A Quantitative Systems Pharmacology Perspective on  Cancer Immunology

Byrne-Hoffman, Christina N.; Klinke, David J.

doi:10.3390/pr3020235

Cited by 10 publications

(11 citation statements)

References 87 publications

(89 reference statements)

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“…Tumors were measured approximately every 7 to 10 d by using an electronic digital caliper (W80152, Performance Tool, Wilmar, Renton, WA), and tumor volumes were calculated by using the formula π/6 × length × width × height. Tumors were allowed to grow to approximately 500 to 1000 mm 3 or until they began to ulcerate.…”

Section: Methodsmentioning

confidence: 99%

“…The lack of appropriate models for thorough preclinical testing of treatment strategies is often blamed for these failures. 3 The metastatic behavior of melanoma is a specific challenge in murine tumor modeling. Typically, an experimental metastasis model involves direct injection of neoplastic cells into the bloodstream, most commonly into the tail vein of mice.…”

mentioning

confidence: 99%

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Factors Affecting Growth Kinetics and Spontaneous Metastasis in the B16F10 Syngeneic Murine Melanoma Model

et al. 2019

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Melanoma is an immunogenic tumor that can metastasize quickly to proximal and distal sites, thus complicating the application of therapeutic modalities. Numerous mouse model systems have been used to gain understanding of the immunobiology and metastatic potential of melanoma. Here, we report the optimization of a syngeneic mouse melanoma model protocol using the mouse B16-derived melanoma cell line B16F10 that ensures the production of tumors on mice pinnae that are similar in size between animals and that enlarge in a time-dependent manner. In this model, B16F10 cells are first allowed to develop tumors after injection in the interscapular area or flank of C57BL/6J mice. Subsequently, the tumors are harvested, cells dissociated and injected into mouse pinnae. Dose-dependent studies revealed that injection of 2 × 10 5 cells allowed for slow tumor enlargement, producing tumors averaging 100 mm 3 within 2 to 3 wk with a metastatic frequency of 100%. This experimental protocol will be useful in dissecting the immunobiology of melanoma tumor development and metastasis and the evaluation of immunotherapeutic antimelanoma therapies.

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Factors Affecting Growth Kinetics and Spontaneous Metastasis in the B16F10 Syngeneic Murine Melanoma Model

et al. 2019

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“…QSP modeling has previously been applied in a number of therapeutic areas, including cardiovascular, 11,12 respiratory, 13 and neurological 14 diseases, as well as diabetes 15 and cancer. 16 However, QSP modeling largely remains a new frontier for the lysosomal storage diseases. Although prior modeling studies have assessed the evolution of storage diseases based on residual enzyme activity levels 17 and the dynamics of pathways related to ASMD, such as sphingolipid metabolism, [18][19][20] these models have focused on behavior at the molecular level.…”

Section: What Does This Study Add To Our Knowledge?mentioning

confidence: 99%

“…QSP modeling has previously been applied in a number of therapeutic areas, including cardiovascular, respiratory, and neurological diseases, as well as diabetes and cancer . However, QSP modeling largely remains a new frontier for the lysosomal storage diseases.…”

mentioning

confidence: 99%

Quantitative Systems Pharmacology Modeling of Acid Sphingomyelinase Deficiency and the Enzyme Replacement Therapy Olipudase Alfa Is an Innovative Tool for Linking Pathophysiology and Pharmacology

Kaddi

Niesner

Baek

et al. 2018

CPT Pharmacom & Syst Pharma

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Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal storage disorder with heterogeneous clinical manifestations, including hepatosplenomegaly and infiltrative pulmonary disease, and is associated with significant morbidity and mortality. Olipudase alfa (recombinant human acid sphingomyelinase) is an enzyme replacement therapy under development for the non‐neurological manifestations of ASMD. We present a quantitative systems pharmacology (QSP) model supporting the clinical development of olipudase alfa. The model is multiscale and mechanistic, linking the enzymatic deficiency driving the disease to molecular‐level, cellular‐level, and organ‐level effects. Model development was informed by natural history, and preclinical and clinical studies. By considering patient‐specific pharmacokinetic (PK) profiles and indicators of disease severity, the model describes pharmacodynamic (PD) and clinical end points for individual patients. The ASMD QSP model provides a platform for quantitatively assessing systemic pharmacological effects in adult and pediatric patients, and explaining variability within and across these patient populations, thereby supporting the extrapolation of treatment response from adults to pediatrics.

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“…While most of our understanding of how information is transmitted between cells is based on normal biology, cancer cells arise through a process of mutation and selection 15,16 .…”

Section: Introductionmentioning

confidence: 99%

Interleukin-12 elicits a non-canonical response in B16 melanoma cells to enhance survival

Byrne-Hoffman

Deng

McGrath

et al. 2019

Preprint

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16Within tissues, cells secrete protein signals that are subsequently interpreted by 17 neighboring cells via intracellular signaling networks to coordinate a cellular response. 18 However, the oncogenic process of mutation and selection can rewire these signaling 19 networks to confer a fitness advantage to malignant cells. For instance, the melanoma 20 cell model (B16F0) creates a cytokine sink for Interleukin-12 (IL-12) to deprive neigh-21 boring cells of this important extracellular signal for sustaining anti-tumor immunity. 22 Alternatively, oncogenesis may also rewire intracellular signaling networks. To test this 23 concept, we asked whether IL-12 provides an intrinsic advantage to B16F0 melanoma 24 cells. Functionally, stimulation with IL-12 promoted the survival of B16F0 cells that 25 were challenged with a cytotoxic agent but had no rescue effect on normal Melan-A 26 melanocytes. We also explored a mechanistic basis for the functional results by sur-27 veying the phosphorylation intracellular proteins involved in canonical IL-12 signaling, 28 STAT4, and cell survival, Akt. In contrast to T cells that exhibited a canonical response § Corresponding author to IL-12 by phosphorylating STAT4, IL-12 stimulation of B16F0 cells phosphorylated 30 both STAT4 and Akt. Collectively, the data suggests that B16F0 cells have shifted 31 the intracellular response to IL-12 from engaging immune surveillance to favoring cell 32 survival. In short, identifying how signaling networks are rewired can guide therapeutic 33 strategies to restore effective immunosurveillance. 34 35 36Responses of the different cell types within tissues, such as T cells and Langerhans cells 38 within the epidermal layer of skin, are coordinated by the extracellular release of protein 39 signals. One such extracellular signal is the cytokine Interleukin-12 (IL-12) [1]. IL-12 is a 40 heterodimer comprised of a p35 and p40 subunit that is produced by antigen presenting cells, 41 like Langerhans and Dendritic cells, to boost natural killer (NK) and cytotoxic T lymphocyte 42 (CTL) activity and to polarize T helper cells towards a type 1 phenotype [2]. Activating 43 NK, CTLs and type 1 T helper cells play important roles in controlling viral infections 44 and defending against malignancy. Towards this aim, local delivery of IL-12 to the tumor 45 microenvironment has been shown to promote tumor regression in both mouse models and 46 human melanoma [3][4][5][6][7][8][9]. 47Inside the cell, these extracellular signals are processed through a series of protein-protein 48 interactions that transmit this information from the cell membrane to the nucleus to orches-49 trate a cellular response. In the case of IL-12, these extracellular signals are transduced by 50 the canonical Janus-Kinase (JAK)-Signal Transducer and Activator of Transcription (STAT) 51 signaling pathway [10]. The IL-12 receptor, composed of a β1 (IL12RB1) and β2 (IL12RB2) 52 subunit, lacks intrinsic enzymatic activity and forms a complex with two JAKs, JAK2 and 53 TYK2. Autoph...

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A Quantitative Systems Pharmacology Perspective on Cancer Immunology

Cited by 10 publications

References 87 publications

Factors Affecting Growth Kinetics and Spontaneous Metastasis in the B16F10 Syngeneic Murine Melanoma Model

Factors Affecting Growth Kinetics and Spontaneous Metastasis in the B16F10 Syngeneic Murine Melanoma Model

Quantitative Systems Pharmacology Modeling of Acid Sphingomyelinase Deficiency and the Enzyme Replacement Therapy Olipudase Alfa Is an Innovative Tool for Linking Pathophysiology and Pharmacology

Interleukin-12 elicits a non-canonical response in B16 melanoma cells to enhance survival

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