about Cancer immunoediting and immunotherapy in cancer that targets and boosts immune system.

1. DR.P. SANTOSH
GENERAL MEDICINE-FIRST YEAR RESIDENT

2. TOPICS UNDER DISCUSSION
1. Introduction
A. Nomenclature.
B. Fundamental and Shared Characters of Cancer
C. Hallmarks of Cancer
2. Cancer and Immune system.
A. Immune response against cancer cells
B. Cancer Immunoediting
C. Tumour Antigens
D. Evasion of Immune surveillance
3. Immunotherapy in Treatment of Cancers.

3. INTRODUCTION
Cancer is the second leading cause of death in USA.
It is not one disease but rather many disorders that share a profound growth
dysregulation.
That is why it is difficult to answer questions regarding the cure for cancer.
Only hope in controlling the cancer is learning more about its pathogenesis .
For example, Hodgkin lymphoma is highly curable cancer where the
pathogenesis is well known.

4. A. NOMENCLATURE
Cancer-Literally means "Crab". given by Hippocrates. Now used routinely for
malignant tumour.
Neoplasia-Literally means "New growth"
Epigenetics- The study of changes in organisms caused by modification of
gene expression rather than alteration of the genetic code itself. [Chemical
modification of specific genes or gene-associated proteins of an organism].
• Eg:Increased DNA Methylation,alteration in Histone modifications.
Mutations-Alteration in genetic code or sequence.
• Eg:Replacement of Adenine for (A) for Guanine(G).
Contd.....

5. Driver Mutation
• Mutations that alter the function of cancer genes and thereby
directly contribute to the development or progression of a given
cancer.
• "Cancer is a disorder that is caused by Driver mutations in
Oncogenes and Tumour suppressor genes."
Passenger Mutation
• Acquired mutations that are neutral in terms of fitness(doesn't
determine the cancer) and do not affect cellular behaviour(No
change in Phenotype).
• These are acquired during somatic evolution of cancer due to high
genomic instability and high mutation rates.

6. B. FUNDAMENTAL AND SHARED
CHARACTERISTICS OF CANCER
1. Cancer is genetic disorder caused by DNA mutations/Epigenetic alterations.
Genetic and epigenetic changes alter the expression or function of key genes that regulate the
fundamental cellular processes(Growth, survival, and Senescence).
2. Genetic alterations in cancer cells are heritable.
all tumours are clonal.
These mutations provide the growth or survival advantage and outcompete their neighbours
and dominate the population.
Darwinian Selection (Survival of Fittest) shapes the evolution of cancer by emergence of the
genetically distinct subclones with more aggressive characteristics(K/as Progression).
3. Mutations and epigenetic alterations impart to cancer cells a set of properties that
are referred to collectively as "Cancer Hallmarks."
These properties produce cellular phenotypes that dictate the natural history of cancers and
their response to various therapies.

7. C. HALL MARKS OF CANCER
All cancers display 8 fundamental
changes in cell physiology, which are
considered "Hallmarks of cancer".
1. Self-sufficiency in growth signals.
2. Insensitivity to growth-inhibitory
signals.
3. Altered cellular metabolism
4. Evasion of apoptosis
5. Limitless replicative
potential(Immortality).
6. Sustained angiogenesis
7. Invasion and metastasis
8. Evasion of immune
surveillance

9. Paul Ehrlich (1909) is the first one to say that Cancer cells are treated as "Foreign"
and eliminated by immune system.
Subsequently,Lewis Thomas(1959) and Macfarlene Burnet(1957) formalised this
concept by coining term "Immune Surveillance".
• Based on the premise that immune system constantly scan body for emerging
malignant cells and destroy them.
This concept is supported by
• Detection of tumour specific T cells and antibodies in patients;
• Extent and quality of immune infiltrates in cancers often correlates with
outcome;
• Increased incidence of certain cancers in immunodeficient people and mice;
• most recent and most directly,the dramatic success of immunotherapy in the
treatment of several cancers.

10. EFFECTIVE IMMUNE RESPONSE
AGAINST TUMOUR ANTIGENS
Immune reactions to cancers are initiated by the death of individual cancer cells
[Damage Associated Molecular Patterns(DAMPs)].
DAMPs stimulate innate immune cells (Resident Phagocytes and APCs like dendritic cells).
These cells (mostly dendritic) phagocytose the dead cancer cells ,migrate to draining lymph
nodes and present tumour neoantigens in context of MHC class I molecules.
Displayed tumour antigens are recognised by Antigen-specific CD8+ T cells(Tc).
These CD8+ become activated,proliferate,differentiate into active Tc cells.
Activated Tc cells migrate to the site of tumour,recognise the tumour cells presenting
neoantigens in context of MHC class I molecules and kill them.

11. Tc cells responses are the most important
defence that host has against tumours.
Human Tumours with high levels of
infiltrating Tc cells and Th1 cells correlate
with better clinical outcome ,when compared
to other cells like NK cells which have been
implicated in anti-tumour responses.
The quality and strength of Tc cell responses
are believed to be of Preeminent importance.

13. Osias Stutman put this hypothesis of cancer immmunosurvilence to the
experimental test no data were obtained to support that.
Methylcholanthrene (MCA)-induced sarcomas that develop in
immunodeficient mice are more immunogenic than similar cancers that
develop in immunocompetent counterparts.
This led us to refine and broaden the cancer immunosurveillance
hypothesis into the concept of "CANCER IMMUNOEDITING".
But thorough understanding of how cancers "manipulate" inflammatory
cells for their growth and survival remained elusive.

14. CANCER IMMUNOEDITING
There is a complex interaction between tumours and the host from the
initiation of the cancer until the establishment of a clinical cancer.
The concept of "CANCER IMMUNOEDITING" was proposed (2001-02) to
explain the complex interactions.
It is an apparent contradictory concept of cancer suppression and cancer
promotion.
Defining them can help in evolving various immunotherapies in treatment of
Cancers.

15. CANCER IMMUNOEDITING
The process wherein immunity not only protects against cancer development
but also promotes outgrowth of cancers capable of escaping immune control.
This describes both
• The ability of the immune response to eliminate highly immunogenic
cancer cells, and also to produce tumour cell variants displaying reduced
levels of immunogenicity(Extrinsic Tumour suppression).
• The ability of the immune system to promote the darwinian selection of
the tumour subclones that are able to avoid host immunity or manipulate
the immune system for their own malignant purposes(Evasion of Immune
response).

16. During cancer immunoediting, the host immune system shapes tumour fate in three phases
through the activation of innate and adaptive immune mechanisms.
1. In the first phase, Elimination, transformed cells are destroyed by a competent
immune system.
2. Sporadic tumour cells that manage to survive immune destruction may then enter an
Equilibrium phase where editing occurs.
3. The Escape phase represents the third and final phase of the process, where
immunologically sculpted tumours begin to grow progressively, become clinically
apparent and establish an immunosuppressive tumour microenvironment.

17. The three E’s of cancer
immunoediting –
elimination,
equilibrium, and
escape .

18. • Tumour sculpting action of immunity is a consequence of T cell–
dependent immunoselection and/or epigenetic mechanisms that
specifically target cancer cells expressing highly immunogenic cancer
antigens including tumour-specific mutant neoantigens.
• The factors that govern the outcome of interactions between tumour cells
and host immunity are numerous and are still being defined.So,It is
helpful to consider few overarching(comprehensive) principles:
1. Tumour antigens,
2. Alterations that abrogate Tc cells responses .

19. 1. TUMOUR ANTIGENS
Cancer cells express a variety of antigens that permitted the immune
system to differentiate between normal and transformed cells.These
stimulate immune response against the cancer cells.So, these have an
important role in preventing emergence of cancers.
The antigens may be
1. mutated proteins,
2. non mutated proteins(Normal proteins) and
3. viral proteins of oncogenic viruses.

20. 1. Proteins produced by the driver mutation and passenger mutations(many)
are new to the immune system and has the ability to elicit an immune
response(immunogenicity),so called "Neoantigens", as they are not
tolerated(not under exposed during central or peripheral tolerance on
immune cells).
2. Normal proteins(Non mutated proteins) produced by the cancer cells also
elicit immune response.The probable explanation is inspite of being normal
proteins,that they are not exposed to the immune system and fails to induce
tolerance.
A. Tyrosinase,enzyme involved in melanin biosynthesis that is expressed
only in normal melanocytes and melanomas.
B. Cancer-testis antigens,Encoded by genes that are silent in all the adult
tissue s except germ cells in the testis.

21. 3. Viral proteins that are expressed in the cancer cells transformed by oncogenic
viruses also comes under tumour antigens.
• Most potent of these antigens are proteins produced by the cells that are
latently infected with DNA viruses.
• Most important in these are HPV and EBV.
• Evidence that supports this were
A. Cytotoxic T Lymphocytes (Tc) recognise viral antigens and plays an
important role in surveillance against virus induced tumours through
their ability to recognise and kill the virus-infected cells.
B. Individuals with defective T cell immunity (HIV) , there is an
increased incidence of the cancers associated with oncogenic
viruses.(Eg:EBV related B-Cell cancer ,HPV related Cervical Cancer)

22. 2. ALTERATIONS THAT
ABROGATE TC CELLS RESPONSE
Tc cells responses are the most important defence that host has against tumours.
The tumour cells show a variety of alterations that abrogate Tc cells
responses.Tumours that reach clinically significant sizes must be composed of cells
that:
A. Evasion(Invisible) to Host immune response,or
B. Express factors that actively suppress host immunity(Tumour
Microenvironment).

23. A. EVASION(INVISIBLE) OF
IMMUNE RESPONSE
Human Cancers often feature acquired mutations that prevent Tc cells from
recognizing tumour cells as foreign.
These include
• Acquired mutations in β2-microglobulins that prevent the assembly of
functional MHC class I molecules.(i.e, down regulation of cell surface
molecules including tumour specific antigens and MHC molecules)
• Increased expression of a variety of proteins that work by activating
"Immune Checkpoints" which inhibit Tc cell function.

25. IMMUNE CHECKPOINTS
These are normal inhibitory pathways.
These maintain self tolerance and control the size and duration of
immune response so as to minimise the collateral tissue damage.
So ,These are often expressed in the tumour cell surfaces to evade the
immune response.
Receptor
(T cell)
Ligand
(Tumour cells)
PD-1
(Programmed Cell Death)
PD-L1
(most often present)
CTLA4
(Cytotoxic T-lymphocyte-associated protein 4)
B7

26. Tumour Microenvironment consists of multiple cell types, including
macrophages,fibroblasts,endothelial cells and a variety of immune and inflammatory
cells;the extracellular matrix; and primary signalling substances such as cytokines,
chemokines and hormones
The ability of cytokine TGF-β to cause the cancer to progress and metastasise depends on
the microenvironment of various cell types and cross talk of signals among cell types.
Factors(TGF-β being the important) released by Macrophages and other stromal cells either
favour recruitment of immunosuppressive T regulatory cells or suppress the function of
CD8+ Tc cells and contribute to an immunosuppressive microenvironment.
Contd....
B. TUMOUR
MICROENVIRONMENT

27. In some cases, The phenotype of a cancer cell can actually normalise when it is
removed from tumour microenvironment and placed in normal environment, and
vice versa.
There is a strong evidence(from cancer models and Human diseases) that advanced
cancers contain mainly alternatively activated (M2) macrophages.
These produce cytokines that promote angiogenesis,fibroblast proliferation and
collagen deposition(all these are common in invasive cancers and wound healing)
giving rise to notion that "Cancers are like wounds that do not heal".
Finally,Essential steps needed for tumour growth and metastasis,such as
angiogenesis and metastatic tumour survival, depend on microenvironment.

28. TUMOUR-HOST INTERACTIONS
THAT SUPPRESS IMMUNE RESPONSE TO THE
TUMOUR

29. A Type of cancer treatment that helps immune system fight cancer.
It is a type of biological therapy(treatment that uses substances made
from living organisms).

30. Immunotherapy in cancer is aimed at activating immune response
against tumours using immunostimulatory molecules such as
interferons, IL-2, and monoclonal antibodies.
The different modalities of treatment was developed targeting different
areas in the pathogenesis of cancer so that it boosts the immune system.
A. Checkpoint blockade therapy(has good response rate),
B. Cytokines to stimulate immune responses
C. Personalised tumour vaccines using neoantigens,
D. Chimeric antigen Receptor T Cells(Adoptive Immunity)

31. A. CHECKPOINT BLOCKADE
THERAPY
Using monoclonal antibodies that block the immune checkpoints.
Blocking immune checkpoints on Tc cells enables them to eradicate
cancer cells that express antigens recognised by the T cells.
response rate is 10-30% in solid tumours and it even higher in some
haematological malignancies(Hodgkin lymphomas).
Contd.....

32. Patients treated with this therapy develop various autoimmune
manifestations ,such as Colitis and other type of systemic inflammations.
This is because the therapy used targets the self antigens.
Most of these reactions can be controlled with Anti-inflammatory agents.
Ipilimumab, Anti CTLA4 is the first monoclonal antibody that got
approval from FDA in 2011 for for the treatment of Metastatic melanoma.

34. DRUG CLASS NAMES TYPE APPROVED FOR
CTLA4 INHIBITORS
Ipilimumab Fully human IgG1 Metastatic Melanoma
Tremelimumab
(formerly Ticilimumab)
Fully human IgG2 Under trails
ANTAGONISTS OF
PD-L1
Atezolimumab
(MPDL3280A)
Fully human IgG1
1. Resistant Metastatic NSCLC
2. Locally Advanced or
metastatic urothelial cancer
Durvalumab Fully Human IgG1-κ
Metastatic urothelial
cancer
Avelumab Fully Human antibody
Metastatic urothelial
and Merkel cell cancer.

35. PD-1 INHIBITORS
Nivolumab
(significant clinical activity
in heavily pre-treated
patients with solid tumours
and haematological
malignancies)
Fully Human IgG4
1. Advanced melanoma.
2. Previously treated
NSCLC,RCC.
3. Advanced head and neck
cancers.
4. Relapsed/refractory
classical Hodgkin
lymphoma.
Pembrolizumab
used for any cancer with
mismatch repair(MMR)
deficiency o High
Microsatellite
instability(MSI-H)
Humanised monoclonal
IgG4-κ isotype
1. Advanced Melanoma
2. Unresectable or
metastatic melanoma in
pt previously t/t with
ipilimumab.
3. PD-L1 Positive NSCLC.
4. Chemotherapy refractory
head and neck cancer.

36. Combination of Anti PD-1 and Anti CTLA4 has significantly improved
therapeutic efficacy in preclinical studies.
Combination of ipilimumab and nivolumab produced positive response
in more than 50% of patients with acceptable level of ADR.
Combination Immunotherapy is more effective than anyother form of
therapy for metastatic cancers.

37. B. CYTOKINES TO STIMULATE
IMMUNE RESPONSES
(Out of 70)Only IFN and IL-2 are used in routine clincal use, often for
actions against cancer.
Aldesleukin possesses the biological activities of native human IL-2.
Approved for use in patients with metastatic renal cell cancer and
metastatic melanoma.

38. C. CANCER VACCINES-LITTLE
EFFICACY EXPECT THE TWO
1. Sipuleucel-T
Cell based approach designed to induce an immune response against Prostatic acid
phsophatase(PAP), expressed in most prostate cancers.
Patient receives treated cells by infusion on three occasions at 2-week intervals.
approved for minimally symptomatic,hormone refractory metastatic prostate cancer.
2. T-Vec(Talimogene Laherparepvec)
World's first approved oncolytic immunotherapy.
it is an Oncolytic herpes virus that replicates within tumours and expresses GM-CSF.
approved for treatment of unresectable cutaneous and nodal lesions in patients with
melanoma.

39. D. CHIMERIC ANTIGEN RECEPTOR
T CELLS(CAR-T CELLS)
It is a more direct approach to enhance the activity of T
cells directed against specific tumours.
Isolating T-Cells from the patients and re-engineering
the cells to express CARs that recognise antigens
present on that Individual's tumour.
most commonly studied till date is to express receptors
targeting the CD-19 antigen on ALL and DLBCL.
This has shown good results in ALL and DLBCL,
including durable remissions in patients refractory to
standard therapies.
Significant issues are Cytokine release
syndrome,Organ Toxicity,Neurotoxicity and aggressive
support and care to patients.

40. Dr.James P. Allison BS, MS, PhD Dr.Tasuku Honjo BS, MD, PhD
The 2018 Nobel Prize in Physiology or Medicine has been awarded jointly to two
cancer immunotherapy researchers, James P. Allison, PhD, of The University of
Texas MD Anderson Cancer Center, and Dr. Tasuku Honjo of Kyoto University
in Japan for their work on uncovering ways to activate the immune system to
attack cancer, a breakthrough in developing new cancer treatments.

41. 1. Harrison's Principles of Internal Medicine, 20th Ed.
2. Robbins & Cotran Pathologic Basis of Disease, 9th Ed.
3. Porth's Pathophysiology 9th Ed.
4. Goodman & Gillman's Pharmacological basis of Therapeutics, 13th Ed.
5. http://scitechconnect.elsevier.com/cancer-immunosurveillance-
immunoediting/
6. https://www.sciencedirect.com/science/article/pii/B9780123742797170
018?via%3Dihub
7. https://www.cancer.gov/about-cancer/treatment/types/immunotherapy
RESOURCES

42. THANK YOU