious complications occurring in 162 children and adults treated among 5 phase 1 CAR T-cell clinical trials. Trials included targeting of CD19, CD22, disialoganglioside (GD2) or B-cell maturation antigen (BCMA). Fifty-three patients (32.7%) had 76 infections between lymphocyte depleting (LD) chemotherapy and day 30 (D30); with the majority of infections (61, 80.3%) occurring between day 0 (D0) and D30. By trial, the highest proportion of infections was seen with CD22 CAR T cells (n = 23/53; 43.4%), followed by BCMA CAR T cells (n = 9/24; 37.5%). By disease, patients with multiple myeloma had the highest proportion of infections (9/24; 37.5%) followed by acute lymphoblastic leukemia (36/102; 35.3%). Grade 4 infections were rare (n = 4; 2.5%). Between D0 and D30, bacteremia and bacterial site infections were the most common infection type. In univariate analysis, increasing prior lines of therapy, recent infection within 100 days of LD chemotherapy, corticosteroid or tocilizumab use, and fever and neutropenia were associated with a higher risk of infection. In a multivariable analysis, only prior lines of therapy and recent infection were associated with higher risk of infection. In conclusion, we provide a broad overview of infection risk within the first 30 days post infusion across a host of multiple targets and diseases, elucidating both unique characteristics and commonalities highlighting aspects important to improving patient outcomes.


Asunto(s)
Inmunoterapia Adoptiva , Mieloma Múltiple , Antígenos CD19 , Humanos , Estudios Retrospectivos , Linfocitos T
20.
Cell Rep Med ; 2(6): 100297, 2021 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-34195677

RESUMEN

Targeting solid tumors must overcome several major obstacles, in particular, the identification of elusive tumor-specific antigens. Here, we devise a strategy to help identify tumor-specific epitopes. Glypican 2 (GPC2) is overexpressed in neuroblastoma. Using RNA sequencing (RNA-seq) analysis, we show that exon 3 and exons 7-10 of GPC2 are expressed in cancer but are minimally expressed in normal tissues. Accordingly, we discover a monoclonal antibody (CT3) that binds exons 3 and 10 and visualize the complex structure of CT3 and GPC2 by electron microscopy. The potential of this approach is exemplified by designing CT3-derived chimeric antigen receptor (CAR) T cells that regress neuroblastoma in mice. Genomic sequencing of T cells recovered from mice reveals the CAR integration sites that may contribute to CAR T cell proliferation and persistence. These studies demonstrate how RNA-seq data can be exploited to help identify tumor-associated exons that can be targeted by CAR T cell therapies.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Glipicanos/genética , Neoplasias del Sistema Nervioso/terapia , Neuroblastoma/terapia , Receptores de Antígenos de Linfocitos T/genética , Receptores Quiméricos de Antígenos/genética , Animales , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/genética , Anticuerpos Monoclonales/metabolismo , Línea Celular Tumoral , Proliferación Celular , Exones , Femenino , Expresión Génica , Glipicanos/antagonistas & inhibidores , Glipicanos/química , Glipicanos/inmunología , Humanos , Inmunoterapia Adoptiva/métodos , Ratones , Ratones Desnudos , Modelos Moleculares , Neoplasias del Sistema Nervioso/genética , Neoplasias del Sistema Nervioso/mortalidad , Neoplasias del Sistema Nervioso/patología , Neuroblastoma/genética , Neuroblastoma/mortalidad , Neuroblastoma/patología , Unión Proteica , Conformación Proteica , Receptores de Antígenos de Linfocitos T/inmunología , Receptores Quiméricos de Antígenos/inmunología , Análisis de Secuencia de ARN , Análisis de Supervivencia , Linfocitos T/inmunología , Linfocitos T/metabolismo , Carga Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto
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