Currently which type of immunotherapy ,we used is discussed.Type of immunotherapy & their Mechanism of action discussed.

1. DR.VASANT GOSAI
IMMUNOTHERAPY

2. INTRODUCTION
8/26/20162
 Treatment that uses certain parts of the
immune system to fight against diseases such
as cancer.
 Basic aim of immunotherapy is to enhance the
immune response to tumours in the host.
 Immunotherapy is a cancer treatment more
than 100 years in the making, beginning most
notably with Dr. William B. Coley, who worked
with patients and multiple doctors to study
how cancer tumors reacted to infections.

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 He treated cancer patients with inoperable
tumors by injecting a combination of bacteria,
which became known as Coley’s Toxins,
directly into their tumors.
 His results showed that this treatment shrank
the tumors and sometimes even cured the
patient.
 He believed that the body’s increased
response to the bacteria also helped fight off
the cancer.

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 Three approaches are being tried currently :
A. 1.Increasing the immunogenicity of tumour
cells so that they themselves lead to a
strong immune response
B. 2.Enhance the passive immunity against
cancers by use of monoclonal antibodies or
adoptive cellular immunotherapy
C. 3.Stimulation of the immune system by
cancer vaccines
 e.g. Active immunization against cancer

5. (A)ENHANCEMENT OF TUMOUR
CELL IMMUNOGENICY
8/26/20165
 This is done in several ways :
1.Making tumour cell capable of providing Co-
stimulatary signal
 Most tumour cells do not provide co-
stimulatory signal because they are unable to
stimulate T-cells.
 It is seen that melanoma cells,transfected with
B-7 gene,on incubation with CTL-Ps,leads to
their differentiation into CTLs.
 Subsequently ,when animals with melanoma
tumours

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were injected with B7+ melanoma cells,40%
of the animals shows complete regression of
tumour.

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2.Making tumour cells to act as good APCs
 By enhancing the presence of APCs around
the tumour cells,so that they capture tumour
antigen ,stimulate TH cells and generate
CTLs specific to tumour antigens
 These CTLs are then expected to kill the
tumour cells.

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 GM-CSF has been found to enhance the
differentiation and APC activity of the dendritic
cells.
 Using this principle,tumour cells transfected
with GM-CSF gene,on reinfusion into
patients,secrete GM-CSF which enhance
dendritic cell population around tumour and
enhance their APC activity.

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 This lead to developement of tumour specific
CTLs and cellular immunity against the
tumour.

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 Alternate approach is to obtain population of
dendritic cells and grow them in invitro culture
in the presence of GM-CSF ,TNF-α and IL-4
and tumour fragments to sensitize them to
tumour antigens.
 Then on injection into patients, they are
expected to mount a strong cell mediated
response.
 This is under investigation.

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3.USE OF CYTOKINES
 Various cytokines are known to augment the
immune response by acting at various stages
of cell differetiation and its immune function.
 E.g . TNF-α,β and γ,IL-1,2,4,5 and 12, GM-
CSF and TNF.
 Use of cytokines as drugs for systemic use in
treatment against diseases including cancers
is loaded with serious problem that prevent
their widespread use at present.

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INTERFERONS
 They enhance tumour immune response by
three mechanisms:
A. They increase MHC-I expression on tumour
cells,so it is likely to restore their APC
activity which leading to activate CTLs
causing tumour cell killing.
 IFN-γ ehnances MHC-II expression
 So they together will increase the overall
tumour cell immunogenicity.

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B. IFN-γ increases activity of cytotoxic cells
e.g. Tc cells, macrophages and NK cells
 They will augment the cell mediated
response against tumour.
C. They also inhibit the cell mitosis in both
normal and cancerous cells.
 Together all three actions increases the
overall antitumour cellular immunity in the
host.

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TUMOUR NECROSIS FACTOR (TNF) :
 TNF-α and β shown to induce visible
hemorrhagic necrosis and tumour regression
 TNF-α inhibit the tumour induced
vascularisation by damaging the vascular
endothelial cells.
 This deprives the tumour of essential nutrients
and O2 leading to necrosis and regression.

15. (B)PASSIVE IMMUNOTHERAPY OF
CANCER
8/26/201615
 Tumour specific immuno effector molecules or
cells are injected into the patients.
 Monoclonal antibodies to specific tumour
antigens and immunotoxins are being tried.
MONOCLONAL ANTIBODIES :
 Antiidiotypic monoclonal antibodies have been
tried in B-cell lymphoma.
 Such antibodies on injection ,will bind to
cancerous B-cells and activate the
complement mediated lysis of the cancerous
cell.

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IMMUNOTOXINS :
 These are monoclonal antibodies combined to
some antitumor toxic agents like radiation
source,anticancer drugs or potent biological
toxins etc.
 They kill tumours in highly specific manner.
 Immunotoxins against melanomas,breast
cancer,colorectal cancer are already
undergoing phase I and phase II clinical trials
with encouraging results.

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Radiolabeled antibodies:
 Radiolabeled antibodies have small
radioactive particles attached to them.
 Ibritumomab tiuxetan (Zevalin® ) is an
example of a radiolabeled mAb.
 This is an antibody against the CD20 antigen,
which is found on lymphocytes called B cells.
 The antibody delivers radioactivity directly to
cancerous B cells and can be used to treat
some types of non-Hodgkin lymphoma.

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Chemolabeled antibodies:
 These mAbs have powerful chemotherapy (or
other) drugs attached to them.
 They are also known as antibody-drug
conjugates (ADCs).
 The drug is often too powerful to be used on
its own – it would cause too many side effects
if not attached to an antibody.

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 Chemolabeled antibodies used to treat cancer
include:
1)Brentuximab vedotin (Adcetris® ) :
o An antibody that targets the CD30 antigen
(found on lymphocytes), attached to a chemo
drug called MMAE.
o This drug is used to treat Hodgkin lymphoma
and anaplastic large cell lymphoma..

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2)Ado-trastuzumab Emtansine (Kadcyla® )
o An antibody that targets the HER2 protein.
o It’s used to treat some breast cancer patients
whose cancer cells have too much HER2.

22. BISPECIFIC MONOCLONAL
ANTIBODIES
8/26/201622
 These drugs are made up of parts of 2
different mAbs, meaning they can attach to 2
different proteins at the same time.
 An example is blinatumomab (Blincyto),
which is used to treat some types of acute
lymphocytic leukemia (ALL).
 One part of blinatumomab attaches to the
CD19 protein, which is found on some
leukemia and lymphoma cells.

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 Another part attaches to CD3, a protein found
on T-cells.
 By binding to both of these proteins, this drug
brings the cancer cells and immune cells
together, which is thought to cause the
immune system to attack the cancer cells.

24. IMMUNE CHECKPOINT
INHIBITORS TO TREAT CANCER
8/26/201624
 An important part of the immune system is its
ability to tell between normal cells in the body
and those it sees as “foreign.”
 This lets the immune system attack the
foreign cells while leaving the normal cells
alone.
 To do this, it uses “checkpoints” – molecules
on certain immune cells that need to be
activated (or inactivated) to start an immune
response.

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 Cancer cells sometimes find ways to use
these checkpoints to avoid being attacked by
the immune system.
Drugs that target PD-1 or PD-L1 :
 PD-1 is a checkpoint protein on T cells.
 It normally acts as a type of “off switch” that
helps keep the T cells from attacking other
cells in the body.

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 It does this when it attaches to PD-L1, a
protein on some normal (and cancer) cells.
 When PD-1 binds to PD-L1, it basically tells
the T cell to leave the other cell alone.
 Some cancer cells have large amounts of
PD-L1, which helps them evade immune
attack.
 Monoclonal antibodies that target either PD-1
or PD-L1 can boost the immune response
against cancer cells.

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PD-1 inhibitors:
 Examples of drugs that target PD-1 include:
• Pembrolizumab (Keytruda)
• Nivolumab (Opdivo)
o These drugs have been shown to be helpful
in treating several types of cancer :
• Melanoma Of The Skin,
• Non-small Cell Lung Cancer,
• Kidney Cancer And Hodgkin Lymphoma.

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PD-L1 inhibitors:
 An example of a drug that targets PD-L1 is:
Atezolizumab (Tecentriq)
 This drug can be used to treat bladder cancer,
and is also being studied for use against other
types of cancer.
 One concern with all of these drugs is that
they can allow the immune system to attack
some normal organs in the body, which can
lead to serious side effects in some people.

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Drugs that target CTLA-4 :
 CTLA-4 is another protein on some T cells
that acts as a type of “off switch” to keep the
immune system in check.
 Ipilimumab (Yervoy) is a monoclonal
antibody that attaches to CTLA-4 and stops it
from working.
 This can boost the body’s immune response
against cancer cells.
 This drug is used to treat melanoma of the
skin.

31. ADOPTIVE CELLULAR
TRANSFER
8/26/201631
 Administration of in vitro activated killer cells-
lymphocytes and NK cells into cancer
patients.
 These activated cells enhance tumour cell
killing.
 Lymphokines activated killer cells (LAK-cells)
and Tumour infiltrating lymphocytes (TILs)
have been tried.

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LAK-cells :
 In the presence of high concentrations of IL-
2,peripheral lymphocytes are converted into
killer cells called lymphokines activated killer
cells (LAK-cells) which display high level of
antitumour activity.
 Most LAK cells (90%) are derived from NK-
cells.

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 In human beings it is tried in stage IV
metastatic cancers with some success,but
serious side effects also.
Vascular leak syndrome :
 Lymphoid cells and plasma migrate from the
vessels into tissues leading to shock.

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TIL :
 They behave and resemble LAK cells in their
anti tumour activity
 They are lymphocytes that infiltrate tumour in
vivo.
 After obtaining from tumour samples, in vitro
cultures done with high doses of IL-2 done.

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 On administration,these require much lower
IL-2 dose than LAK cells (100 times less).
 This has been tried in renal cell carcinoma
patients and malignant melanoma patients
with 20-30% success rate of partial
regression.

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 On administration,these require much lower
IL-2 dose than LAK cells (100 times less).
 This has been tried in renal cell carcinoma
patients and malignant melanoma patients
with 20-30% success rate of partial
regression.

37. (C)CANCER VACCINES
8/26/201637
 Host tumours contain many unique antigens
which are recognized by T-cells and lead to
production of tumour specific CTLs.
 Patients own tumour cells or cell extracts
were used initially as potential immunizing
agents or vaccines.
Two approaches are used :
1. MHC molecules are isolated from the tumour
cells and mixture of peptides bound to them
are eluted,purified and tested individually to
detect the best immunogenic peptide.

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 Its structure is then determined for use as
antigens.
2. DNA made out of tumour cells,is transfected
into MHC-I expressing cells
 These cells are then tested for their ability to
stimulate tumour specific CTL-response.
 The protein encoded by transfected gene on
the cells is identified and its antigenic
fragment detected and sequenced.
 Intact protein administered as to be
complexed with MHC-II molecules on APCs
after processing.

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 Administration of DNA through a vector seems
viable as the DNA would be taken up by the
cells and translated into proteins in the
cytoplasm and then expressed on cell
surface in the combination with MHC-I.

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TYPES OF VACCINES
Tumor cell vaccines
actual cancer cells
Antigen vaccines
only one antigen
Dendritic cell vaccines DNA vaccines

41. VECTOR - BASED VACCINES
8/26/201641
 Vector-based vaccines are made from altered
viruses or bacteria that are injected into the
body to create an immune response, both
specific and overall.
 Tumor-specific vectors are genetically
modified to target specific cancer cells in such
a way that trains the immune system to
recognize and destroy them
 Oncolytic virus immunotherapy uses natural
or modified viruses to directly attack and kill
tumor cells

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 One of the most-studied approaches uses a
modified, weakened version of the herpes
simplex virus called Talimogene
Laherparepvec (TVEC).
 TVEC is a safer herpes virus that contains the
gene for GM-CSF.
 The virus targets only specific cancer cells,
infects them and replicates continuously
within the cell until it explodes.

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44. Sipuleucel-T (Provenge® )
8/26/201644
 This is the only vaccine approved in the US to
treat cancer so far.
 It’s used to treat advanced prostate cancer
that is no longer being helped by hormone
therapy.
 For this vaccine, immune system cells are
removed from the patient’s blood and sent to
a lab.
 There they are exposed to chemicals that turn
them into special immune cells called
dendritic cells.

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 They are also exposed to a protein called
prostatic acid phosphatase (PAP), which
should produce an immune response against
prostate cancer cells.
 The dendritic cells are then given back to the
patient by infusion into a vein (IV).
 This process is repeated twice more, 2 weeks
apart, so that the patient gets 3 doses of cells.
 Back in the body, the dendritic cells help other
immune system cells attack the prostate
cancer.

46. REFERENCES
8/26/201646
 Dr.S.K.Gupta ,Textbook of essential of
Immunology,2nd edition.
 Thao Doan,Roger Melvold,Lippincott’s illustrated
reviews of Immunology,2nd Edition.
 Google images.

47. Thank You