In the intricate web of human health, the immune system stands as a vigilant guardian, tirelessly defending against potential threats. At the forefront of understanding, deciphering, and harnessing the immune system’s power is the immunologist. This article delves into the captivating realm of immunology, shedding light on the indispensable role played by these medical experts in maintaining our well-being.

Immunology

Immunology is the scientific study of the immune system – a complex network of cells, tissues, and molecules working harmoniously to safeguard the body against invading pathogens, such as bacteria, viruses, and other harmful entities. At the heart of this field are immunologists, experts dedicated to unraveling the mysteries of immune responses and applying this knowledge to enhance human health.

Becoming an Immunologist: The Journey and Expertise

Becoming an immunologist requires a rigorous educational path. Typically, individuals pursuing this profession acquire a bachelor’s degree in a related field like biology, followed by advanced degrees such as a Master’s or Ph.D. in Immunology or a related discipline. This academic journey equips them with a profound understanding of the immune system’s complexities.

Decoding the Immune System

Components of the Immune System

The immune system is a symphony of diverse cells and molecules, each with a specific role to play. White blood cells, antibodies, cytokines, and complement proteins collaborate to recognize and neutralize threats.

Innate vs. Adaptive Immunity

Immunologists distinguish between innate and adaptive immunity. Innate immunity provides rapid but generalized defense, while adaptive immunity offers tailored, long-lasting protection based on prior exposures.

The Role of Immunologists

Disease Detection and Diagnosis

Immunologists contribute significantly to diagnosing various diseases by analyzing immune responses. Techniques like ELISA and flow cytometry aid in identifying infections, allergies, and autoimmune disorders.

Research and Development

Immunologists spearhead groundbreaking research, driving medical innovation. They investigate new therapies, study immune-related disorders, and develop advanced diagnostic tools.

Treatment and Management

In collaboration with other medical professionals, immunologists design targeted treatments and therapies. Immunotherapy, such as monoclonal antibody treatments, harnesses the immune system to combat diseases like cancer.

Immunology in Action: Real-Life Applications

Vaccination and Immunization

Immunologists have played a pivotal role in developing vaccines that prevent deadly diseases like polio, measles, and COVID-19. These efforts have saved countless lives worldwide.

Autoimmune Disease Management

Understanding the intricacies of immune responses has led to improved management of autoimmune diseases, offering relief and enhanced quality of life for those affected.

Cancer Immunotherapy

Cutting-edge cancer treatments involve immunotherapy, where the immune system is activated to recognize and eliminate cancer cells. This promising approach offers new hope in the fight against cancer.

The Ongoing Pursuit of Knowledge: Advancements in Immunology

Genetic Immunology

Advancements in genetic research have opened avenues to understand how genetics influence immune responses. This knowledge holds the potential to tailor treatments based on individual genetic profiles.

Immunoinformatics

Immunoinformatics merges immunology with bioinformatics, accelerating the discovery of new vaccines and therapeutic targets by analyzing vast amounts of immunological data.

Collaboration in the Medical Landscape: Interdisciplinary Approach

Immunology and Microbiology

Immunologists collaborate with microbiologists to decipher the intricate relationship between microorganisms and the immune system. This partnership enhances our understanding of infections.

Immunology and Oncology

In oncology, immunologists collaborate to develop personalized treatments that boost the immune response against cancer cells, leading to improved outcomes for patients.

Challenges and Ethical Considerations

Emerging Infectious Diseases

Immunologists are at the forefront during outbreaks of new infectious diseases, where rapid response and understanding of immune reactions are crucial for containment.

Ethical Implications of Immunotherapy

While immunotherapy holds immense promise, ethical considerations arise due to its potential side effects and the fine balance between enhancing immune responses and avoiding harm.

The Path Ahead: Immunologist’s Role in Public Health

Immunologists play a pivotal role in shaping public health policies and strategies, especially in the context of vaccination campaigns, disease outbreaks, and global health crises.

Conclusion

In the realm of health and medicine, immunologists stand as sentinels of the immune system, deciphering its complexities and harnessing its power to conquer diseases. Their expertise drives medical advancements, offering hope for healthier lives.

FAQs

What is the main focus of immunology? Immunology focuses on studying the immune system’s functions and responses to maintain health and combat diseases.

How do immunologists contribute to cancer treatment? Immunologists contribute by developing therapies that enhance the body’s immune response against cancer cells.

What are some examples of autoimmune diseases? Examples include rheumatoid arthritis, lupus, and multiple sclerosis, where the immune system attacks the body’s own tissues.

Can immunotherapy replace traditional cancer treatments? Immunotherapy is a valuable addition to cancer treatments, but its role varies based on the type and stage of cancer.

The post Role of an Immunologist: Exploring the Responsibilities appeared first on Proventa International.

If you or someone you care about has been diagnosed with cancer, you’re likely to come across the term “oncologist.” But what exactly is an oncologist, and what do they do? In this article, we’ll delve into the world of oncology, exploring the definition, role, and crucial responsibilities of an oncologist in the realm of cancer treatment. Let’s begin by breaking down the core aspects of an oncologist’s profession.

An oncologist is a medical professional specialized in the diagnosis, treatment, and management of cancer. Their role extends far beyond administering treatments; they provide holistic care and support to patients and their families throughout the cancer journey. Oncologists work diligently to devise personalized treatment plans that offer the best chances of remission or enhanced quality of life.

Understanding Oncology

Oncology is the branch of medicine that focuses on the study of cancer. It encompasses various disciplines, each contributing to a comprehensive understanding of the disease and its treatments. Medical advancements and breakthroughs in oncology have led to a higher rate of successful cancer treatments and improved patient outcomes.

Different Types of Oncologists

Medical Oncologists

Medical oncologists specialize in treating cancer using systemic therapies such as chemotherapy, targeted therapy, and immunotherapy. They collaborate closely with patients to determine the most suitable treatment plan based on the type and stage of cancer.

Surgical Oncologists

Surgical oncologists are trained to perform surgical procedures to remove tumors and cancerous tissues. They often work alongside other specialists to ensure the complete removal of cancer while preserving organ function.

Radiation Oncologists

Radiation oncologists are experts in utilizing radiation therapy to target and destroy cancer cells. They ensure the precise delivery of radiation while minimizing damage to healthy tissues.

Pediatric Oncologists

Pediatric oncologists specialize in treating cancer in children and teenagers. Their approach involves not only medical expertise but also the emotional support needed for young patients and their families.

Educational Journey to Becoming an Oncologist

Becoming an oncologist requires years of rigorous education and training. After completing medical school, aspiring oncologists undergo specialized residency and fellowship programs to gain the necessary skills to manage complex cancer cases.

Diagnostic Procedures and Evaluation

Accurate diagnosis is the foundation of effective cancer treatment. Oncologists use a combination of techniques, including various imaging studies and biopsies, to identify the type, stage, and extent of the disease.

Creating a Treatment Plan

Oncologists develop individualized treatment plans tailored to each patient’s unique condition. This involves considering factors such as the type of cancer, its stage, the patient’s overall health, and their preferences.

Cancer Treatment Modalities

Oncologists employ a range of treatment modalities to combat cancer:

Chemotherapy

Chemotherapy involves using drugs to destroy cancer cells or impede their growth. It can be administered orally or intravenously and may be used in combination with other therapies.

Radiation Therapy

Radiation therapy employs high doses of radiation to target and shrink tumors. It is a localized treatment that minimizes damage to surrounding tissues.

Immunotherapy

Immunotherapy harnesses the body’s immune system to identify and attack cancer cells. It has shown promising results in treating certain types of cancers.

Targeted Therapy

Targeted therapy targets specific molecules involved in cancer growth. This approach minimizes damage to healthy cells and is effective against certain types of cancer.

Monitoring and Follow-Up Care

Oncologists closely monitor patients throughout their treatment journey. Follow-up appointments and tests help track progress and address any potential complications.

Emotional Support for Patients and Families

Dealing with cancer can be emotionally taxing. Oncologists provide support, empathy, and guidance to patients and their families, helping them cope with the challenges they face.

Research and Clinical Trials

Oncologists actively engage in research and clinical trials to advance cancer treatments. Their involvement contributes to the development of innovative therapies and improved patient outcomes.

The Evolving Landscape of Oncology

The field of oncology is dynamic, with constant advancements. Oncologists stay updated with the latest research and technologies to provide the best care possible.

Common Misconceptions About Oncologists

Only for Terminal Cases

Oncologists are involved in various stages of cancer, not just end-of-life care. They play a crucial role in early diagnosis and treatment planning.

Oncologists and Surgeons Are the Same

While surgical oncologists perform surgeries, medical oncologists focus on non-surgical treatments. Collaboration among different types of oncologists is common.

Frequently Asked Questions (FAQs)

What is the role of a medical oncologist?

A medical oncologist specializes in systemic cancer treatments, such as chemotherapy and immunotherapy, to fight cancer cells throughout the body.

Is radiation therapy always painful?

No, modern techniques aim to minimize discomfort during radiation therapy sessions.

Are oncologists involved in palliative care?

Yes, oncologists often provide palliative care to alleviate symptoms and improve the quality of life for patients.

How do oncologists stay updated with the latest treatments?

Oncologists attend conferences, read medical journals, and participate in research to stay informed about cutting-edge treatments.

Can I get a second opinion regarding my treatment?

Absolutely, seeking a second opinion is encouraged to make informed decisions about your treatment plan.

The post What Does an Oncologist Do? A Comprehensive Guide to Their Role in Cancer Treatment appeared first on Proventa International.

Intrinsically disordered proteins (IDPs) are under the limelight in cancer research. While research is continuous in understanding their dynamic structure, their implication in tumour development is becoming increasingly evident. Some of the latest advancements demonstrate how IDPs can be used to develop a promising, novel approach to drug design. 

Introduction

IDPs are a group of proteins recently recognised that challenge the paradigm of the protein folded structure. Many biologically active proteins comprise a unique, well-defined structure required for their specific function. IDPs however, do not follow this previously defined rule.

These proteins fail to form unique 3D structures under physiological conditions and are structurally very differently from ordered protein. However, they possess a number of crucial biological functions that complement structured proteins including cell signalling and protein-protein interaction.

Their involvement in important biological pathways, however, means that any dysregulation that arises within proteins is typically associated with disease. Dysregulation can arise with misexpression or mismodification which can cause IDPs to engage in unwanted interactions, inducing the development of pathological conditions. Many of the proteins associated with neurodegeneration, cancer, diabetes and cardiovascular disease are IDPs.

Their association with diseases like Parkinson’s and Alzheimer’s has made them attractive drug targets and further research is being conducted to better understand their dynamics. According to a recent review, a number of IPD-targeting compounds have been developed and inhibitors have reached the clinical trial stage demonstrating their druggability. Unfortunately, none of these compounds have reached the market as commercially available drugs.

When targeting IDPs, there are a number of challenges to overcome. Firstly, their inability to adopt a well-defined 3D structure creates obstacles for developing complementary ligands that may need to bind. Secondly, actually understanding the molecular basis of IDPs has been difficult to determine as the conventional techniques do not have the capacity to do so. 

As techniques and technology evolve however, it is clear to see that IDPs are implicated in certain human disease states. The goal is to better define and understand the dynamic nature and structure clearly enough to create IDPs as potential leads for drug development. 

Cancer pathology

The tumorigenic variations that occur at the genome level manifest as alterations in protein properties such as structure, localisation and stability. Therefore the structural, and consequently functional, properties of the affected proteins determine their implication in cancer development.  

Approximately 70% of human cancer-associated proteins have been predicted to contain relatively long, unstructured regions. In addition, the implication of IDPs in gene regulation and protein networks supports the evidence that says IDPs play a role in cancer pathology. However, it has not been systematically analysed whether the mutations of intrinsically disordered regions/proteins have a direct role driving cancer development or what molecular functions and biological processes are altered by these events.

A recent study used an integrated computational approach which identified a set of cancer drivers specifically targeted by mutations in disordered regions. IDRs represent approximately 30% of the residues found in the human proteome and are also a critical component of many cancer-associated proteins. 

These mutations which drive cancer development have shown to be present across a “wide range of cancer types, and can also be the main, or one of the main, driver events for several tumor subclasses, including both malignant and benign cases”.

However, it has been suggested that the association between protein disorder and cancer is more likely indirect – a recent analysis found that cancer-associated missense mutations had a preference for ordered regions. In other words, the extent to which IDPs and IDRs are implicated in mechanisms driving cancer are still largely unexplored.

Therapeutic advancements 

The identification of functional modules that are directly altered in cancer driver genes, like IDPs, can serve with potential targets for pharmaceutical intervention and have been a focus in recent years.

Currently, drug development is mainly focused on ordered protein domains, however IDPs could serve as a new direction for cancer therapeutics. The more recent approaches have been trying to directly target IDPs via small compounds or blocking the interaction partner of IDPs. The molecular strategies to do this however can be radically different and are not yet widespread across the field. 

A 2017 study reviewed the therapeutic interventions of cancers using intrinsically disordered proteins as drug targets, using c-Myc as a model system. The dysregulation of multiple transcription factors (TFs) have been reported in cancer progression, p53 and c-Myc proteins especially. 

Myc proteins (classified as c-myc, N-myc, and L-myc) are TFs that serve as central regulators of many physiological processes including apoptosis, cell proliferation and biosynthesis of proteins. Studies on animal mouse models have demonstrated that inhibition of c-Myc can “completely stop tumour growth and can also inhibit cancer stem cell progression”.

Latest advancements 

In terms of the latest advancements, exciting research has recently been published detailing the designing of a drug candidate, using IDPs, for bladder cancer. The new approach involves the use of an IDP complex found in human milk known as HAMLET – which, when partially unfolded, has shown incredible cancer-killing abilities. 

According to the leader of the project, Dr Ken H Mok, the clinical trials already show great impact in “reducing tumor size in people with this form of bladder cancer without any side-effects”. This is a hugely exciting step in cancer therapeutics, which is contributing to a novel approach to the conventional lock/key molecular drug design.

Charlotte Di Salvo, Lead Medical Writer
PharmaFeatures

For more articles covering the pharmaceutical industry, clinical research and academia, visit our content site PharmaFeatures.

The post Intrinsically Disordered Proteins – The Implication in Cancer and Potential Drug Targets appeared first on Proventa International.

Until now, patients with advanced cervical cancer had relatively low survival rates. The recent approval of Keytruda, a PD-1/PD-L1 checkpoint inhibitor, is the latest breakthrough for cervical cancer immunotherapy. The positive outcome from Merck & Co’s clinical trial now offers hope for the future of treatment which can extend the lives for stage 3 and stage 4 cervical cancer patients. 

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The latest news

Merck’s Keytruda has recently become the first checkpoint inhibitor to help patients with advanced cervical cancer live longer when used alongside standard first-line drugs. Keytruda is currently the only PD-1/PD-L1 inhibitor approved for advanced cervical cancer.

This is huge news for both researchers and patients. Currently, the five-year survival rate for stage 3 and 4 cervical cancer is around 40% and 15% respectively, according to CRUK. The detrimental drop in survival rates emphasises an unmet clinical need for late-stage cervical cancer drugs.  

In addition to hope for patients with advanced cervical cancer, the news of Keytruda achieving approval represents an important step in cancer treatment. Stage 4 cancer especially is difficult to control due to the wide spread across the body through metastasis. If patients with advanced cervical cancer can prolong their life with this drug, there is potential to investigate the same for other advanced cancer types. 

Immunotherapy – checkpoint inhibitors 

Immune checkpoints are components within the immune system which prevent healthy cells from being destroyed by a strong immune response. The inhibition of immune checkpoint molecules such as programmed cell death 1 (PD-1) have shown great efficacy across many cancer types. 

PD-1 plays a critical role in inhibiting the immune response that would otherwise attack the cancer cells and promotes “self-tolerance through modulating the activity of T-cells”. Programmed Cell Death Ligand (PD-L1) is a transmembrane protein which can combine with PD-1 and is considered a co-inhibitory factor within this response. 

Inhibition of these checkpoints aims to prevent an “off” signal from being transmitted within the immune system which would otherwise prevent T-cells from destroying cancer cells.

Accumulating evidence indicates the inhibition of PD-1 supports the immune response against cancer cells. According to a 2020 publication, PD-1 signalling pathway suppression has shown that “the clinical response of patients with different solid tumors and hematological malignancies, mainly relies on T-cells effectively to penetrate the tumor”.

The efficacy of checkpoint inhibition is supported by the increasing number of clinical studies which highlight significant clinical response in a wide range of cancer patients as a result of PD-L1 targeted therapies. 

An example of this success was the approval of Atezolizumab, the first FDA-approved PD-L1 inhibitor.

Atezolizumab is a humanised, anti-PD-L1 monoclonal antibody. These antibodies are engineered within the lab to mimic human-derived antibodies to enhance the immune response.

The drug is used as a first-line combinatorial therapy used to treat six types of cancer, including triple negative breast cancer and melanoma. Atezolizumab is also under investigation for other types of cancer. 

Side effects 

Due to the wide range of uses for Atezolizumab, a number of studies are investigating the short-term and long-term effects of checkpoint inhibitors. Immune-related adverse effects (irAEs) are a common part of treatment with checkpoint inhibitors, although range in severity and persistence with different drugs. 

In comparison with anti-CTLA-4 antibodies, irAEs related to anti-PD-1 antibodies are less frequent and differ in their spectrum of organ involvement. “Approximately 10% of patients receiving anti-PD-1 antibodies have grade ≥3 irAEs”.  

According to the National Cancer Institute, a recent study investigated the medical records of a cohort with advanced melanoma who had undergone surgery followed by treatment with a checkpoint inhibitor. 

In terms of short-term side effects, a number of immune-related problems arose during treatment. The most common short-term effects were “skin rash or itchy skin, inflammation of the thyroid (thyroiditis) or low thyroid hormones (hypothyroidism), and joint pain.

167 patients (43%) experienced immune-related side effects that lasted for at least three months after completing the immune checkpoint inhibitor. 

The vast majority of these long-term side effects were mild, meaning they interfered somewhat with the patient’s daily activities and may have required treatment. It is worth noting that the majority of the long-term side effects didn’t go away during the study. 

Further studies are underway to gain a better understanding of how these side effects arise and how long they will last to determine the best way to treat or control them.

Future direction for research 

Recently, small nucleotide molecules called microRNAs have become a focus for attention in the targeting of PD-1/PD-L1 in cancer. Extensive data from a large number of studies suggest the role of miRNAs as tumour suppressors, carcinogenic, diagnostic and prognostic biomarkers in lung cancer. 

Recent studies have demonstrated that miR-33a, a form of microRNA, can regulate the expression of immune markers. An early study in 2017 found an association between the level of expression of PD-1/PD-L1 and miR-33a, and found that miR-33a was negatively correlated with the expression of PD-1/PD-L1. 

Long non-coding RNAs (incRNAs) are also an area of interest, with recent data reporting the role of lncRNAs in the modulation of the innate immune response. Results from a 2018 preclinical study demonstrated the efficacy of combination therapy using lncRNA UCA1-targeted therapy and PD-1 immune checkpoint inhibition which was shown to support this combination for the clinical treatment of bladder cancer.

While these areas remain at the preclinical stage for now, the speed of cancer research and demand for effective immunotherapy may accelerate these areas through to clinical trials sooner than anticipated.

Charlotte Di Salvo, Lead Medical Writer
PharmaFeatures

For more articles covering the pharmaceutical industry, clinical research and academia, visit our content site PharmaFeatures.

The post The Latest Advancements in Immuno-oncology: Checkpoint Inhibitors appeared first on Proventa International.

While significant progression has been made in cancer therapeutics, the disease remains a serious health risk. The lack of commercially available diagnostic biomarkers hinders accurate early cancer diagnosis which could otherwise save many lives. Protein-based biomarkers have demonstrated the potential to introduce non-invasive diagnostics for cancer patients. 

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Hear from some of the industry leaders including Aleksandra Filipovic who will be providing her expertise in leading a discussion on assessing the industry shift towards protein-based diagnostic biomarkers. To discuss these innovations and more with other leading experts in an informal setting, sign up to Proventa’s Oncology Strategy Meeting, held online on 17 June 2021. 

Biomarkers are an important tool in precision medicine across a number of therapeutic areas. In oncology, genetic profiling technology and targeted cell therapies have seen biomarkers play an important role in disease management for cancer patients. 

A cancer biomarker refers to a “tumor characteristic or a response of the body in the presence of cancer that can be objectively measured and evaluated”. Circulating tumour markers found in bodily fluids like blood and urine are currently implemented in clinical investigations. These biomarkers are often used to measure the risk of developing the disease, response to therapy, and estimate prognosis. 

The prominent issue however is that “although an elevated level of a circulating tumor marker may suggest the presence of cancer… this alone is not enough to diagnose cancer”. This represents an unmet clinical need to identify and validate a diagnostic biomarker that can be used alone (i.e. not in conjunction with other methods) to diagnose cancer types.

Cancer diagnostics based on protein biomarker detection have shown obvious potential for a number of years. For example, serum protein expression is often significantly raised in patients’ samples which are affected by colon and other cancers. 

In the last decade, protein-based diagnostic biomarkers are receiving increasing clinical attention due to their implication in cancer pathology and potential for non-invasive detection. 

Protein-based diagnostic biomarkers

In order to utilise protein-based biomarkers, there must be significant proteomic changes that occur specific to cancer. Mutations in cancer-associated genes, for example, can be manifested in defective protein structure. These defects can impact protein stability and cause the protein to become more susceptible for degradation. 

Proteomic studies into colon cancer have identified a number of protein biomarkers for potential diagnostic and therapeutic applications. “The over-expressed glycoprotein is responsible for tumor growth and spread into distinct parts.” The secreted protein has also been associated with a number of malignancies including the stomach, prostate and liver. 

As of today, there are no protein-based biomarkers that have surpassed clinical studies for application in clinical practice. However, in the last decade, researchers have been focused on continuing to develop assays to more accurately detect potential biomarker candidates in comparison to traditional techniques. 

One example is the proximity extension assay (PEA) which was used in a 2019 study identifying plasma protein biomarker signatures for ovarian cancer. 

PEA technology is high-throughput fluid protein biomarker detection immunoassay. The system is based upon a “unique antibody-oligonucleotide protein binding for quantitative real-time polymerase chain reaction (PCR)-based measurement”. The amplification by PCR and hybridisation of a labelled probe to its DNA target generates a highly sensitive detection of proteins, protein modifications or protein-protein interactions.

Hybridisation, in the context of assays, involves the labelling of nucleic acid which aims to identify related DNA/RNA within a complex mixture of unlabelled nucleic acids.

In this aforementioned 2019 study, it was emphasised that a non-invasive diagnostic test with higher sensitivity and greater specificity could be used to distinguish between women with malignant and benign masses. The benefit of this could prevent over-diagnostic surgery which can be unnecessary and introduce health complications. 

A 2020 study chose to use mass spectrometry-based high throughput screening in order to identify protein biomarker candidates detected in the human blood. The aim of the study was to develop a panel of proteins which can distinguish patients with lung cancer from health donors via plasma samples. 

The results from the assay identified six blood-based proteins which could be used as a potential diagnostic tool in lung cancer. This is an important step forward in identifying biomarker candidates which could be validated and potentially be used for clinical practice. Furthermore, “the 6-protein panel non-invasively detected lung cancer at different stages of the disease (including stage I), suggesting its high potential as a screening tool”.

Challenges

The analytical challenges of screening the vast number of proteins is one of the major stumbling blocks for protein-based biomarker screening. Heterogeneity refers to the level of diversity within individuals. In the context of proteomics, it refers to the magnitude of proteomic variations between normal individuals and different disease states. 

The implication of heterogeneity makes it difficult to standardise protein-based biomarkers for an entire patient population due to proteomic diversity. 

A recent approach in the last few years has been developed to try and circumvent the challenge of tumor heterogeneity. The combination of matrix-assisted laser desorption ionisation with imaging mass spectroscopy allows “proteomics-based studies to provide both patient-specific and cancer-specific information as a means for biomarker discovery and cancer tissue classification. It also provides morphology-based proteomics analysis for cancer tissue”. 

Unfortunately, several technical challenges still exist including low signal-to-noise ratio and low mass accuracy. 

Validation of cancer biomarkers has proven to be a challenge that has hindered progress in reaching the clinic. To meet statistical requirements for a potential protein biomarker, patient samples will be required to expand further accompanied by excellent clinical data. This is not always feasible as patients are not always comfortable with samples being used in clinical studies nor do they appreciate the biopsy procedure. 

One suggested solution to find and validate new biomarkers is to develop biobanks with numerous consecutive samples collected over time from each of large numbers of individuals. A biobank is a “collection of human biological samples and associated information organized in a systematic way for research purposes”. 

In addition to supporting validation, biobanks could also help define the normal protein biomarker concentration ranges. These ranges frequently differ across the population due to genetic and environmental factors, which could provide more information about the level of proteomic diversity with regards to specific cancer types. 

While research needs to overcome the challenges of biomarker validation and heterogeneity, protein-based diagnostic biomarkers show promise. The development of accurate, non-invasive diagnostic tools would allow patients to receive rapid and accurate diagnosis to support clinical decisions for personalised therapies. Furthermore, it could prevent patients receiving unnecessary surgery which could impact their mental and physical health.

To discuss these topics further with sector experts, and to ensure you remain up-to-date on the latest in clinical development, sign up for Proventa International’s Oncology Strategy Meeting, set for 17 June 2021.

Charlotte Di Salvo, Junior Medical Writer
Proventa International

The post Protein-Based Diagnostic Biomarkers for Cancer: Where Are We Now? appeared first on Proventa International.

In 2019, drug manufacturer Genzyme was thought to have lost up to $300m in revenue due to plant shutdown after product contamination. Ensuring appropriate aseptic practices are followed can mean the difference between efficient manufacturing operations and the shutting down of a plant. The devastating impact of cross-contamination has seen the industry develop technology and appropriate practices to reduce the risk of manufacturing failures.  

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Aseptic processing is defined as the “handling of sterile product, containers, and/or devices in a controlled environment, in which the air supply, materials, equipment, and personnel are regulated to maintain sterility”. This is a critical step in pharmaceutical manufacturing, which, if performed incorrectly or poorly, could adversely affect the quality of the drug through contamination. 

The production of sterile drug products is dependent on aseptic processing or terminal sterilisation. Aseptic processing subjects the drug product and container to sterilisation separately before bringing them together in the final stages. Terminal sterilisation, on the other hand, involves filling and sealing product containers under high-quality environmental conditions to minimise the microbial and particulate content of the in-process product. After this stage, the product in its final container undergoes heat or irradiation for the final sterilisation process. 

Aseptic processing and terminal sterilisation require validation and control to prevent avoidable errors. Should an error occur in either of these processes, it could lead to the distribution of a contaminated product, later posing a significant risk for patients. 

In addition to hazardous safety implications, drug product contamination can have a substantial impact on manufacturers. According to a pharmaceutical news article, drug manufacturer Genzyme was forced to close its Massachusetts plant in 2009 after a virus was found to have contaminated a bioreactor. In terms of patient impact, the contamination halted production of two drugs, Fabrazyme and Cerezyme, that were at the time used by 8,000 patients globally.  

From a pharmaceutical perspective, the halt in production was a financial blow for the manufacturer. In addition to a fine of $175m by the FDA, more than $28.4m worth of drug product was written off. 

More recently in 2020, an article reported that the FDA announced that a number of drugs have been contaminated with a potential human carcinogen, NMDA. Metformin, a popular diabetes drug, is an example of a drug implicated in this incident. In said article, there were a number of potential causes for the incident including the useage of contaminated water, lack of pH or temperature control and pre-existing contamination of raw materials. 

This resulted in the presence of NMDA in drugs above the acceptable daily intake (ADI) limit. The number of potential causes for contamination questions the quality control of the aseptic processes and sterile preparation by the manufacturers. This emphasises the need to develop more stringent aseptic and sterilisation protocols to prevent such errors occurring again. 

Aseptic practices in drug manufacturing 

The following are a few examples of conventional and more recent innovations in aspects of aseptic processing. 

Training of personnel

Personnel across the manufacturing system are potential sources for contamination and “a vector for other contaminants”. Lack of appropriate training with aseptic practices, unauthorised access into controlled areas and personal cleanliness are a few of the areas in which personnel can compromise sterile production.

The industry is now focusing on thorough training and documented communication of procedures and best practices. This is vital to optimise facility operations as well as minimising contamination. The WHO good manufacturing practices is an example of such a document aimed to guide manufactures in the production of sterile pharmaceutical drugs. 

Quality control and sanitation are 2 of 13 steps detailed throughout the steps for aseptic practices. During quality control, it is emphasised that while samples for sterility testing should be representative of the whole batch, some samples taken from parts of the batch are considered to be most at risk of contamination. In the case of injectable products, the water for the injection, the intermediate and the final product should be monitored for endotoxins.

Endotoxins are a major challenge for sterilisation. These are toxic substances “bound to the bacterial cell wall and released when the bacterium ruptures or disintegrates”.

Rapid Transfer Port

The Rapid Transfer Port (RTP) allows for transfer of hazardous or sterile materials while maintaining containment of sealed barriers. In order to address the risk of accidental manipulation during the transfer, a number of safety devices are in place.

RTPs are typically installed on isolators or production lines to enable the sterile transfer between two chambers without environmental exposure. This means that ‘clean’ material can be transported from “one sterile zone to another through a non-sterile zone, using the DPTE container or single use bag which can be reconnected without risk because the inside of the container is still sterile.”

According to an industry article, the risk of human error occurring during material transfer is “proportional to the number of manual operations required, of which RTPs generally entails a series of manual interventions”. So while the machinery and mechanisms work well to prevalent environmental exposure between transfer, and devices to reduce the chance of errors, humans are still required to operate them at every stage. This is an issue that needs to be addressed, potentially with the development of more automated systems in aseptic processing. 

The popularity of the RTP system in the pharmaceutical industry is evident, with more than 40,000 Alpha units sold to global locations. Successful, validated systems like RTPs are a prime example of the evolution in developing more stringent aseptic practices.

Single-use technology 

Single-use technology is rapidly emerging in aseptic practices across the pharmaceutical industry, with the potential to reduce cross-contamination risk. This type of equipment can reduce costs by eliminating the need for in-house sterilisation. Although the initial cost of single-use equipment may be high, the benefits of a faster turnaround allows production to move faster and continuously. 

Examples of single-use equipment include chromatography devices, bioreactors and ion exchange membranes. 

One of the main benefits for single use equipment is sterility assurance during the manufacturing process. This is achieved by a reduction in the “possibility of cross-transference of microorganisms; minimising the risk of environmental microbial contamination”. The risk of cross-contamination especially is greatly reduced with the avoidance of cleaning components, thanks to single use equipment.

Due to the infancy of this technology, it is important to assess the possibility of leachables that could arise and pose a concern for quality control. This is echoed in an article which highlights the limited availability of the technology and potential development costs.

Charlotte Di Salvo, Junior Medical Writer
Proventa International

The post Aseptic Processing: Maintaining Sterility in Pharmaceutical Manufacturing appeared first on Proventa International.

Approximately 15-20% of all cancer cases are preceded by infection, chronic inflammation, or autoimmunity at the same tissue or organ site. While inflammation is a natural response to tissue damage, chronic inflammation can become pathological. The role of inflammation in cancer has seen a number of preclinical studies investigating the efficacy of anti-inflammatory drugs for patients.

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Introduction to concept

Inflammation is the body’s response to tissue damage, whether this be due to infection, physical trauma or an ischemic injury. If the control mechanisms for inflammation fail to shut down, it can cause chronic inflammation. The cell mutation and proliferation that can result from this dysfunction can “create an environment that is conducive to the development of cancer. The so-called ‘perfect storm’”.

Inflammation-related biological processes influence all stages of cancer development from tumour initiation to progression. Chronic inflammation specifically is triggered by a number of factors which increase the risk of cancer. Infectious diseases like hepatitis, and autoimmune diseases like inflammatory bowel disease, are often precursors for the chronic inflammation triggering disease development and progression.

Two pathways have been identified linking inflammation and cancer. The intrinsic pathway caused by genetic events initiates “the expression of inflammation-related programs that guide the construction of an inflammatory microenvironment”. The extrinsic pathway, on the other hand, creates the inflammatory conditions which trigger cancer development. 

The inflammatory microenvironment of tumours is characterised by “the presence of host leukocytes both in the supporting stroma and in tumor areas”. Leukocytes, also known as white blood cells, are an important player in the inflammatory response. Tumour-associated macrophages for example are a major component of all tumours. This type of leukocyte can produce growth factors as well as protease enzymes which can stimulate tumour cell proliferation and metastasis through the breakdown of the extracellular matrix. 

The complex network of inflammatory circuits in the tumor microenvironment is forming the basis of developing new therapeutic modalities. Preclinical studies have revealed that anti-inflammatory drugs can suppress cancer development through multiple mechanisms. Achieving positive clinical results is the next step.

Mechanism of anti-inflammatory therapy 

The tumour cell-intrinsic pathway is one of the main inflammatory targets for cancer immunotherapy. However, there are a number of different signalling pathways across the spectrum of disease types which presents additional challenges. 

In liver carcinoma, for example, “the p53 pathway causes increased recruitment and activation of innate immune cells”. Whereas in epithelial ovarian cancer, “the NF-κB pathway causes  Immunosuppression of DCs and macrophages”. Several anti-inflammatory drugs, including NSAIDs like aspirin, have proven to successfully suppress NF-kB activation. This pathway in particular is activated in many cancers and is suppressed by blocking the breakdown of IkB(alpha).

NSAIDs, also known as non-steroidal anti-inflammatory drugs have been used in preclinical cancer studies for a number of years. These drugs, like ibuprofen for example, reduce inflammation by non-specifically inhibiting COX-1 and COX-2 enzymes.  The cyclooxygenase (COX) pathway mediates tissue injury and pain through upregulation of pro-inflammatory agents known as prostaglandins.

This group of anti-inflammatory agents continues to be investigated due to their anti-cancer effects, including their ability to induce apoptosis, inhibit angiogenesis, and enhance cellular immune responses. Angiogenesis is the formation of new blood vessels from existing vascular structures. This plays a substantial part in supporting tumour growth, by maximising the amount of oxygen and nutrients delivered to the tumour site. 

In addition, there are a number of anti-TNF-alpha antibodies approved by the FDA including adalimumab. TNF-alpha is an inflammatory signalling protein produced by macrophages during acute inflammation, and is the activator and effector of the NF-κB pathway.

A 2019 study recently investigated whether low dose anti-inflammatory combinatorial therapy would reduce cancer stem cell formation. This study was performed in patient-derived preclinical models for tumour relapse prevention. They demonstrated that low-dose aspirin with suboptimal dose of doxorubicin (a chemotherapy drug) for 72 hours could generate higher killing efficacy and enhanced apoptosis. The overall results from the study suggest that the combinatorial use of aspirin with conventional cancer therapy could potentially prolong patient survival.

The significance of these results, while not ground-breaking, supports the rationale of future studies using co-treatment of aspirin with other chemotherapy drugs. As a drug, aspirin is relatively cheap, hence would be more accessible to patients across the globe. 

Several studies have also shown that the combination of anti-inflammatory drugs in conjunction with chemotherapy is used to reduce treatment toxicity. Chemotherapy is often effective for many types of cancers. However it is not always targeted, and as a result can damage healthy tissue and cause unpleasant side effects. 

More recent studies have focused on the co-administration of dexamethasone with chemotherapeutic agents like carboplatin. Dexamethasone is a synthetic glucocorticoid steroid which induces immunosuppressive and anti-inflammatory effects predominantly through binding to the glucocorticoid receptor. 

Clinical challenges 

While NSAIDs show potential for targeting cancer-related inflammation, they are yet to be deployed in at-risk populations and properly evaluated for therapeutic applicability. 

Long-term use of NSAIDs can result in a number of adverse side effects. The more common include gastrointestinal (GI) bleeding, liver and kidney dysfunction and osteoporosis. Such adverse effects have been suggested to increase the risk of cancer. In addition, it can elevate “the risk of deep vein thrombosis and its potentially life-threatening complications of pulmonary embolism, myocardial infarction and stroke”.

The use of NSAIDs as a cancer therapeutic remains controversial due to the level of GI toxicity and non-specific activity in the body. Nevertheless, NSAID toxicity is modest in comparison with conventional chemotherapeutic agents, hence various anti-inflammatory agents are still being investigated for cancer therapy and prevention. 

In terms of the future direction, the majority of NSAIDs and other anti-inflammatory agents are being evaluated for combination therapy with chemo- and/or radiation therapy. Preclinical studies have demonstrated the potential of anti-inflammatory agents supporting conventional therapies in reducing toxicity and promoting the therapeutic effect. 

The next step is conducting further research to better understand the molecular mechanisms of anti-inflammatory agents across the spectrum of cancer types and develop more preclinical models that can be translated into clinical studies.

To discuss these topics further with sector experts, and to ensure you remain up-to-date on the latest in clinical development, sign up for Proventa International’s Oncology Strategy Meeting, set for 17 June 2021.

Charlotte Di Salvo, Junior Medical Writer
Proventa International

The post Another Direction for Clinical Oncology: Targeting the Anti-Inflammatory Response in Cancer appeared first on Proventa International.

As a part of Proventa’s Clinical Operations and Oncology Meeting May 2021, we organised a number of interesting keynote sessions pondering the latest innovations, challenges and strategies for the future. The morning keynote, hosted by Tanya Russel Kirkpatrick, VP Clinical Operations Head – Oncology, Global Product Development at Pfizer, was a particularly fascinating panel discussion focused on how the COVID-19 pandemic has impacted oncology and clinical operations.

For daily articles on the latest pharma trends and innovations, as well as interviews with leading experts and in-depth industry White Papers, subscribe to PharmaFeatures.com.

The industry has also seen a significant shift in terms of how it operates clinical trials, focusing on delivering a more patient-centric approach to research and healthcare. There is a “general emphasis on home patient care, remote monitoring and essentially making these trials accessible to patients”. What has been obvious is patients’ concern regarding clinic visits and the risk of catching COVID-19. “In some instances we saw patients who could/could not enroll in trials simply because they did not feel comfortable meeting face-to-face or perhaps because they were part of a vulnerable patient subset or simply it was logistically impossible to do so”.

Clinical trial diversity and equity was something [positive] that came out from the pandemic in particular. “For a long time [as an industry] we have not had representative patient populations enrolling in our oncology trials, and certain indications, for example prostate cancer and triple negative breast cancer”.

Also noteworthy were some differences in how big pharma reacted to the pandemic versus the reaction of smaller biotechs.

Small biotech companies

Despite the world being thrown into turmoil, pharmaceutical startups were able to conduct remote monitoring and patient care almost immediately. Moving quickly into action mode, these smaller pharma companies worked with vendor partners to make sure that the first and foremost, the patient, were not impacted in terms of safety. This is a prime example of the shift to focusing more on patient-centricity.

Start-ups were able to quickly pivot to a substantial amount of remote monitoring, with guidance received from global regulatory bodies like the FDA, which helped these companies to rapidly achieve this. One speaker was happy to report that “none of our patients missed a visit: we worked with our vendors to facilitate patient travel. In oncology, it’s always going to be difficult with infusions and ensuring the patients are comfortable, keeping in mind the patients’ desires and perspectives – all this feeds into our decision-making”. 

Remote technologies 

Across the clinical field, sites immediately implemented remote technologies, allowing doctors to continue to conduct telehealth visits with their patients. Sponsors partnered with sites would work to figure out which visits would be in-person vs those that could be done remotely at a local lab or imaging centre (for oncology).

During the pandemic, a large number of cancer patients were concerned about personal visits, hence were afraid to receive or visit for cancer screenings which further emphasised the need for more telehealth to be implemented. In terms of oncology, one speaker suggested that the status of clinical trials today is hybrid, “where there’ll be some visits closer to home, some at the centre, and some closer to the patient’s”.

There also appears to be a perception that it is more difficult to run decentralised clinical trials for oncology, however one speaker reinforced “it’s all about enabling home health like sending clinicians to patients’ homes to either draw blood, administer medications, collect safety, just checking in general on the patient.”

With regards to remote engagement, “the general feedback from telehealth [from sites] is that they think the patients like it better; it helps to engage and actually ask more questions when they’re doing telehealth and maybe the stress of coming into the office”. 

One of the challenges found with home health , however, is that some patients are uncomfortable having people come into their homes – this is one of the things which pharma is working on improving. 

Initially vendors had no control over which home health visits were meeting patients, so patients were seeing different people each time which was making some uncomfortable. It’s important to establish a relationship between the home health visitor and the patients they’re visiting in order to build a bond of trust.

“It’s all about offering a choice to patients, keeping them at the centre of the decision making”. 

Big pharma

Big pharma initially experienced a high number of [oncology] trials being put on hold. From a Pfizer perspective “we went through the whole pausing trials: we kept open some of the oncology trials, but most of our trials globally were paused briefly because of site shutdowns and then reopened”.

Reopening was a huge effort: site reopening was based on their ability to allow patients on site, their ability to monitor, and also whatever the local shutdown regulations were. Doing this globally was one of the most difficult things to do: “we had our colleagues in countries reporting back on a regular basis on sites regarding their status and ability to allow patients to come into the clinics/not coming to the clinics”. 

Oncology trials were an area that reopened faster than some of the other therapeutic areas because often oncology sites have a separate location – it’s not in the main hospital when they’re treating the patients they’re administering the oncology treatments too. Big pharma’s very quickly adapted to both remote monitoring, set up for working with sites to see how data could be accessed throughout electronic health records. The varying levels of lockdowns globally presented an issue however, as Europe wasn’t allowing that type of monitoring early on, whereas in the US you could get better data from sites depending on the region 

“Because we [Pfizer] developed the vaccine, we quickly pivoted to asking how can we do that in the pandemic. It enabled us to kickstart the things we wanted to do for a long time. We wanted to have a more decentralised approach”. This enabled (remote) monitoring, and thus, more telehealth. Due to the pandemic, big pharma had to adapt to remote clinical research to enable the vaccine trials to run. The success of the rapid changes to decentralised clinical trials has pushed big pharma to continue in this way and make sure they were conducting clinical trials before – this is one of the biggest challenges.

Supplying medication to patients’ homes was “one of the first things we implemented…but you’re less able to do that in oncology”. In oncology, it was often more about trying to figure out how to get the patient into the centre for infusions or something that required monitoring for safety. It was found that oncology centres were more willing to open up because they wanted to push continuity of patient treatment. “Direct-to-patient drug delivery and flexible sample collection is something we’ve been doing – collecting bloods, sending phlebotomists to homes and sending them back to central labs and even local labs”.

“What we’re doing for decentralised trials is more of a concierge approach, so every time we have a new protocol, the protocol team sits down with the decentralised subject matter experts. These are professionals who are dedicated to their subject, looking visit-by-visit to see what’s happening and make suggestions where they could deploy a technique that might be more beneficial for the patient”. 

This typically results in a hybrid approach, where the first couple visits involve travel to the hospital to monitor patients for cytokine release syndrome (CRS) or other safety issues. Visits after that could be done at home.

In oncology, there are often long-term follow ups, with patients on the drug for a long period, receiving benefits. This can go on for years and makes it easier to perform visits from a home-type approach.

Charlotte Di Salvo, Junior Medical Writer
Proventa International

The post How Has The Covid-19 Pandemic Impacted Oncology and Clinical Operations? appeared first on Proventa International.

Biomarkers have shown significant potential across oncology clinical studies, especially in precision medicine for immunotherapy. Therefore, it is important that biomarker discovery and validation is optimised to produce the most effective drugs for patient populations. False positives and experimental bias are a few of the hurdles that arise during these stages. 

For daily articles on the latest pharma trends and innovations, as well as interviews with leading experts and in-depth industry White Papers, subscribe to PharmaFeatures.com.

Biomarker discovery 

Biomarkers have become an important tool in precision medicine across a number of therapeutic areas. In oncology, genetic profiling technology and targeted cell therapies have seen biomarkers play an important role in disease management for cancer patients. 

A cancer biomarker refers to a “tumor characteristic or a response of the body in the presence of cancer that can be objectively measured and evaluated”. Cancer biomarkers can be used to measure the risk of developing the disease; response to therapy; and/or disease progression. This information is typically used to guide clinical decisions regarding choice and timeline of treatment relative to the pathogenesis of the cancer type. 

Cancer biomarkers can be classified into two categories: predictive and prognostic biomarkers. 

Predictive biomarkers are typically used to predict the response to specific therapeutic interventions such as positivity/activation of HER2 that predicts response to trastuzumab in breast cancer. Overexpression of HER2, a human growth factor, results in a clinically aggressive subtype of breast cancer. 

Prognostic biomarkers, on the other hand, aim to inform doctors regarding the likely patient outcome i.e. risk of disease recurrence or potential progression in the future. The 21-gene recurrence score is an example of a prognostic cancer biomarker which was predictive of breast cancer recurrence and overall survival in node-negative, tamoxifen-treated breast cancer. Pharmacokinetic/dynamic/genomic biomarkers can also be used to evaluate drug interaction with the patient. 

The discovery study for biomarkers typically involves pre-clinical investigations of a pool of candidate biomarkers. The objective of this is to identify “a short list of promising markers that are associated with clinical outcome of interests for further investigation”.

The discovery of potential biomarkers, however, is a difficult task with a number of challenges that compromise the reliability of a new marker. 

Challenges

One of the main challenges in biomarker discovery is the high number of false discoveries. This occurs when initial scientific findings associated with a new biomarker cannot be reproduced by other laboratories or independent samples. A number of factors can contribute to false discovery including execution errors, poor study design and bioinformatic shortcomings. 

As discussed in a recent review, false discovery is closely related to the problem of scientific irreproducibility. If a biomarker discovery cannot be reproduced by a number of external sources, then it is not suitable for validation. This not only costs pharmaceutical companies significant amounts of money in funding experiments for an invalid biomarker; it also slows down the progression of biomarkers in drug development for precision medicine. 

One potential solution to this problem is shifting from “the orthodox discovery of biomarkers that are common for a cancer type to screening of serum samples of each patient”. By identifying markers unique for specific tumour types, it could potentially reduce the chance of biomarkers failing to demonstrate specificity and sensitivity for a number of patients. 

Bias is one of the greatest causes of failure in biomarker discovery and validation studies. The study design, through which biospecimens are analysed, is a significant source for bias. Bias occurs when “systematic error [is] introduced into sampling or testing by selecting or encouraging one outcome or answer over others”. 

According to a review, it is ideal to prospectively collect biospecimens based on a succinct inclusion and exclusion criteria “pre-specified in the study protocol”. Therefore, the chance of false positives arising is theoretically lower as the discovered biomarker must meet both criteria before proceeding for validation studies.

Next-generation sequencing (NGS) is a valuable genomic tool used in cancer biomarker discovery. While the high-resolution data achieved with NGS is useful for the identifying large numbers of genomic alterations, it results in a considerable increase in computational analysis and bioinformatics support needed to interpret data. This can present an issue to smaller biotech companies with limited funding and experimental capacity. 

Biomarker validation 

Following discovery studies, candidate biomarker assays must undergo validation- this is split into two types. Analytic validation determines “how accurately and reliably the test measures the analyte(s) of interest in the patient specimen”. Clinical validation, on the other hand, investigates “how robustly and reliably is the test result correlated with the clinical phenotype or the outcome of interest”. 

There are a number of different assay technologies available for biomarker validation depending on the specimen. For analysis of gene expression and DNA mutations, real-time polymerase chain reaction (PCR) is a popular in vitro method that can amplify small samples large enough to study. Assessing protein expression, on the other hand, often falls to immunohistochemistry. 

There are two key statistical approaches for clinical validation of an assay. Internal validation divides a study population into two independent groups. For clarification, the study population “reflects the target population in which the test will be used”. One sample group, defined as the training set, is used to identify and characterise the biomarker. The second group, known as the validation set, is used to assess whether the “external validity of the biomarker/model is maintained in a sample cohort—independent from the training set”. 

Unfortunately, internal validation is not sufficient to clinically validify biomarkers. Hence, external validation is required to be performed on an independent dataset. Any predictive biomarkers must undergo external validation in order to test clinical performance for regulatory approval. 

According to a 2019 review, one of the primary challenges in clinical validation for biomarkers is that there is no institution responsible for monitoring the evidence for or against particular biomarker uses (at the time of publication). As a result, there is no governing body with the authority “to revoke the use of a biomarker in clinical practice if it has been shown to be invalid”. This presents a significant cause for concern with regards to the safety and efficacy biomarkers in drug development.

Clinical validation is a crucial part of biomarker development, which, if not performed correctly, could cause harm in patients. Despite innovations improving the multiple stages of validation, there are a number of challenges which need to be addressed. Continued research into optimising biomarker discovery and validation will no doubt improve the drug development process, producing more effective and safer drugs for patients.

To discuss these topics further with sector experts, and to ensure you remain up-to-date on the latest in clinical development, sign up for Proventa International’s Oncology Strategy Meeting, set for 17 June 2021.

Charlotte Di Salvo, Junior Medical Writer
Proventa International

The post Biomarker Discovery and Validation: Current Challenges in Oncology appeared first on Proventa International.

Precision medicine is a rapidly growing therapeutic area within oncology. Technological innovations have contributed to the refinement of predictive and diagnostic techniques used to tailor therapy for cancer patients. The goal is to not only develop more precise treatments, but to also predict the optimum choice of therapy to maximise the chance of progression free survival.

For daily articles on the latest pharma trends and innovations, as well as interviews with leading experts and in-depth industry White Papers, subscribe to PharmaFeatures.com.

Deep learning for diagnostics 

Deep learning is a specialised area of ML that attempts to model abstraction from large-scale data using multi-layered deep neural networks (DNNs). Abstraction refers to the process of filtering out irrelevant data in order to focus on the desired information. Cancer diagnosis relies upon accurate visual pattern recognition in images and large data sets in order to identify features that cause concern. While oncology physicians are highly specialised and trained in their field, there is only so much data processing that the human brain can handle. Machine learning on the other hand can be programmed to identify abnormalities in vast data sets with greater accuracy land speed than the average human. 

Deep learning has been used for image classification in cancer diagnosis. Such image tasks require a form of deep learning known as a convolutional neural network (CNN). This artificial neural network relies on many layers composed of connected artificial neurons that perform mathematical operations on input data. One of the main reasons why CNN works well for image classification is the ability of the network to mimic the natural visual processing of the human brain “which enables the interpretation of dense information such as the relationship of nearby pixels and objects”. 

During training, labeled image data is inputted into the artificial neural network and undergoes two processes, known as filtering and sub-sampling. These processes enable the network to learn the image features. Labelled image data may comprise images of skin lesions with cancerous features identified. Once a model is trained, it is validated in an independent rest in order to evaluate its final performance.

In 2020, a study published in Nature Research used deep learned tissue “fingerprints” to classify breast cancers. One of the challenges of using deep learning for histopathology was noted in the study as the lack of large, well-annotated data sets required for the algorithms to learn statistical significance. After training the algorithm, they used “the features the network learned, called ‘fingerprints,’ to predict ER, PR, and Her2 status in two datasets”. While the dataset for the study was small, the fact that the fingerprints determined different growth factor status from whole slide images of breast cancer. This supported the potential of using ML in cancer diagnosis. 

Next-generation sequencing 

Next-generation sequencing (NGS) is a DNA-sequencing technique used for high-throughput tumour profiling. With the ability to sequence the entire human genome in a day, NGS offers a significant advantage over traditional genomic sequencing like the Sanger sequencing. According to a recent review, NGS comprises of the following steps:

• Each DNA fragment to be sequenced is bound to a structure called array, followed by the enzyme DNA polymerase which adds labeled nucleotides sequentially. 

• A high-resolution camera captures the signal from each nucleotide as it becomes integrated and notes the spatial coordinates and time. 

• The sequence at each spot can then be inferred by a computer program to generate a contiguous DNA sequence, referred to as a read.

NGS is an important part of genetic sequencing within a diagnostic technique known as liquid biopsy. Liquid biopsy is a non-invasive and real-time monitoring of disease development, which can be applied to all stages within cancer diagnosis and treatment. Liquid biopsy measures the presence of circulating tumour DNA (ctDNA). cTDNA is a type of cancer biomarker used to detect the disease as well as monitor the progress throughout treatment. 

NGS is used in conjunction with liquid biopsies to provide a tumour-specific molecular profile of the cancer. Initially PCR-based methods were used to sequence ctDNA due to their sensitivity and low cost. However, these methods can only screen for known variants, and the input and speed are limited. NGS has shown to provide high throughput and the ability to screen unknown genetic variants. Thanks to NGS technology, the sequencing of ctDNA can be performed at a much higher sensitivity than tissue biopsies and support patients in targeted therapy relative to their tumour profile. 

Microsatellite instability testing

The DNA mismatch repair system (MMR) is a highly conserved repair mechanism for cellular function. However, when the MMR system fails to work properly, it can cause microsatellites. These are regions of repeated DNA that change in length, showing instability.  Lynch syndrome is a common hereditary disease, characterised by mutations in MMR genes. This syndrome is associated with many cancer types, especially so with colon cancer and endometrial cancer.

MSI testing is used to analyse the length of specific DNA microsatellites within a tumour sample in order to measure the level of instability.  

Clinical studies in the last five years suggest that MSI is a predictive biomarker for immunotherapy, seeking further attention for its application in precision medicine. According to a 2019 review, several clinical trials have demonstrated that mismatch repair deficiency or microsatellite instability-high is significantly associated with long-term immunotherapy-related responses and better prognosis in colorectal and noncolorectal malignancies treated with immune checkpoint inhibitors. 

At the time of publication (2019), the drug pembrolizumab has been approved for MMR deficiency/microsatellite instability-high refractory tumours, and nivolumab approved for colorectal cancer patients with MMR deficiency / microsatellite instability-high. The fact that the same biomarker has been used to support immunotherapy for different tumour types is a first in cancer research. This represents a significant step forward in precision oncology, highlighting a promising opportunity to improve the efficacy of immunotherapy.

The three innovations described in this article are a few of the latest developments in precision oncology. As research continues, the hope is that cancer therapy will become more targeted so treatment is more effective and patients receive the best chance of survival.

To discuss these topics further with sector experts, and to ensure you remain up-to-date on the latest in clinical development, sign up for Proventa International’s Oncology Strategy Meeting, set for 17 June 2021.

Charlotte Di Salvo, Junior Medical Writer
Proventa International

The post The Latest Developments in Precision Oncology appeared first on Proventa International.