The document discusses cytokine immunotherapy as a promising approach for cancer treatment. It notes that cytokines can stimulate the immune system to fight tumors, but that mono-cytokine therapy has limitations. Combined cytokine therapy or cytokine therapy combined with other treatments may be more effective by creating a specific immune response. The document advocates focusing research on combination therapies to help overcome drawbacks of traditional cancer treatments.
Therapeutic prospects in Cancer Immunotherapy.
Interleukins for Renal Cell Carcinoma.
BCG for Bladder Cancer.
Vaccination Strategies: Oncolytic virus for melanoma, Dendritic Cell therapy for CA Prostate.
Immune Checkpoint inhibitors. PD1 and PD L1 inhibitors.
Adoptive Cell Therpay. CAR T Cell Therapy
Clinical efficacy. Costs.
Therapeutic prospects in Cancer Immunotherapy.
Interleukins for Renal Cell Carcinoma.
BCG for Bladder Cancer.
Vaccination Strategies: Oncolytic virus for melanoma, Dendritic Cell therapy for CA Prostate.
Immune Checkpoint inhibitors. PD1 and PD L1 inhibitors.
Adoptive Cell Therpay. CAR T Cell Therapy
Clinical efficacy. Costs.
In this webinar:
Dr. Michele Ardolino, Assistant Professor at the University of Ottawa, Department of Biochemistry, Microbiology, and Immunology and Scientist Ottawa Hospital Research Institute, discusses: The body has a phenomenal weapon to fight infections and cancer: the immune system. This seminar focuses on how the immune system recognizes and shapes cancer and on how research in tumor immunology led to the development of life-saving and revolutionizing immuno-therapies.
The webinar is followed by a question & answer session.
View the video:
https://youtu.be/-a7DfHT8dU8
To learn more about CCSN, visit us at survivornet.ca
Follow CCSN on social media:
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n overview of current immunotherapy therapies used to treat cancer. Also provides MOA of various medications, and updates on SITC guidelines for metastatice melanoma.
A detailed ppt about cancer immunotherapy.
includes:-
Immunosurveillance and Immunoediting
Dentritic cell vaccines
Antibody therapy
Combined therapy
immune blockades
Cytokine therapy
T cell therapy
Include latest research finding about therapy.
Global cancer immunotherapy market outlook 2020KuicK Research
"Global Cancer Immunotherapy Market Outlook 2020" Report Highlight:
Introduction & Classification of Cancer Immunotherapy
Global Cancer Immunotherapy Pipeline by Company, Indication & Phase
Marketed Cancer Immunotherapies Clinical Insight & Patent Analysis by Company & Indication
Global Cancer Immunotherapy Pipeline: 1834 Drugs
Marketed Cancer Immunotherapies: 113 Drugs
Cancer Monoclonal Antibodies Pipeline: 622 Cancer mAb
Cancer Vaccines Pipeline: 312 Vaccines
Marketed Cancer mAb: 36 mAb
Marketed Cancer Vaccines: 12 Vaccines
Tumor, Tumor immunology, cancer, hallmarks of cancer, carcinoma, lymphoma, metastasis, malignant, benign, angiogenesis, oncogenes and cancer induction, kuby detailed study quick revision, proto-oncogenes, tumor antigens, antibody, experiments for tumor antigens, methods for characterization of TSTA, Immunoediting, Current research n new approaches, monoclonal antibody
In this webinar:
Dr. Michele Ardolino, Assistant Professor at the University of Ottawa, Department of Biochemistry, Microbiology, and Immunology and Scientist Ottawa Hospital Research Institute, discusses: The body has a phenomenal weapon to fight infections and cancer: the immune system. This seminar focuses on how the immune system recognizes and shapes cancer and on how research in tumor immunology led to the development of life-saving and revolutionizing immuno-therapies.
The webinar is followed by a question & answer session.
View the video:
https://youtu.be/-a7DfHT8dU8
To learn more about CCSN, visit us at survivornet.ca
Follow CCSN on social media:
Twitter - https://twitter.com/survivornetca
Facebook - https://www.facebook.com/CanadianSurv...
Instagram: https://www.instagram.com/survivornet...
Pinterest - https://www.pinterest.com/survivornet...
n overview of current immunotherapy therapies used to treat cancer. Also provides MOA of various medications, and updates on SITC guidelines for metastatice melanoma.
A detailed ppt about cancer immunotherapy.
includes:-
Immunosurveillance and Immunoediting
Dentritic cell vaccines
Antibody therapy
Combined therapy
immune blockades
Cytokine therapy
T cell therapy
Include latest research finding about therapy.
Global cancer immunotherapy market outlook 2020KuicK Research
"Global Cancer Immunotherapy Market Outlook 2020" Report Highlight:
Introduction & Classification of Cancer Immunotherapy
Global Cancer Immunotherapy Pipeline by Company, Indication & Phase
Marketed Cancer Immunotherapies Clinical Insight & Patent Analysis by Company & Indication
Global Cancer Immunotherapy Pipeline: 1834 Drugs
Marketed Cancer Immunotherapies: 113 Drugs
Cancer Monoclonal Antibodies Pipeline: 622 Cancer mAb
Cancer Vaccines Pipeline: 312 Vaccines
Marketed Cancer mAb: 36 mAb
Marketed Cancer Vaccines: 12 Vaccines
Tumor, Tumor immunology, cancer, hallmarks of cancer, carcinoma, lymphoma, metastasis, malignant, benign, angiogenesis, oncogenes and cancer induction, kuby detailed study quick revision, proto-oncogenes, tumor antigens, antibody, experiments for tumor antigens, methods for characterization of TSTA, Immunoediting, Current research n new approaches, monoclonal antibody
Cytokines by Dr Rahul , Physiology SMS MEDICAL JAIPUR MOBILE NO-8764324067Dr.Rahul ,Jaipur
-CYTOKINES
-THEIR PROPERITIES
-TYPES OF CYTOKINES
-CYTOKINES RECEPTOR FAMILY
-CYTOKINES AND PYREXIA
-CYTOKINES AND OBESITY RELATED DISEASE
-CYTOKINES AS DRUGS
Presentation for Plant Physiology. I was in charge of creating and designing the presentation as well as formating the images and information. Our projec won our class competition in regards to overall look and presentation.
A normal cell can be transformed into a cancerous cell. Discuss the therapeutic strategies that are employed to target the cellular transformation process for cancer prevention and treatment.
REVIEWCancer stem cells a new framework for the designo.docxjoellemurphey
REVIEW
Cancer stem cells: a new framework for the design
of tumor therapies
Boyan K. Garvalov & Till Acker
Received: 14 July 2010 /Revised: 27 August 2010 /Accepted: 16 September 2010
# Springer-Verlag 2010
Abstract Modern tumor therapy has achieved considerable
progress, but many tumors remain refractory to treatment or
relapse following initial remission. Recent evidence points
to one possible reason for this limited therapeutic efficiency:
that the design of anticancer agents so far may not have been
aimed at the right target. While conventional tumor therapies
have targeted the main mass of tumor cells, there is now
compelling evidence that tumor initiation and progression are
driven by a subpopulation of tumor cells that possess stem cell
properties and are resistant to traditional cancer treatments—
the cancer stem cells (CSCs). CSCs have been identified in
most types of cancer and can be separated from the rest of the
tumor cells using appropriate markers. CSCs are regulated by
molecular mechanisms and specific, perivascular, and hypox-
ic microenvironments, which largely overlap with those
controlling stem cells from normal tissues. Our improved
understanding of CSC biology has already provided a number
of novel targets and drug discovery platforms for the design of
specific therapies that aim to eradicate the CSC subpopula-
tion. Therapeutic approaches can be targeted either at
eliminating the CSCs themselves or at disrupting the niches
in which CSCs reside. Moreover, the importance of CSCs for
tumor growth, resistance, and progression implies that clinical
trials and preclinical studies of anticancer therapies should
include as a key element an assessment of the abundance and
persistence of CSCs. Thus, CSC research holds great promise
for providing important new impetus to the fields of tumor
biology and clinical oncology.
Keywords Cancer stem cell . Hypoxia .
Microenvironment . Angiogenesis . Antitumor therapy.
Metastasis
The hierarchy model and cancer stem cells (CSCs)
The classical view of tumor formation is based on the
“stochastic” or “clonal evolution” model [1, 2]. It perceives
the tumor as a mass of hyperproliferative cells with similar
potential for driving tumor growth. Tumor heterogeneity
and progression are seen as the result of variations in the
tumor microenvironment and genetic mutations in individ-
ual cells, followed by selection of those that are best
adapted to support the further growth of the tumor (Fig. 1a).
An alternative concept that has been gaining increasing
experimental support is the “hierarchy” or “cancer stem
cell” model [3]. This model posits that tumors are generated
and maintained in a manner similar to the physiological
stem cell system operating in normal tissues, i.e., by cells
with stem cell-like properties, which self-renew and
differentiate into the distinct cellular subtypes of the tumor
(Fig. 1b). The key novel features of this model are that only
a limited population of tumor cell ...
Intracellular Events in Antigen Processing.pptxDr.Kanury Rao
Intracellular signaling or events are caused on the surfaces of the cells. Dr. Kanury Rao, the greatest immunologist of all time, has conducted an in-depth analysis of intracellular events to develop a tool for early detection of cancer.
Clinical oncology basic fundamental For undergraduate studies part I .pdfMona Quenawy
Cancer is a disease of uncontrolled growth and proliferation whereby cells have escaped the body’s normal growth control mechanisms and have gained the ability to divide indefinitely. It is a multi-step process that requires the accumulation of many genetic changes over time (Figure 1). These genetic alterations involve activation of proto-oncogenes to oncogenes, deregulation of tumour suppressor genes and DNA repair genes and ‘immortalisation
Cancer ranks as a leading cause of death and an important barrier to increasing life expectancy in every country of the world.1 According to estimates from the World Health Organization (WHO) in 2019, cancer is the first or second leading cause of death before the age of 70 years in 112 of 183 countries and ranks third or fourth in a further 23 countries . Cancer's rising prominence as a leading cause of death partly reflects marked declines in mortality rates of stroke and coronary heart disease, relative to cancer, in many countries.
Between 30–50% of all cancer cases are preventable. Prevention offers the most cost-effective long-term strategy for the control of cancer. WHO works with Member States to strengthen national policies and programmes to raise awareness and, reduce exposure to cancer risk factors, and also ensure that people are provided with the information and support they need to adopt healthy lifestyles.
To strengthen national efforts to address the burden of cancer and other noncommunicable diseases (NCDs), the WHO Global Action Plan for the Prevention and Control of NCDs 2013–2020 provides a road map to reduce premature mortality from NCDs by 2025 through targeting many of the risk factors below:
Tobacco
Worldwide, tobacco use is the single greatest avoidable risk factor for cancer mortality and kills more than 8 million people each year, from cancer and other diseases. Nearly 80% of the 1.1 billion smokers in the world live in low- and middle-income countries.
Alcohol
Alcohol, as classified by the International Agency for Research on Cancer, is a toxic, psychoactive, and dependence-producing substance and a Group 1 carcinogen that is causally linked to 7 types of cancer, including oesophagus, liver, colorectal, and breast cancers. Alcohol consumption is associated with 740 000 new cancer cases each year. Globally, 1 in 20 breast cancers is attributed to alcohol consumption.
Physical inactivity,infection with HPV,Environmental pollution,Industrial carcinogen and radiation exposure are also global preventable causes.
this basic discussion highlight the topics of the main types of cancer and cancer theory.prevention cancer staging with TNM and other methods .management of emergency situation in clinical oncology .basics of surgical oncology and chemotherapy handling.
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
Cytokine Immunotherapy: A Forthcoming Visible Feature in Cancer Therapeutics
1. Dear Reviewer,
Please find the confined manuscript entitled “Cytokine Immunotherapy: A forthcoming
visible feature in cancer therapeutics”, which I would like to share with you all.
Cytokine are messengers protein produced by varieties of cells whose role in host responses
to cancer are remarkable. Different bioprocesses are interlinked with cytokine functions.
Preclinical research studies have shown the anti-cancerous property of cytokine which
suppress inflammatory and autoimmune microenvironment. Little evidence of rare patient
studies suggesting that the immune system can revoke again if stimulated appropriately. One
of the appropriate stimulation of immune system can be done with therapeutic manipulation
of cytokine balance.
However, at present status, mono-cytokine therapy doesn’t show promising features as
compare to combined cytokine therapy as combined cytokine therapy or cytokine therapy
with other traditional therapeutic module. It is expected that appropriate combination will
result with specific and reliable therapeutics for cancer treatment. It is time to focus on the
remaining checkpoints and else everything to make an option for the accurate efficacy of
treatment.
In this literature work, I have enlightened some therapeutic individuality along with
possibility of combination with other modalities. I think that this literature work will be
fruitful for those seekers who are looking for the appropriate combination of treatment to
overcome the drawbacks of traditional healing remedies.
Thank you for your consideration. I look forward to seeing your critics from you.
Sincerely,
Sachin K. S. Chauhan
New Delhi,
INDIA.
2. Cytokine Immunotherapy: A Forthcoming Visible Feature in Cancer
Therapeutics
Sachin K. S. Chauhan
Abstract: Cell-based cytokine therapy have prodigious promising role for treating a varieties
of diseases. Cytokines are intra- as well as intercellular messengers, which recruit the
immune effecter cells, thereby limiting the tumor growth; however, sometimes these
molecules promote tumor progression. Several studies have attempted the usage cytokines
alone as pharmaceutical targets to alter the immune response, which may eradicate solid
tumors. In the context of advancement in understanding of cytokine biology, there is a
definite need to develop combined cytokine therapy with the advent of gene technology to
improve efficacy of cancer treatment. This review focuses on understanding the factors of
combined cytokine therapy and that allows us to attain durable and long-lasting responses in
cancer therapy.
Introduction
Cancer is a natural wound healing related process, which includes cytokine secretion, tissue
remodeling, and oncogenes activation (1). Every cell has a unique type of characteristic
signature such as the abilities of genes or proteins to perform their function. These
characteristic features also alleviate molecular mechanisms of diseases and will give
prediction about individualization of therapies for suffering people. From many years, all
efforts to treat human malignancies have concentrated on the early detection and cure of
tumor. So these efforts have provided great opportunities for improving the management of
cancer patients by enhancing the efficacy of detection and treatment (2). Now it is well
known that the mutation, competition, and natural selection operating within the population
of somatic cells are basic requirements for initiations, progression, and survival of cancer
cells. These phenomena depend not only on the tumor cell, but on the complex interactions
between the tumor cells and its ‘host’ (3). Hence, it is required to focus on the strategies to
modulate the growth mechanism and host microenvironment, which offers a complementary
perspective to achieve a permanent cure.
Cancer cells are introduced by their heritable properties like they reproduce in defiance of the
normal restraints, invade, and colonize territories reserved for other cells. This renegade
coordination of malignancy has been creating lot of evidences that tumor cells elicit certain
hallmark characteristics which lead the somatic cells to micro-evolutionary developmental
process of malignant cancer (4). (Box 1)
This multistep process of tumor genesis could be explained by the requirement of incipient
cancer cells to adopt the traits of tumorigenic cells and ultimately become malignant (5). :
3. There are several therapeutic modalities have been developing on the basis of cancer
hallmarks individuality (Figure 1). It is mandatory to go through the overall metabolic
network and its acquired hallmarks which explain the majority of manipulated checkpoint for
the growth of tumor cells.
FOUNDATION OF CANCER BIOLOGY
New research applications of cancer biology are transforming our understanding about
cancer. The basic foundation of cancer biology explores these basic principles – cancer
excogitates by somatic selection, neoplasm ripens in complex ecosystems, natural selection
has designed effective cancer defenses (6). The limitations of these principles defenses have
the explanations which present foundation of cancer biology for understanding, preventing
and developing therapeutic modalities (7). The most fundamental traits of cancer cells
overcome cell growth signals and influence cell survival and energy metabolism (8). These
mutagenic signals are release via branched intracellular signaling through cell progression
which should be filtered in case of tumor growth. Alternatively, some tumor cells may be
able to overcome high level of oncogenic signaling by disabling their apoptosis-inducing
mechanism. If we enquire anomaly between level of complex network of proteases,
sulfatases, and other enzymes in normal and tumor cells, then it’ll be easy to find out that it
can switch the pathway in an alternate ways, hence it is necessary to seek a multi target
therapeutic approaches. In addition to two above aspect of fundamental biology of
insensitivity to antigrowth signaling and evasion of apoptosis, cancer cells riddance various
signaling pathways, especially apoptotic which allow them to seed, proliferate, and flourish
in other territories of body. They must also besiege dozens of powerful tumor suppressor
programs that control in various ways to limit the normal cell growth. For example, the
central effectors of apoptosis is caspases whose hypo-phosporylation makes impossible
antigrowth factors such as TGF-β, pRB and p53 from blocking the advancement of cell
growth (9).The other two factors are RB (Retinoblastoma) and TP53 have the function of
inhibition and execution of cell cycle growth in normal cells. Tumor cell with the defect in
these factor mechanisms exclude the check-point service of cell cycle whose absence permits
persistent growth. (10).
At the mechanistic level, several types of surface proteins are involved in the interactions of
metastatic cells through cell adhesions molecules (CAMs) and integrin to establish proper
invasive cell in distinct territories of body. These interactions play a vital role in allowing the
signal to enter into intracellular part of cell. (11). Alterations in expression of these CAMs in
Ig super family play a critical role in the invasion and metastasis processes like change in the
expression of integrin help to invade and proliferating cancer cells (12). E-cadherins are
Box 1
Hallmarks individuality of cancer:
1. The quality to prolong chronic proliferation by deregulating explicit of growth promoting signals.
2. Evading growth suppressors either by persecuting the effect of tumor suppressor genes or by annulling
cell-cell contact inhibition.
3. Resisting cell death and becoming tolerant to multiple apoptotic mechanisms.
4. Unlimited replicate potential by protecting against telomere erosion.
5. Inducing angiogenesis via production of vascular endothelial growth factors.
6. Activating invasion and metastasis by altering expression of cell-cell adhesion molecules.
Because of the proceeding impact of these hallmarks, they are usually mentioned as a starting point to study
for the anticancer strategies. Several progresses in these research studies has revealed two new emerging
hallmarks of cancer to this list – reprogramming of energy metabolism and evading immune destruction
(Douglas Hanahan, Hallmarks of Cancer: The Next Generation, 2011).
4. Box 2
Molecular and cellular pathways linking inflammation and cancer
Schematically, two pathways have emerged; the intrinsic and extrinsic. In the intrinsic pathways, activation
of different classes of oncogenes drives the expression of inflammation-related programs that guide the
construction of an inflammatory milieu. In the extrinsic pathways, inflammatory conditions promote cancer
development. The key factors of the inflammation-mediated tumor progression are transcription factors,
cytokines, chemokine and infiltrating leukocytes. (123).
widely known as a suppressor of invasion and metastasis by epithelial cells, which must be
altered by cancer cell to overcome to progress (13), (14).
As it is known that these CAM molecules are the basis of interaction between cells, so if put
a gate on the expression of these molecules in tumor cells then it’ll be easier to find a cure for
the responsible tumor type. For all malignancies, executing treatments is much harder to
come by. May be a after few years, it may be possible to sequence according to the soul of
tumor and offer up the diagnosis, not of colorectal cancer, but of an RB/TP53/APC/KRAS
malignancy like report. Then different combination system in the form of pills will be
recommended.
Over the past decade when viewed from all these perspective, tumors have been increasingly
recognized as abnormality whose complexity approaches and may even exceed that of normal
healthy tissues. It’s better to understand the biology of a tumor through studying the
specialized cell types within it as well as the ‘tumor Microenvironment’ that they are
interlinked.
These are the overall assessment about different recent aspects of foundation studies of
cancer biology. They were illustrated about cells involved in the proliferation, soluble factors
which enhance the progression, signaling molecules whose alteration promote the survival of
cancer cells, extracellular matrix and mechanical cues that can promote transformation,
invasion and protect the tumor from host immunity. These all aspects indicate toward the link
of cancer progression and tumor microenvironment.
Tumor microenvironment and Immunomodulation
Tumor is composed of stromal constituents like inflammatory cells, endothelial cells which
finally arrange tumor microenvironment to promote tumor growth, progression and survival
(15). In 1909, Paul Ehrlich originally hypothesized that the progression of neoplastic cells
could be constrained by host immune system. In the response to tissue injury induced by
tumor-host interaction, stromal cells represent a defense mechanism of the organism and
release cytokine, chemokine, growth factors, and lipid modulators that exert their effects. For
example, Transforming growth factor- beta (TGF-β) is a critical regulator of tumor
progression and a potent inhibitor of cell differentiation which is secreted by multiple cell
types within the tumor microenvironment (16). This defense mechanism suppressed by tumor
cells which effectively alter the growth inhibitory effect of stromal cells and harness the
growth promoting characteristics for their own beneficial (17). The purpose of studying
limitations of tumor microenvironment and immunomodulation is to identify the optimal
treatment for each individual patient to maximize the treatment benefit.
5. Tumor and immune cells both have been found to secrete inflammatory mediators which play
a dual role in tumor development. On the one side, they promote tumor survival whereas on
the other side they promote immune surveillance mechanisms against tumor cells. It is
during the equilibrium phase that the interplay between several components of the immune
system and the tumor will define the final outcome of the immune response. This immune
selection may be produced due to recognition of cytokine and chemokine in immune system.
The cytokines are endogenous substances behaving like hormones present within the immune
system, sending messages between immune cells mediated by receptors, stimulation of
immune cells showing some direct effect on tumor cells and infections, (18).
Several studies are presently going on chemokine and cytokine levels in tumor cells at
various stage of their growth phase to understand the levels of these factors causing
promotion or inhibition of tumor growth. They revealed that cancer cells amend only those
pathways which make those cells accessible to use them as proliferative agent without any
checkpoint. A new era of effectively harnessing these studies to treat and prevent cancer has
begun. There are several therapies are now approved for cancer treatment and others are on
clinical trials. These studies may lead to elevated interest and movement in developing novel
therapeutic strategies for oversetting the balance of host-tumor interaction toward tumor
growth inhibition. It is clearly practicing to prosper advanced therapies to re-engineer the
overall host ambience and tumor microenvironment to rattle pathways of suppression and
immune system tolerance.
Overall, Chemo, radiation and other traditional therapies are standard therapeutic modalities
for patients suffering from cancer. But the extensive use of antibiotics and chemicals in
human patients has shown several side effects with less efficacy of treatment (19). In another
case, William Coley (1891) attempted to demonstrate the immune system’s ability to cause
inflammation which further stimulates antibacterial phagocytes that might kill spectator
tumor cells also. Further this theory was discounted but it gave a channel towards Cancer
immunotherapy (20). Cytokine being natural messengers of immune response which on
administration eradicate solid tumor, thereby exhibiting bright side of cytokine therapy.
Presently, many researchers have tried the combination of Chemotherapy / radiotherapy with
different specific form of immunotherapy. Although, it is well known that chemotherapy /
radiation cause several lethal effect to rapidly progressive cells like hematopoietic cells,
epithelial lining in gut and sperms. So it is recommending that use chemotherapy /
radiotherapy to deplete tumor load and then introduce immunotherapy to final depletion of
tumor and prevent the re-growth (21).
Recent studies highlight the benefits of specificity of Immunotherapy for cancer which can
enable the induction of immune response via a variety of ways such as
Guidance of co-stimulatory signal molecules
During tumor progression, a tumor cell mutates the co-stimulatory genes and affects the
function of co-stimlatory molecules which are required for the interaction of antigen
presenting cells (APC) with immune cells. Like, B7 (a co-stimulatory molecule) on APC
interact with its receptor i.e. CTLA -4 and CD28 on T cells which provide signal for further
activation of T cells. The absence of expression of B7 molecules renders tumor growth
imperceptible to the immune system while the induced expression of B7 molecule prevent
6. tumor from effective cytolytic T lymphocyte (CTLs). The transfection of B7 molecule in
tumor cell micro-environment led to tumor regression due to induction of effective CTLs
response. The co-stimulation of T cell upto a balanced level may have valuable therapeutic
purpose for generating immunity against tumors (22), (23).
Augmentation of APC activity with monotherapy
This monotherapy attempts to utilize the expression of tumor-specific antigens in the
development of antigen-specific immunotherapy. In one approach, the result approved the
practicability to induce monocyte-derived DCs in the presence of GM-CSF and IL-4 by co-
culturing with melanoma tumor cells (24). This study highlights that tumor cells can be
genetically improvised to be able to identify tumor specific antigens (TSAs) through
activation of different cytokines and other molecules. If patients DCs co-culture with tumor
fragment from patients in the presence of recombinant GM-CSF, then it can induce the
activation of APCs, Th cells, and CTLs specific for TSAs. After decades of research, it is
shown that DCs are the central effecter cells of immune system. Thus, DCs highlighted as
beneficial target generate therapeutic modality against tumor.
Immunotoxins against tumor
Immunotoxins are bifunctional molecules that can induce intracellular toxin activity to kill
the target cells via binding of antibody with specific antigen (25). In an approach,
Immunotoxins as adjuvant which binds with binding domains of monoclonal antibodies,
designed for Cell-targeted treatment. In this design, Monoclonal antibodies were able to
target hematopoietic differentiation antigens whereas immunotoxin have been shown to be
highly cytotoxic toward malignant cells. These therapeutic designed will likely play a
promising role in treatment of leukemia (26). The incidence of antitoxin antibodies
production in bodies after multiple cycles of treatment causes immunogenicity. There are
several approaches are under trial to reduce immunogenicity for the treatment of solid tumor.
Monoclonal Antibodies
The monoclonal antibodies are a promising part of immune system which recognize and
binds with foreign antigens expressed on the cell surface. After binding, they highlight them
for further action of destruction of abnormal cells via antibody dependent cellular
cytotoxicity (ADCC). In addition to other therapy, they are designed to enhance body’s
immune responses which assist to act against cell growth factors. The induction of adaptive
anti-tumor immune responses continues to hold for immunization against cancer.
There is a practice developing for the manipulation of antibody Fcγ domains to further
improvement of efficacy and affinity for Fcγ receptor (s) (27). Still alots of things needs to be
exploring about monoclonal antibody as therapeutic agent like as adjuvant, combination with
other molecules which can activate co-stimulation, CTLs activation or some interleukin
which will give varieties of ways to target and treat tumors in patients.
There are several therapeutic monoclonal antibodies against cancer approved in clinical trial
like, Rituximab (for Non-Hodgkins lymphoma), Ipilimumab (for melanoma), Trastuzumab
(for Breast Cancer), Bevacizumab (For Colorectal Cancer), Cetuximab (For Colorectal, Head
and Neck Cancer), Panitumumab (For Metastatic colorectal carcinoma), Brentuximab
vedotin (For Hodgkins lymphoma), Alemtuzumab (For Fludaribine – refractory chronic
lymphocytic leukemia) (28).
In addition to these, several approaches are under trial to increase the ability of antibodies to
elicit an anti-tumor immune response.
Cytokine Therapy
7. Cytokines are the important regulator of innate immune system: natural killer (NK) cells,
neutrophills and macrophages also rectify adaptive immune system with T and B cell
immune responses. Usually cytokine functions in cascade, so individual cytokine therapy are
not a promising therapy in present. To overcome these drawbacks, there are several trials
going for the combination of different cytokine to target a specific mechanism directly. These
findings provide evidence for the unique therapeutic opportunity based on selective
interference with the action of pro-inflammatory and tumor-promoting cytokines. It has been
established that cancer promotion and exacerbation are linked with the cytokines produced by
activated innate immune cells. Here we provide an overview of the updated understanding of
the role of inflammation-induced cytokines in development of novel therapeutic strategies
(Table 1).
Cell-based Immunotherapies of Cytokine
Cytokine function as autocrine and paracrine, so they function locally or any distant part of
body to enhance or suppress immunity. In cytokine therapy for cancer, cytokine uses to
induce ant-tumor immunity to fight against cancer. Here we will examine cytokines which
are currently under evaluation for cancer therapy.
Tumor Necrosis Factor - alpha (TNF – α)
In 1975, TNF-α was extracted from the serum of mice treated with ‘Coley’s toxin’ and later
on showed the hemorrhagic necrosis of mice tumor (29) , (30). Tumor necrosis factor – α
(TNF- α) is a pleiotropic cytokines involved in regulating diverse functions like apoptosis,
cell survival, tumorigenesis, autoimmunity, inflammation, and immune response via two
receptors i.e. TNFR1 and TNFR2 (31).
The interaction of TNF- α molecule with TNFR1 or TNFR2 receptor leads to the activation
of various signaling pathways in cell microenvironment (32). In an experiment when TNF-α
is administered via ILP (Isolated limb perfusion) into tumor cells, then it was bound with
TNFR1 soluble receptors on the cell surface (33). It is well known that TNFR1 is less in
count on cell surface which inhibit the cause of cytotoxicity. The effect of binding of TNF - α
to TNFR1 results in hyper permeability of the neoplastic vessels and strong extravasations of
erythrocytes resulting into massive hemorrhage and necrosis in tumor (34). This excessive
hemorrhage is responsible for the inhibition of tumor associated vasculature and the growth
of malignant cells. Several clinical studies have also reported that low dose of TNF - α may
induce these antitumor effects (35), (36).
In case of tumor microenvironment, tumor or inflammatory cells induce macrophages, T
lymphocytes and natural killer (NK) cells, which further harvest TNF-α, which induces
gene-encoding NF-κB dependent anti-apoptotic molecules and also promote the tumor cell
survival (37), (38). TNF-α further stimulate the production of genotoxic molecule Nitric
oxide and reactive Oxygen Species that can lead to DNA damage and reduce the antigen-
induced cytotoxicity or enhance the tumor progression through suppression of T cell
responses and cytotoxic activity of activated macrophages (39). Oxidative stress caused by
ROS and NO is a contributor to senescence, which could be an option for developing therapy
for tumor treatment. These studies indicate vast therapeutic applications of TNF-α in tumor
cell depletion.
8. Another attribute of TNF-α induces hemorrhagic necrosis in certain set of tumor types in
which synergistic antitumor effect of the combination treatment with TNF - α and
chemotherapeutic drugs as compared to TNF-α alone. (40). TNF - α effect during solid
tumor treatment cannot be caused by a direct cytotoxic or cytostatic effect toward the tumor
cells (41). However, cell death induction by TNF - α plays only small role in necrosis, but by
combination with Fas ligand, activation of NF-κB pathway which transcript the inhibitory
proteins that interfere with death signaling in tumor cells, can be an alternative blueprint for
developing therapy (42). These strategies of developing combined therapy are very relevant
to show the antagonistic effects of TNF-alpha against tumor growth. The same set up also
revealed that TNF-α improved the accumulation of chemotherapeutic drugs in tumor.
TNF-α super family represents an active target for drug development. Some of the approved
therapeutics are primarily either a soluble receptor which binds the circulating TNF- α and
prevent the interaction between TNF- α and cell surface receptors, or antibodies against TNF-
α. Various antagonist against TNF family have been approved like Golimumab (a humanized
TNF- α monoclonal antibody) (43), Certolizumabpegol (a PEGylated Fab fragment of a
humanized TNF antibody) (44) and still more are in the process of approval.
As described, members of TNF- α are involved in mediation of chronic inflammation, there
is a need to regulate the members of TNF- α family members however the role of TNF-β is
still elusive. In several medical cohort studies in United States in which cytokine was
delivered at appropriate concentration to the tumor site, there are no evidences of
enhancement of cancer growth associated with Tumor necrosis factor alpha antagonists TNF
therapy in either analysis or follow-up after the patients discontinued therapy (45). So there is
much left yet to be learned about TNF-superfamily, and we expect this information to be
forthcoming.
Of note, there is a need to develop a strategy to identify the patient stratification criteria for
the development of individualization of therapy. Therefore, research in the future should be
focus on not only recognizing integrated TNFL/TNFR-based combined immunotherapy but
also on the individualization of appropriate patient treatment.
Interleukin – 6
It is well established that innate and adaptive immunity released several pro-inflammatory
cytokines which contribute to tumor promotion and progression. It is a glycoprotein that
shows pleiotropic activity through binding with its transmembrane receptor (46).
Among these, the IL-6 receptor complex is a heterodimer structure which consist of IL-6Rα
and glycoprotein 130 (gp 130), that is reckon as key anti-inflammatory myokine, pro-
inflammatory cytokine, antiapoptotic and growth-promoting factor (47), (48). Experiments
based on link between inflammation and carcinogenesis entangled few constituents of
inflammatory avalanche such as IL-6 known for its key role in tumor growth and survival
(49). Other studies also revealed the multi-utility of IL-6 during chronic inflammation like it
induces Th17 cells and inhibits the differentiation of Tregs cells. During IL-6 signaling,
soluble IL-6 receptor (sIL-6R) secretion can induce IL-6 trans-signaling which further
promote the development of cancer cells. In addition, it has been suggested that shedding of
sIL-6R from carcinoma cell surface promotes the T cell survival and increase the production
9. of more IL-6 by T cells (50). Such theories suggested that opposing role of IL-6 might be
therapeutically useful for the treatment of colitis-associated colon cancer (CAC) (51).
The indefinite therapeutic methods have been developed for the treatment of disease
including anti-IL-6 or anti-IL-6R antibodies, soluble gp130Fc (sgp130Fc) and selective small
molecule JAK inhibitors which directly/indirectly inhibit the IL-6/STAT3 pathway that is
directly involved in sporadic and inflammation-associated CRC development (52) . The first
therapeutics targeting of IL-6/STAT3 pathway has been started in clinical studies through the
anti-IL-6 antibodies during the 1990s. However, these treatments only produced a limited
response. Another strategy to inhibit IL-6/STAT3 signaling is the inhibition of JAK
activation through ruxolitinib (53) and CEP-33779 i.e. JAK1 and JAK2 inhibitor could
successfully reduce tumor growth in clinical studies (54), (55). The studies of these arrays
can yield new insights on the effect of IL6/STAT3 deregulation.
All of the treatments mentioned above inhibit physiological functions of IL-6 through
inhibition of signaling which has been achieved by binding of sgp130Fc to IL-6 receptors
complexes (56).
It is mentioned in several studies that components of IL-6 signaling pathway such as IL-6, IL-
6R, JAK has been shown to promote tumor proliferation and anti-apoptotic effects in tumor
cells which can be proposed as promising target to achieve therapeutic effects (57), (58). IL-6
is not only involved in tumor growth is also related with the interaction within tumor
microenvironment which may also suggest a target for the development of novel IL-6
antibody based therapies like IL-6 inhibitors are being developed include human anti- IL-6R
Ab (Sarilumab/REGN88/SAR153191) (59), anti-IL-6R nanobody (ALX-0061), anti-IL-6
Abs such as sirukumab (CNTO 136), BMS – 945429 (ALD518), olokizumab (CDP6038),
and MEDI5117, and soluble gp130-Fc fusion protein (FE301) (60) which are in clinical
trials for different disease in human body.
In addition, Chronic inflammation causes DNA damage which has further shown affecting
several pathways including cell based homeostasis like cell-cycle regulation, apoptosis, DNA
repair (61). These conditions nourish the production of IL-6 in patients. However, attenuating
chronic inflammation with surgery, radiation and chemotherapy as well as combining these
therapies with IL-6 inhibition may be one of the ways to decrease inflammation and add
prognostic values to different methods (62).
Recent researches have concluded the potential for IL-6 as a prognostic factor. So there is
need of clinical studies to further evaluate potential which could help direct additional
treatment strategies in the future. However, additional studies and appropriate clinical trials
need to be done to make sure the effectiveness of anti-IL-6 therapeutic modalities in cancer
patients.
Interleukin-17
Recent studies on the role of different T cell subset named Th17 identified by the production
of IL-17 (IL-17A) as well as related cytokine IL-17F cytokine, explain as implication of IL-
17 in inflammatory responses primarily as a proinflammatory factor (63). IL-17A expresses
on tumor cells and develops antitumor immunity in immunocompetent mice which
suppresses tumor progression whereas in some cases it also enhances the angiogenesis in
immune-deficient mice which promote tumor progression (64).
IL-17 is induced by IL-23 that responds to the invasion of immune system and induces
destruction of foreign antigen cellular matrix. IL-17 is the signature cytokine of a unique
lineage of CD4+ T cells termed as Th17 and also known as a potent mediator in delayed-type
10. reactions by enhancing chemokine production throughout body to recruit immune cells to the
site of chronic inflammation (65). The properties of IL-17 like foreign antigen destruction,
induction of chemokine to the site of inflammation, synergistics action with TNF and IL-17
are very promising features to target it as a strategy against tumor reduction.
IL-17 also acts as an angiogenesis factor whose up-regulation may results in blockade of
angiogenesis in tumor and provokes the host inflammatory response to tumor progression
(66). The up-regulation of IL-17F includes modulation of cytokines regulating IL-17F
production (67) whereas blocking of IL-17A signaling may inhibit tumor angiogenesis but
sustains the risk of diminishing host antitumor response. Tumor endothelial marker 8 (TEM8)
expressed on human tumor vasculature is the main factor in promotion of angiogenesis (68).
The anti-TEM8 antibody can be used to inhibit the expression of TEM8 and it is also helpful
to segment the other anti-angiogenesis agent’s activity. By controlling the diminishing of
antitumor response and increase in the blockade of tumor angiogenesis by using the
synergistic effect of different anti-angiogenesis agent, it is possible to inhibit the growth of
tumor.
It is clear that IL-17 is skillful of exerting multiple effects within tumor microenvironment
with bidirectional effects in tumor growth, so further investigation should be approached with
a definite knowledge of complex interaction of IL-17 within the tumor microenvironment.
Therefore, we propose that there should be some novel inhibitory molecule and
immunomodulators mixed with these cytokine based therapy to achieve the beneficiary effect
in treating malignant solid tumors. Several studies are under progress to investigate the
relation, functions and involvement of IL-17F and IL-17A in tumor progression which
provide an unusual strategy for any therapeutic application of these cytokine in therapy for
cancer.
Interleukin-12 and Interleukin-23 (IL-12 cytokine family)
Both of these cytokine are the members of IL-12 cytokine family and can be released by
Antigen presenting cells (APC) like dendritic cells, macrophages, and human B-
lymphoblastoid cells into the inflammatory sites upon microbial infections (69). Recent
studies have shown that there are several similarities between IL-12 and IL-23 receptor
subunits and signaling but still they impel different immunological pathways and exhibit
different response towards tumor development. Research evidences has shown that IL-12
cytokine family members contain anti-proliferative and pro-apoptotic functions like IL-
12Rβ2 which could act as a tumor suppressor gene and IL-12R transfected B lymphoma cells
significantly deplete cell proliferation in animal models (70).
Although, it is well established that IL-23 enhance the production of TH17-mediated
response and induce IL-17 production which further promote end-stage inflammation (71),
whilst the proliferation of memory T cells and induction of IFN-γ are done by IL-12 which
play as a major role in exhibitions the antitumor immune response of IL-23 (72).
Interleukin-12 is a disulfide-linked heterodimer cytokine, composed of two subunits i.e. IL-
12p40 and IL-12p35 (73), (74), whereas another cytokine IL-23 is also an heterodimer
molecule composed of IL-12p40 and IL-23p19 subunits and both of these cytokines belongs
to the IL-12 family of proinflammatory cytokine (75). IL-12 binds to its heterodimer
receptors i.e. IL-12Rβ-IL-12Rβ2, whereas IL-23 binds an IL-12Rβ1-IL-23R heterodimer
(75). This heterodimer cytokine complex stimulate the expression of their receptors to
maintain the expression of several proteins involved in IL-12 based signaling pathways in
NK cells to enhance the cytotoxic activity.
11. IL-12 has been shown to exhibit antitumor activity through the immune-stimulatory effects
on certain T helper cells (Th1), as well as on cytotoxic T lymphocytes (CTL) and natural
killer (NK) cells (76), (77), (78). There are certain other cytokine like IL-1, IL-2, IL-15 and
tumor necrosis factor-α, which act synergistically with IL-12 to induce the secretion of IFN-γ
which exhibit direct toxic effect on tumor and antiangiogenic activity (77), (79), (80). This
type of enhanced functional response of IL-12 is demonstrated by IFN-γ production and
killing of target cells. As it is clear that IL-12 has the ability to induce anti-angiogenic
activity and immune system, there should be studies on using IL-12 as a possible anti-cancer
therapy.
Another synergistic property of IL-12 and IL-23 is that they both activate TYK2 and JAK2 as
well as STAT1, STAT3, STAT4 and STAT5, whilst IL-12 alone activates STAT4 efficiently
and IL-23 preferentially activates STAT3 (75). IL-23 has been known as a key factor
controlling inflammation in peripheral tissues which is mediated by induction of JAK/STAT
pathway following IL-23 binding.
As described above that IL-23 suppresses the innate immune response during tumor
progression and metastasis. Based on these hypotheses, IL-23 neutralization strategies may
promise to modulate immunosuppression in combination with immunostimulatory agents
(81). In an experimental study, α-IL-23 mAb has been given to wild-type mouse resulted in
fewer lung metastasis than in mice treated with control Ig (α-AGP3), which respond in the
form of NK cell-mediated antitumor immune response of α-IL-23 mAb (82). Collectively, the
use of α-IL-23 mAb in combination with IL-2 mAb treatment significantly inhibited
subcutaneous growth of established mammary carcinoma and suppressed established
experimental and spontaneous lung metastases.
In other trial studies, the anti-IL-23R treated mice displaced a significant reduction in the
number of tumor infiltrating Tregs compared with control antibody treated mice. These
studies exhibit another role of IL-23 driven STAT3 activation in tumor-infiltrating Tregs with
the addition of IL-23R dependent signaling pathway (83).
Since past 15 years, IL-12 cytokine family based therapies have acquired so much attention
and are apparently developing more effective therapy for the survival and treatment of
cancer-bearing patients (84). Of note, current studies postulated that over-expression of IL-
23R mainly suppress the expression of anti-apoptotic factor like Bcl-xL and induce the
intrinsic apoptotic pathways in 293ET and HeLa cell lines during trial (69). But tumor
immunosuppression still remains one of the major barriers in the development of novel
cancer therapies and vaccines. Several studies have been shown that initial stage of cancer
treatment, mAb neutralizing IL-23 alone and exerting a temporary effect. So there is a need
to target the combination of α-IL-23 mAb with other cytokine based antibodies to exert
potential effect in treatment of cancer.
Interleukin-10
Interleukin-10, also known as human cytokine synthesis inhibitory factor (CSIF), having a
pleiotropic effects in inflammation and immune-regulation which directly affect the function
of antigen-presenting cells by inhibiting the expression of MHC and co-stimulatory molecule
(85), (86). In 1989, Mosmann and his coworkers postulated that T helper 2 (Th2) cell clones
produced a cytokine which inhibit the synthesis of interferon (IFN) in Th1 cell clones (87),
and inhibit the NF-κB activation through ill-defined mechanisms (88) (89), is known as
interleukin -10 (IL-10). It is also known for the production of proinflammatory cytokine like
12. TNF-α, IL-6, and IL-12 (90) and down-regulation of the expression of MHC class II antigens,
co-stimulatory molecules on macrophages.
Several transcription factor responsive elements promotes the major source of IL-10 i.e.
macrophages to modulate the production of IL-10 through these exogenous and endogenous
factors such as endotoxin via Toll-like receptor, tumor necrosis factor (TNF) , catecholamines
and cAMP-elevation drugs via protein kinase A (91), (92), (93), (94), (95), (96). In contrast
to these observations, IL-10 produced by B-cell lymphoma functions as an autocrine growth
factor (97). These previous mentioned reports concluded that IL-10 production within the
tumor microenvironment is a common phenomenon in cancer metastasis which might be the
major hurdle for anticancer immunotherapy such as cancer vaccines. In case of metastatic
melanoma patients, it was reported that high IL-10 production were used for synthesis of
homologous melanoma cell vaccine estimated fewer survival after vaccine treatment (98).
In another trial, anti-IL-10 antibody treatment has been administered in two mouse models of
acquired hepatitis (99). This study revealed that IL-10 plays a protective role down regulating
the expression of several other inflammations causing cytokine including IL-12, TNF-α and
INF-γ (100).
IL-10 is able of affecting the tumor cells and inhibiting the immune cells which may convert
tumor cells to a CTL resistant phenotype. Kiessling and his coworkers reported that IL-10
treatment results in 50% reduction of expression of MHC class-I in human melanoma cells
and 100% inhibition of CTL-mediated lysis of tumor cells (101). The consequence of IL-10
has been demonstrated in transgenic mice by uncontrolled growth of immunogenic tumors
because of the blockade of the antitumor immune reaction. The anti-IL-10 antibodies
treatment thus reinstates the anticancer response (102).
Several studies conducted on Systemic Lupus Erythematosus (SLE) patients concluded that
treatment of anti-IL-10 antibody to SLE-patients results in the lessening of autoantibody
production due to the depletion of IL-10 (103). Some other experimental models suggest that
IL-10 may retain antitumor response and immune stimulation (104), (105) like transfection of
mouse melanoma cell lines with IL-10, extorts induced immunogenicity following a strong
lymphocyte and antibody-dependent immune memory (106).
Additionally, IL-10 induces the production of Treg cells (107), (108). So rather than giving
anti-IL-10 therapy alone, it is suggested that a combination of anti-IL-10 antagonist with
other immune-stimulants such as cancer vaccines, other cytokine will be more synergistically
effective in inhibiting the tumor-specific immune tolerance and promoting antitumor immune
responses. It suggests that balance of IL-10 should be maintained to regulate the immune
response against any infection in body. These trials give new insights to the IL-10
immunobiology to become a new therapeutic target.
In contrast, complex effect of IL-10 may cause reduced potency of treatment depending upon
IL-10 rather than promising effect of other combined approaches. Given the overall outcomes
of systemic IL-10 therapies of disease, it has become apparent that future studies on the
sources of IL-10 and kinetics of IL-10 production may lead to the identification of new target
with better therapeutic efficiency and also facilitates the development of treatment strategies
aimed at regulating inflammation. These studies will have to understand the details of
circulating levels of cytokines and their gene variations inside the patients which will assist in
development of therapy with defined parameters of treatment side effects.
These above proclamation about IL-10 cytokine revealed the utility as an essential
immunoregulatory which favorably react toward different treatment, evaluating the assistance
13. of IL-10 for counteracting the inflammatory effects in the human body. The generalized
therapeutic effect of IL-10 in cancer treatment is hard to predict as both tumor-suppressive as
well as tumor-promoting effects have been demonstrated. Since, IL-10 is produced in
metastatic stage of cancer, it insinuate more equitable to clock the effects of IL-10, rather
than administrating IL-10 to cancer patients. These features can assist in the development of
recombinant therapy for several diseases.
TGF-β
TGF-β is known as a secreted polypeptide skillful of inducing fibroblast growth and collagen
fructification which was further discovered as a pervasive and essential key regulator of
proliferation, differentiation, migration, cell survival, cell survival, angiogenesis and
immunosurveillance (109), (110), (111). Tumor progression is stimulated by TGF- β by two
mechanisms: firstly intrinsic activity and, another extrinsic activity (112).
During the growth phase of tumor, excessive amount of TGF-β is produced whereas in
normal epithelial cells, it is known as a potent growth inhibitor. Normally, TGF- β blocks the
G1 stage of normal cells to regulate the balance of growth in body but when a cell is
transformed into a malignant cell TGF- β signaling pathway is altered and it losses the
control on cell growth resulting into cancer and surrounding cells escalated the production
and increase in their own TGF- β which acts on microenvironment (113). It causes
immunosuppression and angiogenesis, which makes the malignant cells violent.
TGF-β has the dichotomous function in human cancers. First it is having the capability to act
as a tumor suppressor (via its effects on replication, proliferation, and apoptosis) and another
as a tumor promoter (via its effects on progression, metastasis, invasion and angiogenesis)
(114). So profiling of TGF-β ligand (in serum, urine, and tissue), TGF-β receptor levels and
TGF-β mRNA (in tissue) may serve as a diagnostic and therapeutic tools for cancer
treatment.
It is predicted that strategies such as inhibition of signaling pathway, monoclonal TGF-β-
neutralizing antibodies, large molecule ligand snare, lowering translational efficiency of
TGF-β ligand by antisense technology and estranging TGF-β receptor I/II kinase function by
inhibitor molecule which are the most conspicuous methods being investigate these days
(115), (116). For example, first is the utilization of soluble TGFIIR (human α2-
macroglobulin) plasma protein that binds TGF-β isoform, blockade the interaction between
cytokine and its receptor (117) and two other TGF-β1 and TGF-β2 specific humanized
monoclonal antibodies like CAT-192 and CAT-152 respectively, are going under clinical trial
for cure of fibrosis and their development will embolden the therapeutic application to anti-
cancer therapy (118), (119).
Antisense TGF-β treatment in a variety of cancer has also been delineating the response in
the form of reactivation of number of different therapeutic scope. In addition, it has been
shown that combined treatment with tumor cell vaccines and antisense TGF-β therapy or
monoclonal antibodies therapy respond synergistically and downsize the tumor volume and
escalate the survival benefit (120), (121), (122).
Now it is well known that increased quantity of TGF-β has superlative role in tumorigenesis
due to reprogramming of immune surveillance which makes it a very advisable target for
different therapeutic modalities like monoclonal TGF- β antibody, antisense oligonucleotide
or receptor kinase inhibitors. From different outcome of studies, it is revealed that continuous
14. suppression of TGF- β signaling pathway may lead to harmful off-target effect. So there is a
need to focus on combined therapy with these inhibitors for the therapeutic profit in future.
There are three leading therapeutic targeting of TGF- β in clinical trials: TGF-B antibodies,
antisense oligonucleotide, and receptor kinase inhibitors. These all strategies have their own
limitations. So it is necessary to reengineer the TGF- β inhibitors within a combinational
therapy.
Of note, it is known that increased level of TGF-β in tumor microenvironment induce the
tumorigenesis through various processes, thereby making it possible to target these for
therapeutic development. Conclusively, the precise mechanisms involved in transformation
of TGF-β during malignancies needs to be deeply understood only. After that, it will be
possible to prosper successful therapies as well as provide new therapeutic targets to fix the
normal TGF-β function.
Conclusion
We have sought here to revisit, refine, and extend the concept of therapeutic targeting of
cytokine, which has provided a useful conceptual framework for understanding the complex
foundation of cancer biology. Advancement of role of cytokines in immune and
inflammatory diseases has promoted the development of cytokine-based therapies. Cytokine
therapies have tremendous capabilities for treating a variety of diseases either by inhibiting or
restoring the activity of specific cytokines. As cancer is caused due to an alteration in cellular
programming, cytokine therapy is the one best choice to treat cancer. However, as cancer is a
part of the wound healing process, single cytokine therapy may not be effective. This might
increase the likelihood of cancer recurrence and development of alternate signaling pathway
to facilitate tumor cell growth. So it is necessary to work on dominant module in modern
immunologic research, which is the illustration of commutative effect of different cytokine
therapies. One of the approaches is known as Gene therapy as they enable therapy to restrict
to tumor cells only which will decrease the side-effect and increases the efficacy of therapy.
As prescribed above, several studies indicate the role of combined cytokine therapy like the
combination of TNF-α and IL-6, it is evident that IL-6 signaling embellished the protraction
of TNF-α, this interference restrict tumor progression and IL-6 production.
IL-23 induces IL-17 production which further endorses end-stage inflammation whilst the
rise of memory T cells and induction of IFN-γ are made by IL-12 which serves as a foremost
role to reveal the antitumor immune response of IL-2. As previously revealed that IL-12
based therapy is more valuable with smaller tumor burden, so there is a need to investigate
the role of combination of IL-10 with other therapy as an adjuvant to get more effective
therapeutic effects. The contribution of CD4 T cells, CD8 T cells, and IFN-γ and NK cells in
induction of antitumor effect of IL-12 therapy is still unclear and itmay give a better
opportunity to investigate the role of combined therapy in treatment.
Through the rapidly growing research of intricate signaling system of different cytokines,
new effective therapies have become available to treat oncology patient like blocking or
neutralizing cytokine action with monoclonal antibodies and one of the drugs that inhibit
release of inflammatory cytokines, such as tumor necrosis factor-α (TNF- α). It is thus
predictable that new combined therapies of cytokine which are based on innovative
technologies will progressively reach the efficacy of new cancer treatment strategies. In some
cases, the cure afforded of by these cell based cytokine therapies may prove to be even more
effective than chemotherapies and other traditional treatment methods.
15. In my vision, I can foresee the limitative single cytokine therapy being overcome by the help
of combined cytokine therapy along with gene therapy.
What do we expect in the future?
Combined immunotherapy may be the next great hope in the treatment of cancer. Several of
these trials have shown impressive clinical results signaling that we are in the entry and
exciting phase of cancer treatment. It is likely our responsibility to combat cancer from all
fronts. Additional studies required to define the mechanism of cytokine cascade in body
which will help to reduce the opposite effect of therapy and make it specific for every cancer
type. One of the hurdles have been identified, i.e. immunogenicity, which may be resolved by
depleting or suppressing T and B cell epitopes. At present, nonspecific and specific
immunotherapy combination showing promise for another potent strategy for treatment.
Even, the effect of any aforementioned therapy module in combination with some traditional
cancer treatment method is another avenue, as it is come out in trial in terms of duration /
remission period with cytokine and chemotherapy.
All through with these concerted efforts, our decisive ambition may be a long-lasting anti-
tumor immune response that can be maintained throughout patient’s lifespan.
…………………………………..
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