Emerging Concepts in Biomarker Discovery: Cancer Immunotherapy and Degenerative Disease of the Eye as Model Systems

2016 ◽  
pp. 143-176
Keyword(s):  
Cancer Immunotherapy ◽  
Biomarker Discovery ◽  
Degenerative Disease ◽  
Model Systems

scholarly journals Development of preclinical and clinical models for immune-related adverse events following checkpoint immunotherapy: a perspective from SITC and AACR

2021 ◽  
Vol 9 (9) ◽  
pp. e002627
Author(s):  
Nicholas L Bayless ◽  
Jeffrey A Bluestone ◽  
Samantha Bucktrout ◽  
Lisa H Butterfield ◽  
Elizabeth M Jaffee ◽  
...  
Keyword(s):  
Adverse Events ◽  
Cancer Immunotherapy ◽  
Immune Cell ◽  
Cytotoxic T Lymphocyte ◽  
Action Plan ◽  
Treatment Strategies ◽  
Model Systems ◽  
Preclinical Model ◽  
Programmed Death ◽  
Organ Systems

Recent advances in cancer immunotherapy have completely revolutionized cancer treatment strategies. Nonetheless, the increasing incidence of immune-related adverse events (irAEs) is now limiting the overall benefits of these treatments. irAEs are well-recognized side effects of some of the most effective cancer immunotherapy agents, including antibody blockade of the cytotoxic T-lymphocyte-associated protein 4 and programmed death protein 1/programmed-death ligand 1 pathways. To develop an action plan on the key elements needed to unravel and understand the key mechanisms driving irAEs, the Society for Immunotherapy for Cancer and the American Association for Cancer Research partnered to bring together research and clinical experts in cancer immunotherapy, autoimmunity, immune regulation, genetics and informatics who are investigating irAEs using animal models, clinical data and patient specimens to discuss current strategies and identify the critical next steps needed to create breakthroughs in our understanding of these toxicities. The genetic and environmental risk factors, immune cell subsets and other key immunological mediators and the unique clinical presentations of irAEs across the different organ systems were the foundation for identifying key opportunities and future directions described in this report. These include the pressing need for significantly improved preclinical model systems, broader collection of biospecimens with standardized collection and clinical annotation made available for research and integration of electronic health record and multiomic data with harmonized and standardized methods, definitions and terminologies to further our understanding of irAE pathogenesis. Based on these needs, this report makes a set of recommendations to advance our understanding of irAE mechanisms, which will be crucial to prevent their occurrence and improve their treatment.

scholarly journals P06.07 In vivo studies of immunomodulatory a-CTLA-4 antibody in a humanized mouse model

2021 ◽  
Vol 9 (Suppl 1) ◽  
pp. A22.1-A22
Author(s):  
C Reitinger ◽  
F Nimmerjahn
Keyword(s):  
Immune System ◽  
Mouse Model ◽  
Cancer Immunotherapy ◽  
Model Systems ◽  
Checkpoint Control ◽  
Human Immune System ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Human Immune

BackgroundRecent findings in cancer immunotherapy have reinforced the hypothesis that the immune system is able to control most cancers. Immunomodulatory antibodies can enhance immune responses, having the potential to generate anti-cancer immunity.1–4Materials and MethodsMost current studies addressing this question are performed in murine mouse model systems or use in vitro culture systems, which do not reflect the human in vivo situation, potentially leading to results that cannot be fully translated into human cancer therapy. Therefore, it is necessary to establish a new mouse model, which allows the study of cancer immunotherapy in the context of a human immune system. We focused on the establishment of a humanized mouse model, in which different immunomodulatory antibodies can be tested in the presence of a human immune system.ResultsFirst experiments concerning the suitability to test immunomodulatory antibodies in the humanized mouse model, revealed that effects of checkpoint-control antibody a-CTLA-4 were similar to the effects seen in patients of clinical studies. To analyse the anti-tumor activities of immunomodulatory antibodies in vivo we are establishing a human melanoma-like tumor model in humanized mice.ConclusionsThis enables us to test the efficacy of immunomodulatory agonistic antibodies (such as CP-870,893) and checkpoint control antibodies (such as anti-CTLA-4) in eliminating a melanoma-like tumor. Furthermore, parameters like tumor infiltrating human cells und cytokine/chemokine production can be analysed.ReferencesSchuster M, Nechansky A, Loibner H. Cancer immunotherapy. Biotechnol J 2006;1:138–147.Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature rev 2011;480:480–489.Finn OJ. Immuno-oncology: understanding the function and dysfunction of the immune system in cancer. Annals of Oncology 2012;23:vii6–vii9.Langer LF, Clay TM, Morse MA. Update on anti-CTLA-4 in clinical trials. Expert Opin Biol Ther 2007;8:1245–1256.Disclosure InformationC. Reitinger: None. F. Nimmerjahn: None.

scholarly journals Metabolomics and Cardiovascular Biomarker Discovery

2012 ◽  
Vol 58 (1) ◽  
pp. 139-147 ◽  
Author(s):  
Eugene P Rhee ◽  
Robert E Gerszten
Keyword(s):  
Metabolite Profiling ◽  
Biomarker Discovery ◽  
Structural Information ◽  
Chemical Diversity ◽  
Model Systems ◽  
Small Scale ◽  
Resonance Spectroscopy ◽  
Analytical Sensitivity ◽  
Metabolic Disturbances ◽  
Systematic Analysis

Abstract BACKGROUND Metabolomics, the systematic analysis of low molecular weight biochemical compounds in a biological specimen, has been increasingly applied to biomarker discovery. CONTENT Because no single analytical method can accommodate the chemical diversity of the entire metabolome, various methods such as nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS) have been employed, with the latter coupled to an array of separation techniques including gas and liquid chromatography. Whereas NMR can provide structural information and absolute quantification for select metabolites without the use of exogenous standards, MS tends to have much higher analytical sensitivity, enabling broader surveys of the metabolome. Both NMR and MS can be used to characterize metabolite data either in a targeted manner or in a nontargeted, pattern-recognition manner. In addition to technical considerations, careful sample selection and study design are important to minimize potential confounding influences on the metabolome, including diet, medications, and comorbitidies. To this end, metabolite profiling has been applied to human biomarker discovery in small-scale interventions, in which individuals are extremely well phenotyped and able to serve as their own biological controls, as well as in larger epidemiological cohorts. Understanding how metabolites relate to each other and to established risk markers for diseases such as diabetes and renal failure will be important in evaluating the potential value of these metabolites as clinically useful biomarkers. SUMMARY Applied to both experimental and epidemiological study designs, metabolite profiling has begun to highlight the breadth metabolic disturbances that accompany human disease. Experimental work in model systems and integration with other functional genomic approaches will be required to establish a causal link between select biomarkers and disease pathogenesis.

scholarly journals A three dimensional human immune-tumor cell model reveals the importance of isotypes in antibody-based immunotherapy

2020 ◽  
Author(s):  
Sandra Lara ◽  
Jessica C. Anania ◽  
Alexander Virtanen ◽  
Viktoria Stenhammar ◽  
Sandra Kleinau
Keyword(s):  
Tumor Cell ◽  
Cancer Immunotherapy ◽  
Three Dimensional ◽  
Human Tumor ◽  
Tumor Model ◽  
B Cell Lymphoma ◽  
Model Systems ◽  
Tumor Cell Death ◽  
Human Immune ◽  
3D Spheroids

AbstractMonoclonal antibodies (mAb) have revolutionized clinical medicine, especially in the field of cancer immunotherapy. The challenge now is to improve the response rates in the patients, as immunotherapy still fails for many patients. Strategies to enhance tumor cell death is a fundamental aim, but relevant model systems for human tumor immunology are lacking. Herein, we have developed a novel pre-clinical human immune – three-dimensional (3D) tumor model (spheroids) to map the efficiency of tumor-specific isotypes for improved tumor cell killing. Different anti-CD20 Rituximab (RTX) isotypes alone or in combination, were evaluated for mediating complement-dependent cytotoxicity and antibody-dependent phagocytosis by human monocytic cells in 3D spheroids, in parallel with monolayer culture, of human CD20+ B-cell lymphoma. We show that the IgG3 variant of RTX has the greatest tumoricidal effect over other isotypes, mediating strong infiltration of monocytic effector cells into 3D spheroids. Hence, the human immune-3D tumor model is an attractive ex vivo system to help filter out mAbs for best efficacy in cancer immunotherapy.

scholarly journals Uncovering extensive post-translation regulation during human cell cycle progression by integrative multi-’omics analysis

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Gregory M. Parkes ◽  
Mahesan Niranjan
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Computational Models ◽  
Biomarker Discovery ◽  
Cellular Protein ◽  
Model Systems ◽  
Translation Regulation ◽  
Expression Levels ◽  
Protein Levels ◽  
Quantitative Separation

Abstract Background Analysis of high-throughput multi-’omics interactions across the hierarchy of expression has wide interest in making inferences with regard to biological function and biomarker discovery. Expression levels across different scales are determined by robust synthesis, regulation and degradation processes, and hence transcript (mRNA) measurements made by microarray/RNA-Seq only show modest correlation with corresponding protein levels. Results In this work we are interested in quantitative modelling of correlation across such gene products. Building on recent work, we develop computational models spanning transcript, translation and protein levels at different stages of the H. sapiens cell cycle. We enhance this analysis by incorporating 25+ sequence-derived features which are likely determinants of cellular protein concentration and quantitatively select for relevant features, producing a vast dataset with thousands of genes. We reveal insights into the complex interplay between expression levels across time, using machine learning methods to highlight outliers with respect to such models as proteins associated with post-translationally regulated modes of action. Conclusions We uncover quantitative separation between modified and degraded proteins that have roles in cell cycle regulation, chromatin remodelling and protein catabolism according to Gene Ontology; and highlight the opportunities for providing biological insights in future model systems.

scholarly journals SITC cancer immunotherapy resource document: a compass in the land of biomarker discovery

2020 ◽  
Vol 8 (2) ◽  
pp. e000705
Author(s):  
Siwen Hu-Lieskovan ◽  
Srabani Bhaumik ◽  
Kavita Dhodapkar ◽  
Jean-Charles J B Grivel ◽  
Sumati Gupta ◽  
...  
Keyword(s):  
Cancer Immunotherapy ◽  
Biomarker Discovery ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Tumor Vaccines ◽  
Term Survival ◽  
Novel Technologies ◽  
Clinical Responses ◽  
Biomarker Research ◽  
Tumor Types

Since the publication of the Society for Immunotherapy of Cancer’s (SITC) original cancer immunotherapy biomarkers resource document, there have been remarkable breakthroughs in cancer immunotherapy, in particular the development and approval of immune checkpoint inhibitors, engineered cellular therapies, and tumor vaccines to unleash antitumor immune activity. The most notable feature of these breakthroughs is the achievement of durable clinical responses in some patients, enabling long-term survival. These durable responses have been noted in tumor types that were not previously considered immunotherapy-sensitive, suggesting that all patients with cancer may have the potential to benefit from immunotherapy. However, a persistent challenge in the field is the fact that only a minority of patients respond to immunotherapy, especially those therapies that rely on endogenous immune activation such as checkpoint inhibitors and vaccination due to the complex and heterogeneous immune escape mechanisms which can develop in each patient. Therefore, the development of robust biomarkers for each immunotherapy strategy, enabling rational patient selection and the design of precise combination therapies, is key for the continued success and improvement of immunotherapy. In this document, we summarize and update established biomarkers, guidelines, and regulatory considerations for clinical immune biomarker development, discuss well-known and novel technologies for biomarker discovery and validation, and provide tools and resources that can be used by the biomarker research community to facilitate the continued development of immuno-oncology and aid in the goal of durable responses in all patients.

scholarly journals Evaluation of Small Molecule Drug Uptake in Patient-Derived Prostate Cancer Explants by Mass Spectrometry

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Shadrack M. Mutuku ◽  
Paul J. Trim ◽  
Bala K. Prabhala ◽  
Swati Irani ◽  
Kayla L. Bremert ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Androgen Receptor ◽  
Small Molecule ◽  
Biomarker Discovery ◽  
Tissue Concentration ◽  
Maldi Mass Spectrometry ◽  
Drug Uptake ◽  
Model Systems ◽  
Gelatin Sponge ◽  
High Signal

Abstract Patient-derived explant (PDE) culture of solid tumors is increasingly being applied to preclinical evaluation of novel therapeutics and for biomarker discovery. In this technique, treatments are added to culture medium and penetrate the tissue via a gelatin sponge scaffold. However, the penetration profile and final concentrations of small molecule drugs achieved have not been determined to date. Here, we determined the extent of absorption of the clinical androgen receptor antagonist, enzalutamide, into prostate PDEs, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and matrix-assisted laser/desorption ionisation (MALDI) mass spectrometry imaging (MSI). In a cohort of 11 PDE tissues from eight individual patients, LC-MS/MS quantification of PDE homogenates confirmed enzalutamide (10 µM) uptake by all PDEs, which reached maximal average tissue concentration of 0.24–0.50 ng/µg protein after 48 h culture. Time dependent uptake of enzalutamide (50 µM) in PDEs was visualized using MALDI MSI over 24–48 h, with complete penetration throughout tissues evident by 6 h of culture. Drug signal intensity was not homogeneous throughout the tissues but had areas of markedly high signal that corresponded to drug target (androgen receptor)-rich epithelial regions of tissue. In conclusion, application of MS-based drug quantification and visualization in PDEs, and potentially other 3-dimensional model systems, can provide a more robust basis for experimental study design and interpretation of pharmacodynamic data.

scholarly journals Mouse Models for Studying Oral Cancer: Impact in the Era of Cancer Immunotherapy

2018 ◽  
Vol 97 (6) ◽  
pp. 683-690 ◽  
Author(s):  
J.J. Luo ◽  
C.D. Young ◽  
H.M. Zhou ◽  
X.J. Wang
Keyword(s):  
Oral Cancer ◽  
Cancer Immunotherapy ◽  
Cancer Genetics ◽  
Tumor Stroma ◽  
Model Systems ◽  
Therapeutic Interventions ◽  
In Vivo Model ◽  
Oral Cancer Patients ◽  
The Impact

Model systems for oral cancer research have progressed from tumor epithelial cell cultures to in vivo systems that mimic oral cancer genetics, pathological characteristics, and tumor-stroma interactions of oral cancer patients. In the era of cancer immunotherapy, it is imperative to use model systems to test oral cancer prevention and therapeutic interventions in the presence of an immune system and to discover mechanisms of stromal contributions to oral cancer carcinogenesis. Here, we review in vivo mouse model systems commonly used for studying oral cancer and discuss the impact these models are having in advancing basic mechanisms, chemoprevention, and therapeutic intervention of oral cancer while highlighting recent discoveries concerning the role of immune cells in oral cancer. Improvements to in vivo model systems that highly recapitulate human oral cancer hold the key to identifying features of oral cancer initiation, progression, and invasion as well as molecular and cellular targets for prevention, therapeutic response, and immunotherapy development.

Functional genomics in cancer immunotherapy: computational approaches for biomarker and drug discovery

2019 ◽  
Vol 4 (4) ◽  
pp. 689-700 ◽  
Author(s):  
Wee Loong Chin ◽  
Rachael M. Zemek ◽  
W. Joost Lesterhuis ◽  
Timo Lassmann
Keyword(s):  
Drug Discovery ◽  
Functional Genomics ◽  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Biomarker Discovery ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Computational Approaches

A hitchhiker's guide to biomarker discovery in immune checkpoint blockade.

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