The Hematology of Tomorrow Is Here—Preclinical Models Are Not: Cell Therapy for Hematological Malignancies

Arranz, Lorena

doi:10.3390/cancers14030580

Cited by 5 publications

(3 citation statements)

References 130 publications

(163 reference statements)

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“…However, several essential cytokines do not cross-react between species, obstructing differentiation and maturation of several immune cell types. Thus, NSG-SGM3 (NSGS) mice have been developed that express supraphysiological concentrations (>200 pg/mL) of the human hematopoietic cytokines SCF, GM-CSF and IL-3, which support the engraftment of leukemic cells and the generation of a competent human immune system [16,17]. This results in improved human myelopoiesis, Treg and natural killer (NK) cell development, albeit with decreased erythropoiesis compared to NSG mice [18,19].…”

Section: Introductionmentioning

confidence: 99%

Humanized Ovarian Cancer Patient-Derived Xenografts for Improved Preclinical Evaluation of Immunotherapies

Kleinmanns

Gullaksen

Bredholt

et al. 2022

Cancers

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High-grade serous ovarian cancer (HGSOC) has poor prognosis and new treatment modalities are needed. Immunotherapy, with checkpoint inhibitors, have demonstrated limited impact. To evaluate the suitability for immunotherapeutics, contextualized preclinical models are required to secure meaningful clinical translation. Therefore, we developed and characterized humanized patient-derived xenograft (hu PDX) murine models of HGSOC, which were established by orthotopic implantation of tumor cell suspensions and intravenous injection of CD34+ cells isolated from umbilical cord blood samples. The developing human immune system in NSG and NSGS mice was followed longitudinally by flow cytometry and characterized by mass cytometry with a panel of 34 surface markers. Molecular imaging of tumor burden, survival analysis, and characterization of tumor-infiltrating immune cells was performed to assess the treatment response to anti-PD-1 (nivolumab) monotherapy. Successful generation of hu PDX models was achieved. Mice treated with nivolumab showed a decrease in tumor burden, however no significant survival benefit was identified when compared to untreated controls. No correlation was seen between PD-L1 expression and CD8 T cell infiltration and response parameters. As the characterization showed an immune infiltration of predominantly myeloid cells, similar to what is observed in HGSOC patients, the models may have the potential to evaluate the importance of myeloid cell immunomodulation as well.

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Section: Introductionmentioning

confidence: 99%

Humanized Ovarian Cancer Patient-Derived Xenografts for Improved Preclinical Evaluation of Immunotherapies

Kleinmanns

Gullaksen

Bredholt

et al. 2022

Cancers

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“…Other than immunological factors, non-immunological factors may also constrain the recapitulation of human malignancy in mice. Many efforts were input to optimize human hematological malignancy mouse models from this aspect in the last two decades ( 128 ). The microenvironment of hematological malignancies is composed of the bone marrow, blood vessels, and peripheral lymphoid organs providing nutrition and survival factors, which can affect the survival and growth of tumor cells.…”

Section: Optimization Of Human Hematological Malignancy Mouse Modelsmentioning

confidence: 99%

Progress in construction of mouse models to investigate the pathogenesis and immune therapy of human hematological malignancy

Lang,

Lyu,

Tan

et al. 2023

Front. Immunol.

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Hematological malignancy is a disease arisen by complicate reasons that seriously endangers human health. The research on its pathogenesis and therapies depends on the usage of animal models. Conventional animal model cannot faithfully mirror some characteristics of human features due to the evolutionary divergence, whereas the mouse models hosting human hematological malignancy are more and more applied in basic as well as translational investigations in recent years. According to the construction methods, they can be divided into different types (e.g. cell-derived xenograft (CDX) and patient-derived xenograft model (PDX) model) that have diverse characteristics and application values. In addition, a variety of strategies have been developed to improve human hematological malignant cell engraftment and differentiation in vivo. Moreover, the humanized mouse model with both functional human immune system and autologous human hematological malignancy provides a unique tool for the evaluation of the efficacy of novel immunotherapeutic drugs/approaches. Herein, we first review the evolution of the mouse model of human hematological malignancy; Then, we analyze the characteristics of different types of models and summarize the ways to improve the models; Finally, the way and value of humanized mouse model of human immune system in the immunotherapy of human hematological malignancy are discussed.

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“…In NOG mice, the Il2rg mutant gene is expressed and produces a protein that binds cytokines but does not signal. Conversely, Il2rg gene expression does not occur in NSG mice (27,28). The use of the xenograft models gives us opportunity to assess the effect of the human CAR-T cells on human tumors but there are no interactions with other immune cells or healthy tissues.…”

Section: Human Xenograft Modelsmentioning

confidence: 99%

Preclinical Mouse Models in Adoptive Cell Therapies of Cancer

Rajčević¹,

Smole²

2022

SVR

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Engineered T cell-based therapies are an advanced approach for cancer immunotherapy using genetically modified T cells. To date, CD19 and BCMA targeting Chimeric Antigen Receptor (CAR) T cells have been approved for the treatment of certain hematologic malignancies. The success of CAR-T cells is offset by limited efficacy, particularly in solid tumors, and safety risks. Preclinical in vivo research, which is highly dependent on reliable mouse models, has been a cornerstone of the success story of adoptive cell therapies and continues to provide invaluable information for the development of the next generation of cellular immunotherapies. In this review we describe four of the most common preclinical mouse models: Xenograft models, syngeneic models, immunocompetent transgenic models and humanized mouse models. All of these have advantages and disadvantages and no mouse model can fully recapitulate the human situation because of inherent differences and treatment complexity. Reports suggest that using a combination of mouse models in preclinical in vivo research prior to translating the treatment to humans in clinical trials can help incrementally improve the quality, safety, and efficacy of the treatment and provide more comprehensive information than a single model. PREDKLINIČNI MIŠJI MODELI PRI ADOPTIVNIH CELIČNIH TERAPIJAH RAKA Povzetek: Napredne terapije na osnovi biotehnološko spremenjenih limfocitov T predstavljajo moderen pristop k imunoterapiji raka z uporabo genetsko spremenjenih limfocitov T. Do danes sta bili za zdravljenje hematoloških malignosti odobreni terapiji s himernimi antigenskimi receptorji usmerjenimi proti antigenoma CD19 in BCMA. Uspeh zdravljenja s celicami CAR-T pa ovirajo omejena učinkovitost, še posebej pri solidnih tumorjih in varnostna tveganja. Predklinične raziskave in vivo, ki so močno odvisne od zanesljivih mišjih modelov, so bile kritični dejavnik zgodbe o uspehu adoptivnih celičnih terapij in še vedno zagotavljajo neprecenljive podatke za razvoj naslednje generacije celičnih imunoterapij. V preglednem članku povzemamo štiri najpogostejše predklinične mišje modele: ksenografte, singenetske modele, imunokompetentne transgenske modele in humanizirane mišje modele. Vsi opisani modeli imajo svoje prednosti in slabosti in noben mišji model ne more do popolnosti preslikati situacije v človeškem pacientu zaradi med-vrstnih razlik ter izjemne zapletenosti zdravljenja. Podatki iz literature kažejo na to, da lahko uporaba kombinacije mišjih modelov v predkliničnih in vivo raziskavah pred translacijo zdravljenja na ljudi v kliničnih poskusih pripomore k postopnemu izboljšanju kakovosti, varnosti in učinkovitosti zdravljenja in zagotovi bolj celostni nabor podatkov kot en sam model. Ključne besede: mišji model; ksenograft; singenetski; transgenski; humanizirani; CAR-T; adoptivna celična terapija

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The Hematology of Tomorrow Is Here—Preclinical Models Are Not: Cell Therapy for Hematological Malignancies

Cited by 5 publications

References 130 publications

Humanized Ovarian Cancer Patient-Derived Xenografts for Improved Preclinical Evaluation of Immunotherapies

Humanized Ovarian Cancer Patient-Derived Xenografts for Improved Preclinical Evaluation of Immunotherapies

Progress in construction of mouse models to investigate the pathogenesis and immune therapy of human hematological malignancy

Preclinical Mouse Models in Adoptive Cell Therapies of Cancer

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