Harnessing the Immunotherapy Revolution for the Treatment of Childhood Cancers

Majzner, Robbie G.; Heitzeneder, Sabine; Mackall, Crystal L.

doi:10.1016/j.ccell.2017.03.002

Cited by 121 publications

(109 citation statements)

References 119 publications

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“…47 In contrast with evidence for TAMs associating with outcome in NB, there is no published clinical evidence for an adaptive T lymphocyte response against human NBs. 48 T lymphocyte responses in NB patients may be limited by absent expression of MHC class I molecules and by a low frequency of somatic mutations in the tumor cells. 24–27 We therefore used NSG and NOD/SCID mice as models for deficient T lymphocyte responses.…”

Section: Discussionmentioning

confidence: 99%

Colony stimulating factor 1 receptor blockade improves the efficacy of chemotherapy against human neuroblastoma in the absence of T lymphocytes

Webb

Sun

Sheard

et al. 2018

Intl Journal of Cancer

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Tumor-associated macrophages can promote growth of cancers. In neuroblastoma, tumor-associated macrophages have greater frequency in metastatic versus loco-regional tumors, and higher expression of genes associated with macrophages helps to predict poor prognosis in the 60% of high-risk patients who have MYCN-non-amplified disease. The contribution of cytotoxic T-lymphocytes to anti-neuroblastoma immune responses may be limited by low MHC class I expression and low exonic mutation frequency. Therefore, we modelled human neuroblastoma in T-cell deficient mice to examine whether depletion of monocytes/macrophages from the neuroblastoma microenvironment by blockade of CSF-1R can improve the response to chemotherapy. In vitro, CSF-1 was released by neuroblastoma cells, and topotecan increased this release. In vivo, neuroblastomas formed by subcutaneous co-injection of human neuroblastoma cells and human monocytes into immunodeficient NOD/SCID mice had fewer human CD14 and CD163 cells and mouse F4/80 cells after CSF-1R blockade. In subcutaneous or intra-renal models in immunodeficient NSG or NOD/SCID mice, CSF-1R blockade alone did not affect tumor growth or mouse survival. However, when combined with cyclophosphamide plus topotecan, the CSF-1R inhibitor BLZ945, either without or with anti-human and anti-mouse CSF-1 mAbs, inhibited neuroblastoma growth and synergistically improved mouse survival. These findings indicate that depletion of tumor-associated macrophages from neuroblastomas can be associated with increased chemotherapeutic efficacy without requiring a contribution from T-lymphocytes, suggesting the possibility that combination of CSF-1R blockade with chemotherapy might be effective in patients who have limited anti-tumor T-cell responses.

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Section: Discussionmentioning

confidence: 99%

Colony stimulating factor 1 receptor blockade improves the efficacy of chemotherapy against human neuroblastoma in the absence of T lymphocytes

Webb

Sun

Sheard

et al. 2018

Intl Journal of Cancer

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“…Potential targets for new treatments for CCSK patients might be BCOR ITDs (identified in about 80-90% of CCSKs), hypermethylation of TCF21 (identified in about 80-90% of CCSKs) or the YWHAE-NUTM2 fusion gene (identified in 5-10% of CCSKs) 9,13,14 . Finally, immunotherapy might be a therapeutic option for patients with CCSK in the future 73 .…”

Section: Future Perspectivesmentioning

confidence: 99%

Rationale for the treatment of children with CCSK in the UMBRELLA SIOP–RTSG 2016 protocol

et al. 2018

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“…Sur 8 patients évaluables 2, ont obtenu une réponse objective. Cependant l'utilisation de CAR de 2 e génération a été décevante avec une absence de réponse chez 11 patients après la 6 e semaine de traitement et l'absence de persistance des CAR [31].…”

Section: Neuroblastomeunclassified

CAR-T cells : indications actuelles en pédiatrie et perspectives de développement

et al. 2018

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Les leucémies aiguës lymphoblastiques B (LAL-B) représentent la première cause de cancer chez l'enfant. Malgré un taux de survie à 5 ans supérieur à 90 %, les LAL sont une des causes majeures de décès lié au cancer dans l'enfance. Une nouvelle classe d'immunothérapie se basant sur des lymphocytes T génétiquement modifiés pour exprimer à leur surface un récepteur antigénique chimérique (CAR) ciblant le CD19, marqueur présent sur la majorité des cellules leucémiques B, va potentiellement révolutionner la prise en charge des LAL B en rechute ou réfractaire. Les taux de réponse au traitement vont de 60 % à 90 % dans des essais de phase I/II incluant des patients en deuxième rechute ou plus ou porteurs d'une maladie réfractaire. Des rémissions persistantes voire des guérisons ont été observées. Ces très bons résultats préliminaires permettent d'envisager dans un futur proche leur utilisation en 1 re ligne dans le cas de maladies de particulièrement mauvais pronostic. Cependant la production de ces cellules, leur coût ainsi que la gestion des effets secondaires sont des enjeux majeurs pour le futur de cette thérapeutique. La survenue de rechutes « CD19 négatives » a conduit à élaborer des CARs multispécifiques. Les CAR-T cells allogéniques permettraient quant à elles d'avoir à disposition un arsenal thérapeutique adapté à la cible dès le diagnostic. Les perspectives de développement des CAR T cells résident désormais dans l'optimisation des techniques dans les leucémies et lymphomes et dans l'extension des domaines d'application aux tumeurs solides de l'enfant. Abstract CAR T cells: current indications in children and perspectivesAcute lymphoblastic leukemia (ALL) is the first cause of cancer in children. Five-year overall survival is greater than 90% but leukemia remains a major cause of death from cancer in children.A new class of immunotherapy based on a chimeric antigen receptor "CAR" targeting the CD19 on the B leukemic cells and that is transduced in an autologous or allogenic T lymphocyte will allow to transform the prognosis of refractory or relapsed B-ALL. Overall response rates range

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Harnessing the Immunotherapy Revolution for the Treatment of Childhood Cancers

Cited by 121 publications

References 119 publications

Colony stimulating factor 1 receptor blockade improves the efficacy of chemotherapy against human neuroblastoma in the absence of T lymphocytes

Colony stimulating factor 1 receptor blockade improves the efficacy of chemotherapy against human neuroblastoma in the absence of T lymphocytes

Rationale for the treatment of children with CCSK in the UMBRELLA SIOP–RTSG 2016 protocol

CAR-T cells : indications actuelles en pédiatrie et perspectives de développement

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