Novel RNAs Insights Toward AML Development


Somatic mutations in the additional sex comb-like 1 (ASXL1) gene have been identified in multiple hematologic malignancies, including acute myeloid leukemia (AML), and are associated with poor prognoses1. ASXL1 encodes a nuclear protein that regulates epigenetic remodeling and transcription through interactions with polycomb complex proteins and transcriptional activators and repressors. Several ASXL1 mutations have been associated with loss of protein expression that leads to myeloid transformation2. In contrast, gain-of-function mutations in ASXL1 result in expression of a truncated ASXL1 protein that can bind to BRCA-1 associated protein 1 (BAP1) and cause leukemogenesis3,4. Targeted reduction of BAP1 activity is sufficient to prevent this malignancy process5.

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UnTIL We Meet Again: Testing TIL Therapies in an Ex Vivo Platform

Tumor infiltrating lymphocyte (TIL)-based immunotherapy is currently at the forefront of cutting-edge immuno-oncology treatments. TILs are a type of adoptive cellular therapy (ACT) using lymphocytes that are found within tumor tissues; most of these lymphocytes are T cells that can specifically target tumor cells. For TIL-based therapies, these T cells are harvested from a tumor biopsy, expanded ex vivo, and infused back into the patient. Advances in TIL-based therapies are driven by preclinical characterization and screening of TILs against a wide array of tumor types.

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Prostate Cancer: Drivers of Genetic Mutations & Their Role in Disease Progression

Prostate cancer is one of the most common forms of cancer that affects the prostate gland in the male urogenital tract. Most prostate cancers are slow growing and are detected in individuals older than age 50. Although environmental factors contribute to the development of prostate cancer, risk is significantly associated with incidence among first-degree relatives. In recent years, several inherited and spontaneously mutated genes have been linked to prostate cancer. Here we highlight these findings and how they provide insight into the development of targeted prostate cancer therapies.

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Datasets Discovered: DLBCL Cohort

Importance of the Dataset

Diffuse Large B-Cell Lymphoma (DLBCL) is a cancer of the B cells and is the most common form of non-Hodgkin’s Lymphoma (NHL) among adults. Champions’ DLBCL models encompass various subtypes of the disease, including ABC (Activated B cell), GCB (Germinal Center B cell), and Richter. These models are well-characterized and include patient clinical attributes, disease status, treatment history and in vivo drug responses to a range of therapies, including CHOP or a Rituximab-CHOP (R-CHOP) combination treatment. Champions DLBCL model cohort includes diverse molecular features such as double and triple hit mutations, as well as mutations in several key pathways such as proliferation, oncogenic signaling, and B cell differentiation. This unique dataset includes next generation sequencing (NGS), proteomics and phospho-proteomics from Champions’ DLBCL cohort.

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In Vivo Imaging with Bioluminescence: Ancient Scientific Phenomena Driving Cutting-Edge Tumor Research

Preclinical In Vivo Imaging is a technique that allows scientists to observe biological processes at the cellular level in real time. Preclinical In Vivo Imaging has been especially useful for imaging the tumor microenvironment (TME) and tracking the complex interactions between tumor cells and immune system cells that can result in tumor growth and development or tumor regression. Preclinical In Vivo Imaging is a noninvasive technique that relies on visualization of specific cells that emit light through bioluminescent reactions that can be detected within living animal models with highly sensitive cameras. Here we provide an overview of bioluminescence-based Preclinical In Vivo Imaging methods that are being used in preclinical oncology research.

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Regulatory T Cells in CLL: Immune System Exhaustion and Potential Restoration, and the Role of Immuno-Oncology Therapies

Chronic lymphocytic leukemia (CLL) is one of the most commonly occurring hematologic malignances with no known cure and is defined by the clonal expansion and accumulation of CD5+ B cells in the blood and bone marrow. Standard treatments to manage disease include chemotherapy and rituximab (anti-CD20 monoclonal antibody). Newer therapies that are less prone to resistance or treatment failure are currently being examined, such as Bruton tyrosine kinase (BTK) inhibitors and anti-CD20 biosimilars[1],[2].

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Lumin Bioinformatics Spotlight: Feature Exploration

Champions Oncology is illuminating the cellular dynamics of cancer by providing a tool to accelerate biomarker discovery for all cancer researchers. Champions proprietary PDX (patient-derived xenograft) models have been shown to recapitulate patient response to clinical treatments1. The Lumin Bioinformatics platform incorporates NGS and proteomic data obtained from Champions unique and highly characterized PDX tumor bank as well as publicly available data sets (i.e. TCGA, CPTAC, GEO).

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PARP Inhibitors for Ovarian Cancer Treatment

Ovarian cancer remains one of the leading causes of mortality for women with gynecological cancers and continues to be associated with stubbornly low 5-year survival rates. Depending on the stage or type of ovarian cancer, localized treatments including surgical resection or radiation may be sufficient. Treatment of metastatic ovarian cancer may include surgery and radiation combined with chemotherapy. Hormone therapy is also typically combined with chemotherapy for targeted reduction of estrogen and/or stimulation of progesterone for the targeted treatment of ovarian stromal tumors that produce high levels of estrogen. Nonetheless, many of these treatments have limited efficacy for treating metastatic ovarian cancer.

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Receptor Occupancy and Flow Cytometry

The development of new oncology treatments has focused on strategies that alter immune responses. Many of these novel therapies use antibodies that bind to receptors on different immune cell subsets and either activate or suppress their functions depending on the immune response being targeted. Antibody-drug conjugates are also becoming more widely used for improved targeting of drugs to specific cell subsets. Flow cytometry-based receptor occupancy (RO) assays are a valuable tool for quantifying cell surface expression of target molecules and are used to generate pharmacodynamic (PD) data, which can be used with pharmacokinetic (PK) data to guide dosing strategies. Consider these different types of receptor occupancy assays as you develop the most useful tools for screening therapeutic molecules.

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In Living COLOR: Using Bioluminescence Imaging to Quantify Tumor Burden

Bioluminescence imaging (BLI) is a highly sensitive non-invasive molecular imaging technique that has been used across biological research areas for insights into how tissues and organs function in real-time under normal physiological conditions or different disease states. BLI was developed using transgenic mice that expressed the luciferase enzyme as a reporter in specific cells. These cells can be visualized in the presence of oxidated luciferin substrate, which generates bioluminescent light (photons) that can be detected using microscope-based or portable photon detectors[1]. This method can detect biologically active tumor cells and can monitor changes in the growth or clearance these cells because bioluminescence is an ATP-dependent process in living animals[2], [3]. More recently, functional BLI probes have been developed that use caged luciferin substrates that must be cleaved through a specific biological process for luminescence[4]. These functional probes have been useful in monitoring metabolism and enzyme activity, and such read-outs can be used to understand basic tumor biology or identify mechanisms of action for anti-tumor drugs.

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Factors to Consider When Selecting Next-Generation Sequencing (NGS) Technology

Next-generation sequencing (NGS) technology has transformed the biomedical research landscape. Only a few years ago, high resolution genome or exome sequencing would be cumbersome and cost-restrictive, but current NGS technology platforms now allow for basic and clinical researchers to include these approaches for routine DNA and RNA sequencing needs. What are the different NGS sequencing approaches and how are they applied to oncology research?

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Sarcoma Immunotherapeutic Strategies

Sarcomas are a group of aggressive heterogeneous tumors for which more than 100 histological subtypes have been defined1. Sarcomas are found in a variety of solid tissues, including bone and gastrointestinal stromal cells. Current treatment options include radiotherapy, surgical resection, targeted therapies, and chemotherapy, but these treatments have had limited efficacy on intermediate to high grade tumors. Investigations into the molecular and cellular mechanisms that drive sarcomas have helped identify potential biomarkers that can serve as potential therapeutic targets. In addition, recent studies have also focused on the tumor microenvironment (TME) within sarcomas and the roles of different immune cell subsets creating an immunosuppressive microenvironment. These observations directly inform novel immunotherapeutic approaches that are being examined in preclinical and clinical studies.

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Current Trends in Gastrointestinal Cancer – CRISPR/Cas9-based Immunotherapy

Gastrointestinal cancers are a heterogeneous group of cancers that can be caused by H. pylori bacterial or Epstein-Barr virus infection, chronic inflammation, or inherited or spontaneous genetic mutations. Advances in solid tumor immunotherapy for gastrointestinal cancers includes the development of methods that improve the screening, evaluation, and development of more precise and robust treatments. Breakthroughs in basic and translational research are leading to better treatment options for gastrointestinal cancer, and CRISPR/Cas9-based (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) gene editing technology is at the forefront of these discoveries.

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Profiling TILs in Syngeneic Mice to Support Drug Development

Mouse models have been essential to the development of novel immunotherapies that target solid tumors and hematological malignancies. Several types of mouse models exist, and syngeneic mouse models offer several advantages for screening potential drugs and biologics since tumors are derived from the same genetic background as the mouse strain. Syngeneic tumor models are particularly useful for profiling tumor infiltrating lymphocytes (TILs) that are found within the tumor microenvironment (TME) of solid tumors.

Highlighted below is how immune profiling of TILs can be carried out in syngeneic mouse models and how this informs preclinical studies.

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Triplet Therapy for Genetic Subtypes of AML

Acute myeloid leukemia (AML) is one of the most frequently occurring types of leukemia and can have widely varying treatment outcomes. Multiple mutations and cytogenetic abnormalities have been characterized in AML, and recent studies have been essential to defining specific mutations that confer resistance to standard chemotherapies or molecular inhibitors. A mutation in the tyrosine kinase domain of FMS-like tyrosine kinase 3 (FLT3) has been associated with resistance to FLT3 inhibitors[1], and molecular diagnostics are critical to identifying mutations that lead to treatment failure.

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Immunohistochemistry (IHC) in Cancer Research

Plasmacytoid carcinoma of the urinary bladder – H&E Staining

 

Immunohistochemistry (IHC) is a technique that originates in the early twentieth century but continues to be a valuable method that forms the backbone of molecular pathology. IHC is used for histological examination of tissues and specifically detects the presence of a molecule, such as a tumor antigen. IHC uses antibody-based labeling in which the primary antibody detects the target of interest and the secondary antibody detects the primary antibody which is linked to a molecule for microscopic visualization. Many different secondary antibody labeling modalities exist, including fluorescence, enzyme-mediated reactions and colloidal gold, and different labels are suited to specific microscopy platforms.

Consider these five aspects of IHC as you implement this technique in preclinical cancer research:

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Preclinical Oncology NGS Applications

Advances in preclinical oncology research are dependent on gaining insights into tumor biology and applying these insights to the development of novel diagnostics or therapeutics. Next-generation sequencing (NGS) technology has been instrumental in bridging basic immuno-oncology findings and preclinical applications. Here we provide an overview of NGS applications that are transforming preclinical oncology research.

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A Needle in a Haystack – Finding Rare AML Cell Populations by Flow Cytometry

Hematologic malignancies include a wide array of lymphomas and leukemias that affect different immune cell subsets. Acute myelogenous leukemia (AML) is one of the most commonly occurring leukemias in adults and children. AML is a highly heterogenous disease that can be caused by spontaneous gene mutations or chromosomal translocations, which results in the proliferation of dysfunctional myeloid cells. Cytogenetic and morphologic analyses have been the gold standard methods used in AML diagnosis, but flow cytometry-based protocols are becoming more widely used and validated as complementary diagnostic methods that can be coupled with these analyses to better guide treatment plans. Flow cytometry has also become an essential tool to understand AML progression and develop and evaluate novel therapeutics.

Consider these aspects of flow cytometry-based analysis of AML for exploratory or preclinical research.

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Stem Cell Transplantation in CLL: Almost Gone but Not Forgotten

Advances in molecular diagnostics and ex vivo drug sensitivity screening have greatly improved the use of targeted therapies for the treatment of chronic lymphocytic leukemia (CLL), such as B cell receptor signaling inhibitors, which include the Bruton tyrosine kinase (BTK) inhibitors like ibrutinib[1] and acalabrutinib and the phosphoinositide 3-kinase (PI3K) inhibitors duvelisib and idelalisib[2], as well as the BCL2 inhibitor venetoclax[3]. For most patients that are matched appropriately with these treatments, they show greatly improved progression-free survival and overall survival.

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Insights and Advances in Bladder Cancer

Bladder cancer is a relatively common form of cancer that is defined as either pre-invasive or invasive, and non-muscle invasive bladder cancer (NMIBC) is the most-commonly diagnosed subtype[1]. NMIBC is typically treated by surgical resection and/or intravesical delivery of chemo- or immunotherapy-based adjuvant treatment, and long-term efficacy is monitored by urine testing or cystoscopy. Muscle-invasive bladder cancer (MIBC) is relatively resistant to current treatment options and occurs more frequently in men. MIBC also has high rates of morbidity and mortality, and novel therapies or combination therapies area being developed to better treat this form of bladder cancer.

Here we highlight recent findings about invasive bladder cancer biology and how these observations are informing the development of new therapies.

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Current Trends in Glioblastoma Therapies

Glioblastoma multiforme (GBM) is an aggressive form of primary malignancy of the central nervous system (CNS) that causes brain tumors. GBM has been associated with poor prognoses and high mortality rates and a 5-year relative survival rate ranging from 6-22% percent depending on age of onset[1]. Currently, standard-of-care treatments include cytoreductive surgery followed by chemoradiotherapy, but these are not considered curative treatments, and efficacy varies widely between patients[2]. Temozolomide is a DNA alkylating agent prodrug commonly used for adjuvant chemotherapy in GBM, but treatment resistance is a common occurrence, and this drug is also associated with clinically significantly toxicity[3].

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What’s behind the mask? Lumin Bioinformatics – using Champions’ powerful data visualization and analytic software to drive target discovery

Answers provided by Alexis Santana, PhD – Manager, Business Development at Champions Oncology

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Culture Clash: Autologous versus Allogeneic Cells in Oncology

Adoptive cell therapies (ACTs) are being broadly tested and implemented in the treatment of a wide range of cancers, but the success of these therapies has been limited by the challenges of expanding cells of interest ex vivo. Most studies collect peripheral blood cells from a patient and expand, enrich or modify tumor-specific cells in a laboratory environment to create a blood product with tumor-targeting cells that can be reinfused into the patient. If the blood product is re-infused into the same patient, it is considered an autologous transplant, but if the cells originate from a different donor, it is considered an allogeneic transplant.

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Now that's a SMARTrial: Ex Vivo Drug Screening in CLL as a Biomarker for Clinical Outcomes

The current landscape for immunotherapy treatment of blood cancers has been advanced by breakthroughs in molecular diagnostics and personalized medicine. Now patients not only know the type of hematologic malignancy they have, but they may also be aware of unique mutations or variations associated with their cancer that can instruct treatment choices.

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Head and Neck Cancers: New Mutation Insights Lead to New Therapies

 

Head and neck squamous cell carcinoma (HNSCC) is one of the most common forms of cancer in the world. This heterogeneous disease is most often seen in men and is closely linked to tobacco usage, which can be enhanced by alcohol usage. Human papillomavirus (HPV) infection is an independent risk factor for HNSCC[1]. Most HPV- HNSCCs occur in the larynx and oral cavity, and HPV+ HNSCCs typically arise in the oropharynx[2]. Both HPV+ and HPV- HNSCCs are typically diagnosed at advanced disease stages and are often treated with an aggressive combination of surgery, radiotherapy (RT), and chemotherapy[3]. More recently, cetuximab, an IgG1 monoclonal antibody that targets epidermal growth factor receptor (EGFR) has been used in combination with radiotherapy and has shown some improvements in progression-free survival (PFS) and overall survival (OS)[4].

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Applications of IHC for Oncology Research

Immunohistochemistry (IHC) is one of the oldest and widely used diagnostic techniques that continues to be a valuable tool for immuno-oncology research. IHC is a method for visualizing the tissue localization of specific antigens and has evolved since its development in the 1940s[1]. This method has been an essential diagnostic tool for oncology because it enables pathologists to determine the histological grade of a tumor, which is a critical parameter for predicting the prognosis of tumors and determining the best treatment options. IHC is dependent on the skilled preparation and staining of thin tissue sections that are read by diagnostic pathologists or research scientists.

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Overcoming Drug Resistance in AML: Targeting Tricky Signaling Pathways

Resistance to anti-cancer treatments is a significant therapeutic challenge and is typically associated with mutations in signaling pathways that are involved in cell proliferation, survival, and tumorigenesis. Genomic analyses of relapsed pediatric acute myeloid leukemia (AML) patients have identified mutations, deletions, and changes in promoter methylation associated with Wnt-β-catenin signaling[1],[2]. Mutations in the PI3K-Akt pathway are also frequently associated with treatment resistance in AML and many other cancers[3],[4]. Hematopoietic stem cells are particularly sensitive to mutations in these signaling pathways and numerous studies have shown that targeting each of these pathways separately is associated with poor efficacy and emergence of resistance[5]. AML resistance not only emerges from chemotherapy but can also be seen in response to immunotherapy[6].

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Next Generation Sequencing: Revolutionizing Oncology Research One Base-Pair at a Time

Advances in oncology research have led to the development of personalized treatments based on specific knowledge of a patient’s tumor. New therapies have been customized to target signaling pathways that are hyperactivated or block specific variants of cell surface molecules, thus leading to better anti-tumor responses. Next generation sequencing (NGS) technology has been at the forefront of these breakthroughs by enabling researchers to rapidly sequence RNA transcripts (RNA-seq) or exons (whole exome sequencing; WES) within tumor tissue and translate these findings into novel therapies.

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Malignant Melanoma, Mutations, and Modifying Immune Responses

Melanoma broadly defines cancers that originate in melanocytes in the skin, eye, and inner ear. Cutaneous malignant melanoma is one of the most aggressive and fatal forms of this disease, but advances in immuno-oncology have dramatically improved outcomes1.  Advances in cancer genomics have been critical to evaluating which mutations are involved in a shift toward metastasis and have been valuable to informing treatment options using novel inhibitors that target specific gene mutations. Here we highlight mutations that are critical to tumor formation and metastasis and feature immuno-oncology treatments that are in use or being evaluated as individual or combination treatments.

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Immune Checkpoint Blockade Strategies in Renal Cell Carcinoma

 

Renal cell carcinoma (RCC) is a common cancer of the genitourinary tract that has very poor survival outcomes if metastatic. RCC is now understood to be composed of several different types of cancer with different genetic features and varied clinical responses. Histological diagnosis has been the primary method to diagnose RCC and has been used to define three major RCC subtypes, including the most common subtype, clear cell renal cell carcinoma (ccRCC), papillary renal cell carcinoma (PRCC; further divided into two subtypes), and chromophobe renal cell carcinoma (ChRCC)[1]. More recent comparative genomic and phenotypic analysis has identified mutations and epigenetic modifications associated with different histological subtypes[2]. Across all subtypes, increased DNA hypermethylation and gene alterations in CDKN2A were associated with a poor prognosis as was an increased Th2 immune gene signature. For ccRCC, increased levels of mRNA transcripts associated with ribose metabolism and the immune response were associated with poor survival. ccRCC is also defined by the early loss of chromosome 3p, which in turn causes a loss of heterozygosity for the VHL, PBRM1, SETD2, and BAP1 tumor suppressor genes and subsequent mutation of these genes that leads to tumorigenesis[3]. There is also a subset of ChRCC with a unique metabolic expression pattern that is associated with extremely poor survival2. PRCC can be classified as type 1, for which PBRM1 mutations are linked to poor survival but type 2 PRCC has increased expression of glycolysis and metabolism related mRNA transcripts2.

 

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Novel RNAs Insights Toward AML Development


Somatic mutations in the additional sex comb-like 1 (ASXL1) gene have been identified in multiple hematologic malignancies, including acute myeloid leukemia (AML), and are associated with poor prognoses1. ASXL1 encodes a nuclear protein that regulates epigenetic remodeling and transcription through interactions with polycomb complex proteins and transcriptional activators and repressors. Several ASXL1 mutations have been associated with loss of protein expression that leads to myeloid transformation2. In contrast, gain-of-function mutations in ASXL1 result in expression of a truncated ASXL1 protein that can bind to BRCA-1 associated protein 1 (BAP1) and cause leukemogenesis3,4. Targeted reduction of BAP1 activity is sufficient to prevent this malignancy process5.

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Targeted Therapy for Biliary Cancers


Biliary tract cancers, which are also known as cholangiocarcinomas (CCA), describe malignancies that occur in the biliary tract and include the pancreas, gallbladder and bile ducts. These are relatively rare cancers but are associated with a poor prognosis given that these cancers are difficult to detect and are usually diagnosed at later stages of disease. Histologically, CCAs are predominantly adenocarcinomas and are classified by growth patterns (mass forming, intraductal, or periductal) and anatomical locations (intrahepatic, perihilar, or distal), and mixed hepatocellular CCAs are defined as a separate subtype of primary hepatic cancer1.

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Understanding PD-1/PD-L1 for Ex Vivo Drug Screening for AML

Acute myeloid leukemia (AML) is an aggressive hematological malignancy that has been treated in the same way for the last several decades and typically includes standard chemotherapy protocols as well as bone marrow (BM) transplantation.  Despite advances in the field of immunotherapy, AML has been challenging to treat with immune checkpoint inhibitors that target Programmed Death (PD) - 1/PD-Ligand (L) 1 inhibitors.

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Oncolytic Viruses as Cancer Therapies

We typically consider viruses as infectious agents or vaccine vectors, which are non-replicating entities that express vaccine antigens. More recently, researchers have been working to develop oncolytic viruses, which are viruses that are engineered to specifically infect and replicate in tumor cells. This targeted infection results in tumor cell lysis and activation of anti-tumor immune responses as well as the release of new oncolytic virus particles that can infect other tumor cells. The concept of oncolytic viruses emerged in the early 20th century when scientists observed that a leukemia patient spontaneously went into remission for a brief time following influenza virus infection. Early attempts to develop non-specific oncolytic viruses were plagued with complications related to poor efficacy and safety issues. As our understanding of targeted immunotherapy for the treatment of tumors has evolved, oncolytic viruses are gaining traction again and an oncolytic herpesvirus (T-VEC or talimogene laherparepvec) engineered to target metastatic melanoma was approved for clinical use by the FDA in 2015.

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Colorectal Cancer and the Benefits of Immuno-Oncology

Colorectal cancer (CRC) is a leading cause of cancer deaths globally. Advances in early detection have improved survival rates, but patients diagnosed with metastatic CRC still have stubbornly poor 5-year survival rates. Standard treatments for CRC include surgery, chemotherapy, and radiotherapy, but alternative immuno-oncology therapies are showing promising results in CRC patients. Here we highlight advances in immuno-oncology therapies that are being used to treat CRC patients or are being pursued in preclinical and clinical studies.

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Prognostic Indices in Chronic Lymphocytic Leukemia (CLL)

The management and treatment of patients with chronic lymphocytic leukemia (CLL) has improved greatly in recent years due to new insights in genetic and molecular factors that contribute to disease progression. Clinical staging systems were first developed more than 40 years ago and include the Rai system[1], which is based on the presence of lymphocytosis (at least 5,000 mm3 monoclonal lymphocytes), enlargement of lymph nodes, spleen or liver, and changes in red blood cells and platelets. The Binet staging system is an alternative method based on the number of affect lymphoid tissue groups and the occurrence of thrombocytopenia and anemia. The Rai system is more common used in the United States, whereas the Binet system is used more frequently in Europe[2].

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The Pros & Cons: Syngeneic Mouse Models with Human Drug Targets

A wide range of mouse models are currently available to researchers working on the preclinical development of oncology therapeutics. Syngeneic mouse models, also known as allograft mouse tumor models, are mice engrafted with mouse-derived cancer cell lines. These mice have an intact murine immune system and thus are appealing for proof-of-concept immuno-oncology studies. However, one limitation of traditional syngeneic models is that they are not suitable for human-specific therapies. To overcome this, scientists have developed genetically engineered mice that express human immune targets, such as PD-1, PD-L1, CTLA4 and OX40, in an otherwise immunocompetent model. Tumor cell lines have been developed that also express immune checkpoint molecules, which can have a significant effect on the efficacy of potential immune checkpoint inhibitors being evaluated.

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BTK Therapies and Binding Site Implications in Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is one of the most common forms of adult leukemia, and its chronic nature has made it a challenging blood cancer to completely cure. CLL affects B cells and is typically classified into two categories: little or no somatic hypermutation in the immunoglobulin heavy chain variable region (IGHV), called unmutated CLL, or high mutation levels in the IGHV gene, called mutated CLL[1]. Unmutated CLL is associated with more aggressive disease than mutated CLL, and the presence of these abnormal IGHV sequences, which is a part of the B cell receptor (BCR), leads to abnormal BCR signaling and the uncontrolled proliferation of these leukemic cells.

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UnTIL We Meet Again -- Testing TIL Therapies in an Ex Vivo Platform

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The Do’s & Don’ts of Flow Cytometry in the Clinic

Clinical flow cytometry is now a standard tool used by clinical researchers in numerous fields, especially immuno-oncology. Consider these “Do’s & Don’ts” of clinical flow cytometry as you decide to use this tool for clinical research.

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Targeting DNA Damage in Cancer

DNA damage is one of the primary triggers of cancer development and has been linked to many types of cancers, including prostate, stomach, liver and skin cancers as well as leukemia. Within cells, the DNA sequence encodes all the instructions required for building proteins that are needed for cellular functions such as metabolism, replication, tissue and organ maintenance. The fidelity of the DNA sequence in a cell is maintained by multiple mechanisms but errors and mutations can occur, which sets off a chain of events that lead to tumor growth.

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Ex Vivo Expertise – Things to Consider when using Ex Vivo Systems for Hematologic Malignancies

Advances in precision medicine have transformed treatments for many types of solid tumors, but similar treatment options have been more limited for hematologic oncology. Now, new ex vivo models are being developed that use patient-derived lymphoma or leukemia cells for screening experimental drugs or biologics. Therapeutic antibody screening is well-suited to these platforms and can inform preclinical research decisions as well as clinical care.

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Better Options: Flow Cytometry as an In Vivo Model Endpoint

In vivo models for numerous diseases and conditions have endpoints that have involved animals being gravely ill or dying. As researchers have sought to utilize animal models in more humane and practical ways, surrogate endpoints have been developed that prevent animals from suffering and provide critical research data. Flow cytometry has been instrumental to these advances. Consider these aspects of preclinical flow cytometry endpoint analysis as you develop new protocols.

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Quantitative IHC: At the Cutting Edge of Molecular Pathology for Cancer Diagnostics

Molecular pathology has been used for decades together with anatomic pathology for disease diagnosis and evaluating treatment efficacy. Immunohistochemistry (IHC) has been a key technique used on molecular pathology that involves staining tissue sections with molecular markers and evaluating staining patterns that may correspond to different tumor stages or other disease pathologies.

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Developing Assays in Non-Human Primates (NHPs)

Non-human primates (NHPs) continue to be a valuable resource for preclinical research because of similarities they share with humans. NHPs, especially rhesus macaques, are used in preclinical studies for evaluating new drugs or vaccines for safety and efficacy. Flow cytometry assays can be easily adapted to study cells from NHP. Consider these three factors if you are planning to adapt a flow cytometry assay for use with NHP samples.

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Top 5 things to consider when outsourcing in vivo models

Most preclinical cancer studies are heavily dependent on in vivo (animal) models, especially those using genetically engineered mice. The hundreds of existing mouse models allow scientists to study specific tumor types, including tumors derived from patients (PDX), visualize different immune cell subsets in vivo, and screen large panels of potential drugs or biologics for anti-tumor properties.

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Immune Checkpoint Inhibitors and Clinical Flow Cytometry

Caner Cells

The field of oncology has been transformed by the approval and implementation of immune checkpoint inhibitors. Cancer cells can tamper with a variety of self-defense mechanisms, including upregulating expression of immune checkpoint molecules on cytotoxic T cells and natural killer (NK) cells, such as PD-1 and CTLA-4. Overexpression of these markers is associated with T cell exhaustion and allows for tumor cells to evade detection. Immune checkpoint inhibitors target these molecules, which restores immune surveillance and anti-tumor responses by T cells.

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ERK at Work: Targeting the ERK Pathway in Cancer

Splitting cancer Cells

Signal transduction networks are essential to normal cell growth and function, but signaling abnormalities, such as those caused by spontaneous mutations in signaling components, are the leading causes of tumor growth. The extracellular signal-regulated kinase (ERK) signaling pathway contributes to normal cell proliferation, differentiation, and survival, but components of the ERK pathway are upregulated in many tumor types, including those associated with melanoma, lung, colon and pancreatic cancer.

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Human Immune System (HIS) and Patient-Derived Xenograft (PDX) models

ImmunoGraft

Champions Oncology and others in the field working with patient derived xenografts (PDX) are developing and providing translationally relevant preclinical models to test therapeutic efficacy of IO agents as monotherapy or rational combinations in humanized mice engrafted with functional human immune system.

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