Eradication of melanomas by targeted elimination of a minor subset of tumor cells

Schmidt, Patrick; Kopecky, Caroline; Hombach, Andreas; Zigrino, Paola; Mauch, Cornelia; Abken, Hinrich

doi:10.1073/pnas.1009069108

Cited by 110 publications

(105 citation statements)

References 25 publications

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“…A CD20 + sejtek viszont nem mutattak nagyobb tumoriniciátor kapacitást a CD20 -adherens populációkhoz képest, ráadásul differenciációs képességük is idővel csökkent. Ugyanakkor a CD20 ellen kifejlesztett immunsejt- [39] és antitest-terápia [40] ígéretes eredményeket hozott a melanomasejtek progresszió-jának megakadályozásában. Mindez arra utal, hogy a CD20 + melanomasejteknek komoly jelentősége van a melanomák heterogenitásában és terjedésében.…”

Section: őSsejteredetű Markerek Melanomábanunclassified

“…NSG-egerekbe xenotranszplantált melanomasejtek által létrehozott tumorokat sikeresen eradikáltak a CD20 ellen kifejlesztett citotoxikus T-sejtekkel [39]. A T-sejteket olyan kimérareceptorral transzfektálták, amelynek extracelluláris doménje egy anti-CD20 antitest antigénkötő (Fab) régióját hordozta, citoplazmatikus doménje pedig a T-sejtek aktiválódásá-ért felelős CD3ζ intracelluláris doménjét tartalmazta.…”

Section: Terápiás Stratégiák Melanoma-őssejtmarkerekkel Szembenunclassified

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Tumorőssejtek szerepe a melanoma progressziójában és heterogenitásában

et al. 2016

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A szolid és hematológiai tumorok legtöbbjében mára olyan sejtpopulációkat azonosítottak, amelyek a daganatok kis százalékát alkotják, mégis kiemelkedő szerepet töltenek be a daganat terjedésének előmozdításában. Ezek az úgyneve-zett tumorőssejtek a szomatikus és embrionális őssejtekhez hasonló viselkedést mutatnak, aszimmetrikus osztódással önmegújításra képesek és heterogén sejtpopulációkat is létrehoznak. Egyre több kutatás alátámasztja, hogy a malignus melanomák progressziója mögött is tumoros őssejtek állnak. Nem tisztázott kérdés azonban, hogy a tumorigenicitá-sért vajon kizárólag melanomaőssejtek szubpopulációi felelősek vagy pluripotens őssejtté bármely melanomasejt dedifferenciálódhat. Jelen közlemény a pluripotens melanomaőssejtekről kíván átfogó képet nyújtani, különös tekintettel azokra a mechanizmusokra, amelyek a melanocyta-őssejtek differenciálódását szabályozzák, ugyanakkor a melanomaőssejtekben szabályozatlanul működnek. Bemutatásra kerül a mikrokörnyezet sejtjeinek, sejtadhéziós molekuláinak és szolúbilis faktorainak szerepe a melanomák progressziójában és heterogenitásának kialakulásában. Végül szó esik a melanoma terjedését leíró modellekről és azokról a sejtszintű markerekről, amelyek a melanomaőssejtek elkülönítésére, újabb célzott terápiák kifejlesztésére lehetőséget nyújthatnak. Orv. Hetil., 2016. 157(34), 1339-1348. Kulcsszavak: melanoma, tumorőssejt, mikrokörnyezet, marker Role of cancer stem cells in the progression and heterogeneity of melanomaOver the past decade a rare cell population called cancer stem cells has been identified in both solid tumors and hematologic cancers. These cells are reminiscent of somatic and embryonic stem cells and play a critical role in the initiation and progression of malignancies. As all stem cells, they are able to undergo asymmetric cell division and hence renew themselves and create various other progenies with heterogenous phenotypes. A growing body of literature suggested that stem cell subpopulations contribute significantly to the growth and metastatic properties of melanoma. This review gives a comprehensive overview of the current literature on melanoma stem cells, with a special emphasis on the signaling pathways responsible for the homeostatic growth of melanocytes and the uncontrolled proliferation of melanoma cells. The importance of the local microenvironment are demonstrated through summarizing the role of various cell types, soluble factors and cell adhesion molecules in the progression of melanoma and the creation of treatment resistant cancer cell clones. Last but not least, the models of melanoma progression will be introduced and a variety of cellular markers will be presented that may be used to identify and therapeutically target melanoma.Keywords: melanoma, cancer stem cell, microenvironment, marker Széky, B., Silló, P., Fábián, M., Mayer, B., Kárpáti, S., Németh, K. [Role of cancer stem cells in the progression and heterogeneity of melanoma]. Orv. Hetil., 2016, 157(34), 1339-1348. ÖSSZEFOGLALÓ KÖZLEMÉNYRövidítések ADCC = antigé...

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Section: őSsejteredetű Markerek Melanomábanunclassified

Section: Terápiás Stratégiák Melanoma-őssejtmarkerekkel Szembenunclassified

Tumorőssejtek szerepe a melanoma progressziójában és heterogenitásában

et al. 2016

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“…83 Targeting a minor subset of tumour cells, such as cancer stem cells, may obviate the requirement for extensive T cell recruitment. 84,85 Innovative cell delivery systems such as focused ultrasound may also lead to improvements in this area. 86 Investigation into a combination of targeted and immune therapies are warranted, for example, a combination of CAR T cell therapy with immunomodulatory protocols to tackle the immunosuppressive microenvironment induced by solid tumours.…”

Section: Future For Car T Cell Therapymentioning

confidence: 99%

Clinical Development and Manufacture of Chimeric Antigen Receptor T cells and the Role of Leukapheresis

Fesnak¹,

O’Doherty²

2017

European Oncology &Amp; Haematology

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Adoptive transfer of chimeric antigen receptor (CAR) T cells is a powerful targeted immunotherapeutic technique. CAR T cells are manufactured by harvesting mononuclear cells, typically via leukapheresis from a patient’s blood, then activating, modifying the T cells to express a transgene encoding a tumour-specific CAR, and infusing the CAR T cells into the patient. Gene transfer is achieved through the use of retroviral or lentiviral vectors, although non-viral delivery systems are being investigated. This article discusses the challenges associated with each stage of this process. Despite the need for a consistent end product, there is inherent variability in cellular material obtained from critically ill patients who have been exposed to cytotoxic therapy. It is important to carefully select target antigens to maximise effect and minimise toxicity. Various types of CAR T cell toxicity have been documented: this includes “on target, on tumour”, “on target, off tumour” and “off target” toxicity. A growing body of clinical evidence supports the efficacy and safety of CAR T cell therapy; CAR T cells targeting CD19 in B cell leukemias are the best-studied therapy to date. However, providing personalised therapy on a large scale remains challenging; a future aim is to produce a universal “off the shelf” CAR T cell.

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“…[57] Deng et al, [58] for instance, demonstrated that CAR T cell therapy could inhibit tumor growth of highly metastatic prostate cancer that expresses low levels of EpCAM. Other CSC-targeting adoptive T cell therapies include CAR T cells which bind to a CSCspecific N-glycosylation-dependent epitope of CD133, [59] high-molecular weight melanoma associated antigen or chondroitin sulfate proteoglycan 4-specific CAR T cells that were reported to specifically eliminate melanoma with a CSC phenotype, [60,61] and epidermal growth factor receptor variant III (EGFRvIII) specific CAR T cells which target glioma SCs. [62] Cells in the tumor microenvironment was also found to express several negative immune regulators such as programmed cell death 1(PD-1) and its ligand (PD-L1), cytotoxic T lymphocyte associated 4 (CTLA-4), and transforming growth factor β (TGF-β).…”

Section: Enhancing Immune Responsesmentioning

confidence: 99%

Therapeutic strategies for targeting cancer stem cells

Kim¹,

Siegler²,

Siriwon³

et al. 2016

JCMT

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The therapeutic limitations of conventional chemotherapeutic drugs present a challenge for cancer therapy; these shortcomings are largely attributed to the ability of cancer cells to repopulate and metastasize after initial therapies. Compelling evidence suggests that cancer stem cells (CSCs) have a crucial impact in current shortcomings of cancer therapy because they are largely responsible for tumor initiation, relapse, metastasis, and chemo-resistance. Thus, a better understanding of the properties and mechanisms underlying CSC resistance to treatments is necessary to improve patient outcomes and survival rates. In this review, the authors characterize and compare different CSC-specific biomarkers that are present in various types of tumors. We further discuss multiple targeting approaches currently in preclinical or clinical testing that show great potential for targeting CSCs. This review discusses numerous strategies to eliminate CSCs by targeting surface biomarkers, regulating CSC-associated oncogenes and signaling pathways, inhibiting drug-efflux pumps involved in drug resistance, modulating the tumor microenvironment and immune system, and applying drug combination therapy using nanomedicine.

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Eradication of melanomas by targeted elimination of a minor subset of tumor cells

Cited by 110 publications

References 25 publications

Tumorőssejtek szerepe a melanoma progressziójában és heterogenitásában

Tumorőssejtek szerepe a melanoma progressziójában és heterogenitásában

Clinical Development and Manufacture of Chimeric Antigen Receptor T cells and the Role of Leukapheresis

Therapeutic strategies for targeting cancer stem cells

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