The document discusses the innate and adaptive immune systems. It provides details on key components of the innate system, including phagocytes and pattern recognition receptors. The adaptive system involves T and B lymphocytes that develop antigen-specific memory. Mechanisms of antigen presentation by MHC I and II are described. Immunotherapies seek to overcome tumor immunosuppression and induce anti-tumor responses by the immune system.
In this presentation, I discuss a new standard of treatment in cancers which is immunotherapy. I also discuss the few cancers for which it has been approved.
Immuno-Oncology: An Evolving Approach to Cancer Care
Review a downloadable slide deck by Thomas F. Gajewski, MD, PhD, covering the most clinically relevant new data reported from Immuno-Oncology: An Evolving Approach to Cancer Care.
Target Audience
This activity is designed to meet the educational needs of oncologists and other healthcare professionals involved in cancer care.
Format: Microsoft PowerPoint (.ppt) | File size: 26.2 MB | Date posted: 6/20/2012
Slide Deck Disclaimer
This slide deck in its original and unaltered format is for educational purposes and is current as of June 2012. All materials contained herein reflect the views of the faculty, and not those of IMER, the CE provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should not rely on this information as a substitute for professional medical advice, diagnosis, or treatment. The use of any information provided is solely at your own risk, and readers should verify the prescribing information and all data before treating patients or employing any therapeutic products described in this educational activity.
Usage Rights
This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published in print or electronically as a promotional or certified educational activity without prior written permission from IMER. Additional terms may apply. See Terms of Service on IMERonline.com for details.
Studying the Adaptive Immune Response - Tools for T & B Cell Research: Host D...QIAGEN
Adaptive immunity, powered by T cells and B cells, provides specific, long-lasting protection of the host from harmful invaders. This slidedeck provides an overview of T cells and B cells and their role in cell-mediated immune responses and antibody responses, respectively, against pathogens. There is also information on tools that enable analysis of T and B cell gene expression and regulation, genotyping and signal transduction pathway activation.
In this presentation, I discuss a new standard of treatment in cancers which is immunotherapy. I also discuss the few cancers for which it has been approved.
Immuno-Oncology: An Evolving Approach to Cancer Care
Review a downloadable slide deck by Thomas F. Gajewski, MD, PhD, covering the most clinically relevant new data reported from Immuno-Oncology: An Evolving Approach to Cancer Care.
Target Audience
This activity is designed to meet the educational needs of oncologists and other healthcare professionals involved in cancer care.
Format: Microsoft PowerPoint (.ppt) | File size: 26.2 MB | Date posted: 6/20/2012
Slide Deck Disclaimer
This slide deck in its original and unaltered format is for educational purposes and is current as of June 2012. All materials contained herein reflect the views of the faculty, and not those of IMER, the CE provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should not rely on this information as a substitute for professional medical advice, diagnosis, or treatment. The use of any information provided is solely at your own risk, and readers should verify the prescribing information and all data before treating patients or employing any therapeutic products described in this educational activity.
Usage Rights
This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published in print or electronically as a promotional or certified educational activity without prior written permission from IMER. Additional terms may apply. See Terms of Service on IMERonline.com for details.
Studying the Adaptive Immune Response - Tools for T & B Cell Research: Host D...QIAGEN
Adaptive immunity, powered by T cells and B cells, provides specific, long-lasting protection of the host from harmful invaders. This slidedeck provides an overview of T cells and B cells and their role in cell-mediated immune responses and antibody responses, respectively, against pathogens. There is also information on tools that enable analysis of T and B cell gene expression and regulation, genotyping and signal transduction pathway activation.
THIS SEMINAR HAS BRIEF ABOUT T CELLS , TYPES, FUNCTIONS, CLUSTER OF DIFFERENTIATION, MHC MOLECULE, TOLERANCE , ROLE OF T CELLS IN PROGRESSION AND PREVENTION, T CELL IMMUNODEFICIENCY DISORDERS
Immunity is the ability of the body to defend itself against disease-causing organisms.
The immune system refers to a collection of cells, chemicals and processes that function to protect the body from foreign antigens, such as microbes (organisms, such as bacteria, fungi, and parasites), viruses, cancer cells, and toxins.
The structural and chemical barriers which protect us from infection, the immune system can be classified into two “lines of defense”: innate immunity and adaptive immunity
Introduction
History
Types of immunity
Tissues of immunity
Cells of immunity
Basic aspects of immunology
Major histocompatibility complex
Cytokines
Disorders of immune system
Immune responses in periodontal pathogenesis
Periodontal vaccine
Host modulation
Conclusion
References
Immune System - The immune system is a complex network of cells and proteins that defends the body against infection.
The immune system keeps a record of every microbe it has ever defeated so it can recognize and destroy the microbe quickly if it enters the body again.
Abnormalities of the immune system can lead to allergic disease, immunodeficiencies and autoimmune disorders.
Antigen - Any factors or agents that can enter the body and create an immune response are called antigen.
Formation of immune cells - Immune cells are produced by hematopoietic stem cell in bone marrow
Hematopoietic stem cells are self-renewing and reside in the medulla of the bone ( bone marrow ).
HSCs are divided into two main lineages, lymphoid progenitor cells or myeloid progenitor cells.
Myeloid cells - Neutrophil, Eosinophil, Basophil, Mast cells, Monocyte, Macrophage, Dendritic Cell
Lymphoid cells - B Lymphocytes,
T Lymphocyte, NK Cells
Antigen presenting cells - Professional antigen presenting
cells : Macrophage, Dendritic cell, B Lymphocyte
Non professional antigen presenting cell: Non-professional antigen presenting cells include all nucleated cell types in the body.
Proteins of immune system - Set of serum proteins that co-operate with both Innate and adaptive immune system to eliminate blood and tissue pathogen.
Organs of immune cells - Spleen, Lymph node, Tonsils , MALT, Bone marrow, Thymus
Types of immunity -
Innate Immunity: Innate immune response is in born and is the first line of defense against pathogen
Adaptive immunity: Antigenic specificity. It have immunological memory
Immune Receptors - It is a specialized structures found in the cell membrane. They are mainly composed of proteins, which bind to pathogens and causes a response in immune system
This is a powerpoint presentation on the Topic of Diseases of the immune system, part 1 - Chapter 6, based on Robbin's textbook of pathology. Prepared by Dr. Ashish Jawarkar, who is Assistant professor at Parul institute of medical sciences and research, Vadodara. Please subscribe to our youtube channel https://www.youtube.com/channel/UCwjkzK-YnJ-ra4HMOqq3Fkw . Our facebook page: facebook.com/pathologybasics. Instagram handle @pathologybasics
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
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
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
MANAGEMENT OF ATRIOVENTRICULAR CONDUCTION BLOCK.pdfJim Jacob Roy
Cardiac conduction defects can occur due to various causes.
Atrioventricular conduction blocks ( AV blocks ) are classified into 3 types.
This document describes the acute management of AV block.
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
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.
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.
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
2. • Innate immune system is absolutely
indispensible for survival
• Comprised of both cellular and acellular
components
• CO-ORDINATES the ADAPTIVE SYSTEM
• Direct effects on pathogens: Phagocytosis,
lysis
3. Innate Immune System
• First line defense;
response is the same
each and every time (no
memory)
• Phagocytes:
Neutrophils, monocytes
& macrophages
• Natural killer (NK) cells
4. System / Organ Active component Effector mechanism
Skin Squamous cells , Sweat Flushing , organic acids
Serum Lactoferrin and Transferrin Iron binding
Serum IFN
TNF-alfa
Lysozyme
Fibronectin
Complement
Anti-viral proteins
Anti-viral phagocyte activation
Peptidoglycan hydrolysis
Opsonisation and phagocytosis
Opsonisation, phagocytosis and
inflammation
6. Innate Immune System
• First line defence; response is the same each
and every time (no memory)
• Non-specific: although can detect the
difference between self and non-self!
• Innate immune cells recognise
PathogenAssociated Molecular Patterns via
pattern recognition receptors
• TOLL-like receptor family considered to be the
primary sensors of pathogens
8. Monocyte/ macrophage
• Play a major role tissue repair, clearance of
apoptotic cells and necrotic debris
• Potent APCs (antigen presenting cells)
9.
10. Natural Killer cell
• Activation of NK cells
depends on the balance
of stimulatory and
inhibitory signals. The
Killer Inhibitory
Receptor (KIR) searches
for MHC-I (present on
virtually all nucleated
cells) – ligation of the
KIR with MHC-I
prevents cell death
• NK cells generally
require signals from
accessory cells for
activation – these can
be soluble factors i.e.
proinflammatory
cytokines IFNα/β, IFNγ,
TNFα, IL-12 or contact
dependent signals such
as NKG2D
11. Phagocytosis
• Innate cells such as neutrophils, macrophages
and dendritic cells are highly phagocytic and
can engulf free bacteria/virus and whole cells
that are either infected or
• The formation of a phagylysosome acidifies
the contents and leads to proteolytic
degradation of the pathogen
14. Adaptive Immune System
• Comprised of T and B lymphocytes: both
derived from the bone marrow
• Cells do not rely on recognition of pathogen
associated molecular patterns like the innate
system
• Express receptors that can differentiate
between self and non-self by sequence-
specific recognition of antigen
15.
16. T cells
• Cytotoxic T cells (TC , CD8+ ): effector immune cells
that can identify and kill infected / neoplastic cells
• Helper T cells (TH , CD4+ ): produce cytokines that
can promote CD8+ (e.g. IL-12) or B cell activation
and function (e.g. IL-4)
• Regulatory T cells (Treg, CD4+CD25+FOXP3+ ):
mediate peripheral tolerance of CD8+ T cells
through production of both soluble factors e.g.
TGFβ or cell-cell contact e.g. CTLA-4
17. Adaptive Immune System
• Comprised of T and B
lymphocytes: both derived
from the bone marrow
• Specific and can differentiate
between infections agents
e.g. HSV/HPV
• Adaptive Immune System
Adaptive: ability to ‘learn’
and respond more efficiently
during subsequent infections
>> Immunological Memory
19. Key concept - Clonality
• Each lymphocyte is specific for a restricted
number of antigens
• Specificity is developed randomly - many
lymphocytes never encounter an antigen
• During a primary response few cells are
specific (perhaps ~1/50,000-1/100,000)
• Antigen specific cells divide and produce
effector and memory populations
• ~50% of all T cells in adults memory, the result
of previous antigen exposure
20. What are T cell antigens?
• T cell antigens are peptides typically 9 - 12 amino
acids in length
• Recognition is sequence specific
• Bound in the groove of an antigen-presenting
Major HistoCompatibility antigen
• Antigens are presented by specialised antigen
presenting cells (APC)
• T cells require the capacity to respond to non-self
but must be tolerant of self antigens (or will
produce autoimmunity)
21. T-Cell Receptor-MHC Interaction
• TCR does not recognize
MHC antigens alone
• The TCR sees both MHC
and the peptide complexed
with it
• The whole complex defines
a TCRs specificity
• If the combined affinity
(1+2+3) is above a certain
value the T-cell is activated
and can perform its
effector functions
22. The Major Histocompatibility Complex
• Region on the short-arm of
chromosome 6
• Contains the genes for many
proteins of importance for
the immune response
• Of primary relevance for T
cell immunity are the human
leukocyte antigens (HLA);
these are sometimes called
MHC antigens Class I: HLA-A,
HLA-B, HLA-C Class II: HLA-
DR, HLA-DP, HLA-DQ
• Each person expresses 2
variants of each antigen; HLA-
type
23. MHC Polymorphism
• Class I MHC Molecules -
HLA-A
n = 893
• HLA-B
n = 1,431
• HLA-C
n = 569
• Σ= 3,007 alleles
• Class II MHC Molecules
HLA-DR (A + B chain)
n = 817
• HLA-DP (A + B chain)
n = 164
• HLA-DQ (A + B chain)
n = 141
• Σ= 1,154 alleles
24. MHC class I binds intracellular peptide
antigens
• MHC-I presents viral /
mycobacterial / self & mutated
peptides
• MHC class I (MHC-I) is expressed by
virtually all nucleated cells
• Antigens are processed into
peptides in the
immunoproteosome and shuttled
into the ER via the transporter
associated with Ag processing (TAP)
• Peptides are loaded onto MHC-I
and can present antigen only to
CD8+ T cells
25. MHC class II binds extracellular peptide
antigens
• MHC class II (MHC-II) presents
exogenous antigens following
phagocytosis
• Expression of MHC-II is restricted
to professional Antigen Presenting
Cells (APC)
• Antigens are processed in through
the endolysosomal pathway and
loaded onto MHC-II
• Peptides bound to MHC-II can
present antigen only to CD4+ T
cells
26. MHC class II binds extracellular
peptide antigens
• MHC class II (MHC-II) presents
exogenous antigens following
phagocytosis
• Expression of MHC-II is restricted to
professional Antigen Presenting Cells
(APC)
• Antigens are processed in through the
endolysosomal pathway and loaded
onto MHC-II
• Peptides bound to MHC-II can present
antigen only to CD4+ T cells
• Professional APC can also load
exogenous antigen onto MHC-I for
presentation to CD8+ T cells
28. Review of Antigen Presentation
• MHC-I is present on virtually all nucleated cells
permitting CD8+ T cells to scan intracellular
antigens and identify / kill infected cells and those
expressing altered self peptides
• T cell activation requires 2 simultaneous signals TCR
- MHC Co-stimulation e.g. CD28 (T cell) – CD80/86
(APC)
• Not all cells can license T cell activation - Most
efficient 3. APC is the Dendritic Cell
• Once activated, T cells can mediate cytotoxicity
through a variety of mechanisms e.g.
perforin/granzyme
29. The Dendritic Cell (DC)
• Immature DC Non Stimulated
DC (Day 10 of Culture x40)
• Mature DC Stimulated with
1.25x105 cfu/ml of BCG (Day 10
of Culture x40)
30.
31. • In addition to being APCs, Dendritic Cells express a
diverse array of cytokines/chemokines that
influence the intensity and phenotype of the
nascent immune response
32. 435 immune-based clinical trials currently open in oncology
(27/10/15 NCI database search term ‘immunotherapy and
cancer’)
33. Immunotherapeutics- Objectives
• To consider the role of the immune system
during cancer initiation and progression
• Consider the processes that lead to immune
failure in the control of neoplastic disease
• To review some of the different
immunotherapeutic approaches being
developed in oncology
34. Immune system has 3 primary roles in
tumour prevention
1. Elimination of virus’s that drive neoplasia
2. Resolution of acute inflammation (i.e. to pathogens) to prevent
a chronic inflammatory environment that can directly influence
neoplastic transformation
3. Identification and elimination of transformed cells
35. This study in colorectal cancer characterised the
tumour-infiltrating immune cells in large cohorts
of patients by gene expression and in situ
immunohistochemistry. Data paired to long-
term outcome
36. • 415 patients assessed by IHC for CD3 infiltration
Tumour infiltration by CD3+ T cells predicts OS
42. Immunoediting Model of Cancer
Development - Evidence for Escape
• Tumours may evolve by a Darwinian-selection
mechanism to circumvent the immune response or
may induce local immuno-suppression…. or both?
• When a immune cell recognises a foreign antigen
(i.e. viral/bacterial peptide) the result is normally
activation
• But when the immune system ‘sees’ a tumour cell
the result is often anergy or tolerance
• To launch an anti-tumour immune response we
must first break tolerance - Without eliciting an
auto immune disease!
43. • M2 macrophage: Express TGFβ, PGE2 , IL-10, IL-4
contribute to suppression of effector T cell
function and support Treg / tolerogenic DC
Differentiation. Express Indoleamine deoxygenase
(IDO) and Arginase (Arg)
• As for Tumour Associated Macrophage but also
expresses high levels of reactive oxygen species
that can modify the TCR
• Express TGFβ. Also express high levels of IL-2
receptor and can sequester available IL-2
depriving effector T cells of survival signal. Can
express CTLA-4 and LAG-3 which are negative
regulators of DC function.
• Express TGFβ and other suppressive cytokines.
Present antigens on class I and II MHC but in the
ABSENCE of co-stimulation
44. Tumour cells can drive immunological
tolerance
• Tumour cells actively induce tolerance – Loss of
MHC expression
• Up-regulation of inhibitory molecules e.g. PD-L1,
CTLA-4 >TNFα, IL-1β –normally associated with
infection and cellular stress, ischaemia > Low level
of damage-associated molecular patterns (DAMPs)
• Sterile environment i.e. no pathogen associated
molecular patterns (PAMPs).
• Also lack of ‘danger’ signals e.g. Heat shock
proteins, Inflammatory factors
45. Tumour cells can drive immunological
tolerance
• Tumour cells can
produce
immunosuppressive
factors e.g. TGF-b, IL-10,
PGE2 , IDO
(indoleamine
deoxygenase), arginase
• Many of these are
targets for
immunotherapy
48. Immunotherapeutic Strategies
1.Therapeutic vaccination
• Various strategies employed e.g. Autologous DC-
based vaccines, Allogeneic tumour cell vaccines,
recombinant viral vectors delivering Tumour
associated antigens (TAAs +/- costimulatory
molecules), oncolytic virus’s
2.Targeting co-stimulatory / co-inhibitory pathways
– Targeting immune checkpoints
• Specific agonists i.e. TLR-ligands
• Antagonists i.e. αCTLA-4, αPD-1 / αPD-L1
49. Dendritic cell-based cancer vaccine –
Provenge
• First ever cancer vaccine to achieve FDA approval (April
2010) for metastatic castration resistant prostate cancer
• Tumour antigen: Prostatic acid phosphatase, expressed in
the prostate and elevated in cancer. This is linked to
Granulocyte Macrophage Colony Stimulating Factor (GM-
CSF) stimulating DC maturation
50. Dendritic cell-based cancer vaccine –
Provenge
• Phase III IMPACT trial in asymptomatic or minimally
symptomatic metastatic Castration-resistant
prostate cancer – Patients received either
Sipuleucel-T q2w x 3 or placebo
51. Targeting immunological checkpoints
• Numerous options for
investigation!! These are
the various ligand/receptor
interactions between an
APC and a T cell
• CTLA-4
• B7-H1 (PD-L1)
• PD-1
• TLRs (TOLL-like receptors)
55. • 62% 1 year survival, 43% 2 year
survival
• Median response duration in patients
with objective tumour regressions (31%)
was 2 years
• 71% of patients maintained responses
following treatment discontinuation
61. • Phase 2 study in first line
• Response rates were 61%
for ipi/nivo combination vs.
11% for ipi alone
• CR in 22% of combined
group and 0% for ipi alone
• Grade 3 or 4 AE’s reported
in 54% in combined
therapy vs 24% for ipi
alone
• This led to 38% and 13%
patients with grade 3 or 4
AEs discontinuing therapy
66. Preclinical tool compound
• R848: selective murine
TLR7 agonist (also hits
TLR8 in man) - a more
potent analogue of
Imiquimod (which is
approved for topical
treatment of BCC and
genital warts)
69. • Patients had low-grade B-
cell lymphoma (relapsed)
n=15 • Low-dose RTx was
administered to a solitary
tumour site (2x2Gy
fractions) • CpG (PF-
3512676; Pfizer) 6mg
intra-tumoural
immediately before the
first radiation dose, after
the second dose and q1w
x 8
70. Intratumoural vaccination induces objective clinical
responses
A) Complete response in
patient 3, treated site:
occipital; visualized site:
bilateral axillae.
B) Partial response in
patient 10, treated site:
suprasternal cutaneous;
visualized site: supra-
orbital cutaneous
71. Conclusion
• Targeting one molecule / pathway is not enough for
therapy due to redundancy in pathways
• Combination may be key to tackle overlapping layers of
immunosuppression
• »i.e. with adoptive T cell therapy, multiple checkpoint
blockade and/or non-myeloablative therapies i.e.
Radiotherapy
• Need for a personalized approach
• –Biomarker assays that can predict responders/non-
responders
• –Patient selection criteria