cancer immunotherapy

Cancer ImmunotherapyCancer Immunotherapy
Arun.V.
3rd semeste, MSc. Biochemistry
and Molecular Biology
14368005

Immunosurveillance and Immunoediting
The greatest trouble
with the idea of
immunosurveillance is
that it can’t be shown to
exist in experimental
animals
(Thomas, 1982)
There is little ground for
optimism about cancer
(Burnet, 1957)
The greatest trouble
with the idea of
immunosurveillance is
that it can’t be shown to
exist in experimental
animals
(Thomas, 1982)
Cirrhosis.pptx by Arun Viswanthan is licensed under a Creative Commons Attribution 4.0 International License.

• In 1909, Paul Ehrlich proposed that the incidence of cancer
would be much greater were it not for the vigilance of our
immune defense system in identifying and eliminating
nascent tumor cells.
• About 50 years later, two scientists, Lewis Thomas and
Frank MacFarlane Burnet, took Paul Ehrlich’s original idea a
step further and proposed that T cell was the pivotal
sentinel in the immune system’s response against cancer.
• This elaboration led to the coinage of the term “immune
surveillance or immunosurveillance” to describe the
concept whereby the immune system is on perpetual alert
against transformed cells
• In 1909, Paul Ehrlich proposed that the incidence of cancer
would be much greater were it not for the vigilance of our
immune defense system in identifying and eliminating
nascent tumor cells.
• About 50 years later, two scientists, Lewis Thomas and
Frank MacFarlane Burnet, took Paul Ehrlich’s original idea a
step further and proposed that T cell was the pivotal
sentinel in the immune system’s response against cancer.
• This elaboration led to the coinage of the term “immune
surveillance or immunosurveillance” to describe the
concept whereby the immune system is on perpetual alert
against transformed cells

• Osías Stutman showed in the 1970s that mice supposedly lacking an intact immune
system (so-called nude mice) did not become more susceptible to tumor growth as
predicted by the theory.
• Thus, the theory of immunosurveillance remained controversial
• until an important scientific article entitled this paper was published in Nature on April
26, 2001.
• this paper unambiguously showed that the immune system can and often does prevent
tumors from developing, and thus plays a strong protective role against cancer.
• These researchers also uncovered important new insights regarding the immune system
and tumor development that they coined immunoediting

• Utilizing nude mouse, the authors showed that lymphocytes and IFN-
gamma, cooperate to inhibit the development of both spontaneous
and carcinogen-induced tumors.
• Immune system imperfect, and some tumor cells escape
identification and go on to cause cancer.
• Such tumors are imposed with selection pressure by immune system
only those which manage to escape this pressure cause cancer
• same way as bacteria can become resistant to antibiotic treatment
and lead to more potent and harmful strains
• researchers demonstrate that there are ways to over come the
“camouflage” of such escaped tumors by increasing their antigen
expression and making them visible to the immune system.
• This suggests that even tumors that have escaped recognition can be
turned into targets for an immune response.
• This has yet to be implemented in the field of therapy
• Utilizing nude mouse, the authors showed that lymphocytes and IFN-
gamma, cooperate to inhibit the development of both spontaneous
and carcinogen-induced tumors.
• Immune system imperfect, and some tumor cells escape
identification and go on to cause cancer.
• Such tumors are imposed with selection pressure by immune system
only those which manage to escape this pressure cause cancer
• same way as bacteria can become resistant to antibiotic treatment
and lead to more potent and harmful strains
• researchers demonstrate that there are ways to over come the
“camouflage” of such escaped tumors by increasing their antigen
expression and making them visible to the immune system.
• This suggests that even tumors that have escaped recognition can be
turned into targets for an immune response.
• This has yet to be implemented in the field of therapy

• connection between cancer and the immune system was first uncovered
nearly 100 years ago
• In the early 1890s, Dr. William B. Coley, a NY physician he observed dramatic
disappearance of malignant tumors that he observed in cancer patients who
had contracted acute streptococcal infections.
• he injected live streptococci into a patient with inoperable cancer to see
whether the patient’s tumor would regress.
• After trying 3 different bacterial cultures to the patient, he finally injected a
fourth that resulted in the complete disappearance of the tumor.
• Dr. Coley continued to pursue his approach and ultimately developed a
mixture of killed bacteria that became known as Coley’s mixed bacterial toxin
• He and other physicians treated over 1,000 cancer patients with this
substance, with varied success
• bacterial products of which it was composed had acted as immune
potentiators. they had stimulated certain immune cells to kill the cancer
• Today, cancer immunology is a rapidly advancing field and Dr. Coley has come
to be regarded as the “father of cancer immunotherapy.”
Coley’s mixed bacterial toxin
• connection between cancer and the immune system was first uncovered
nearly 100 years ago
• In the early 1890s, Dr. William B. Coley, a NY physician he observed dramatic
disappearance of malignant tumors that he observed in cancer patients who
had contracted acute streptococcal infections.
• he injected live streptococci into a patient with inoperable cancer to see
whether the patient’s tumor would regress.
• After trying 3 different bacterial cultures to the patient, he finally injected a
fourth that resulted in the complete disappearance of the tumor.
• Dr. Coley continued to pursue his approach and ultimately developed a
mixture of killed bacteria that became known as Coley’s mixed bacterial toxin
• He and other physicians treated over 1,000 cancer patients with this
substance, with varied success
• bacterial products of which it was composed had acted as immune
potentiators. they had stimulated certain immune cells to kill the cancer
• Today, cancer immunology is a rapidly advancing field and Dr. Coley has come
to be regarded as the “father of cancer immunotherapy.”

• Dentritic Cell Vaccines
• Antibody Therapy
• Cytokine Therapy
• Adoptive T cell Therapy
• Immune checkpoint blockade
• Combined Therapy
Types of Immunotherapy
• Dentritic Cell Vaccines
• Antibody Therapy
• Cytokine Therapy
• Adoptive T cell Therapy
• Immune checkpoint blockade
• Combined Therapy

Dentritic Cell Vaccines
Dentritic cells express
high levels of class I and
class II MHC and co-
stimulatory molecules -
unique ability to
activate naive T cells

• CD8+ cytotoxic T lymphocytes (CTLs), are the principle effectors of
anti-tumor immunity
• CTLs become sensitized to Ag by encountering peptide-class I MHC
on the surface of professional APCs
• But this is not sufficient to activate the effector response. CD4+ T
helper cells must also be present to recognize peptides displayed on
the class II MHC molecules of the APCs
• this results in secretion of Cytokines by TH cellsthat - expansion and
maturation of CTLs
• Coexpression of co-stimulatory molecules, such as CD80/B7.1 and
CD86/B7.2, by the APCs is also required to deliver a second
confirmatory signal to the T cells via the CD28 molecule expressed on
their surface
• No co-stimulatory signals - T-cell anergy and is a mechanism for
maintaining peripheral tolerance to self antigens
Why Dentritic Cell ?
• CD8+ cytotoxic T lymphocytes (CTLs), are the principle effectors of
anti-tumor immunity
• CTLs become sensitized to Ag by encountering peptide-class I MHC
on the surface of professional APCs
• But this is not sufficient to activate the effector response. CD4+ T
helper cells must also be present to recognize peptides displayed on
the class II MHC molecules of the APCs
• this results in secretion of Cytokines by TH cellsthat - expansion and
maturation of CTLs
• Coexpression of co-stimulatory molecules, such as CD80/B7.1 and
CD86/B7.2, by the APCs is also required to deliver a second
confirmatory signal to the T cells via the CD28 molecule expressed on
their surface
• No co-stimulatory signals - T-cell anergy and is a mechanism for
maintaining peripheral tolerance to self antigens

TumorAg’recognizedbyTcellsTumorAg’recognizedbyTcells

• DC are activated in the presence of tumor antigens, which
may be a single tumor-specific peptide/protein or a tumor
cell lysate (a solution of broken down tumor cells).
• activated dendritic cells are put back into the body where
they provoke an immune response to the cancer cells.
• Adjuvants are sometimes used
• More modern dendritic cell therapies include the use of
antibodies that bind to receptors on the surface of dendritic
cells. Antigens can be added to the antibody and can induce
the dendritic cells to mature and provide immunity to the
tumor.
• clinical response takes time to build up but remissions can be
very long-lasting
Targeting antigen to DCs Ex vivo
• DC are activated in the presence of tumor antigens, which
may be a single tumor-specific peptide/protein or a tumor
cell lysate (a solution of broken down tumor cells).
• activated dendritic cells are put back into the body where
they provoke an immune response to the cancer cells.
• Adjuvants are sometimes used
• More modern dendritic cell therapies include the use of
antibodies that bind to receptors on the surface of dendritic
cells. Antigens can be added to the antibody and can induce
the dendritic cells to mature and provide immunity to the
tumor.
• clinical response takes time to build up but remissions can be
very long-lasting

Sipuleucel-T Ex Vivo
• treatment of metastatic prostate cancer with sipuleucel-T
(also known as APC 8015), which is a cellular product based
on enriched blood APCs that are briefly cultured with a
fusion protein of prostatic acid phosphatase (PAP) and
GM-CSF
• an approximately 4-month-prolonged median survival in
Phase III trials.
• Sipuleucel-T has been approved by the US Food and Drug
Administration (FDA)Cirrhosis.pptx by Arun Viswanthan is licensed under a Creative Commons Attribution 4.0 International License.

Sipuleucel -T
Mechanism
of action

• rilimogene alvacirepvec
a.k.a rilimogene
glafolivec
• by Bavarian Nordic for
the treatment of
metastatic castration-
resistant prostate
cancer (mCRPC).
• Passed Phase 3, waiting
for FDA approval
PROSTVAC Ex Vivo
• rilimogene alvacirepvec
a.k.a rilimogene
glafolivec
• by Bavarian Nordic for
the treatment of
metastatic castration-
resistant prostate
cancer (mCRPC).
• Passed Phase 3, waiting
for FDA approval
•designed to enable immune system to recognize &
attack PC cells by triggering a specific & targeted T
cell immune response to cancer cells that express the
tumor-associated antigen prostate-specific antigen
(PSA).

• administered subcutaneously
• trigger immune response by using virus-based
immunotherapies that carry the tumor-associated antigen
PSA (prostate-specific antigen) along with 3 natural human
immune-enhancing costimulatory molecules collectively
designated as TRICOM (LFA-3, ICAM-1, and B7.1).
• Adjuvant low-dose granulocyte-macrophage colony-
stimulating factor (GM-CSF, 100 µg)
PROSTVAC Ex Vivo
• administered subcutaneously
• trigger immune response by using virus-based
immunotherapies that carry the tumor-associated antigen
PSA (prostate-specific antigen) along with 3 natural human
immune-enhancing costimulatory molecules collectively
designated as TRICOM (LFA-3, ICAM-1, and B7.1).
• Adjuvant low-dose granulocyte-macrophage colony-
stimulating factor (GM-CSF, 100 µg)
regimen consists of an initial PSA-TRICOM vaccinia-based priming dose,
followed by 6 subsequent PSA-TRICOM fowlpox-based boosting doses.
These 7 subcutaneous injections are given within a 5-month treatment
period. Cirrhosis.pptx by Arun Viswanthan is licensed under a Creative
Commons Attribution 4.0 International License.

PROSTVAC
Mode of Action

Vaccines under clinical trial Ex Vivo
Cancer immunotherapy via
dendritic cells
Karolina P and Jacques B
NATURE REVIEWS | CANCER
VOLUME 12 | APRIL 2012
Cancer immunotherapy via
dendritic cells
Karolina P and Jacques B
NATURE REVIEWS | CANCER
VOLUME 12 | APRIL 2012

• using chimeric proteins that are comprised of an
Ab that is specific for a DC receptor fused to a
selected antigen
• Ralph Steinman and colleagues demonstrated that
the specific targeting of antigens to DCs in vivo
elicits potent antigen-specific CD4+ and CD8+ T
cell-mediated immunity
• They activated two subsets of DCs : CD8+ DCs &
CD8– DCs
Targeting antigen to DCs in vivo
• using chimeric proteins that are comprised of an
Ab that is specific for a DC receptor fused to a
selected antigen
• Ralph Steinman and colleagues demonstrated that
the specific targeting of antigens to DCs in vivo
elicits potent antigen-specific CD4+ and CD8+ T
cell-mediated immunity
• They activated two subsets of DCs : CD8+ DCs &
CD8– DCs

Targeting antigen to DCs in vivo
CD8– DCsCD8+ DCs
CD205
A marker antigen
recognized by
mAb 33D1
CD205
A marker antigen
recognized by
mAb 33D1
MHC I MHC II
ActivatesTH1 cell
IL-12-independent
mechanism
ActivatesTH1 cell
IL-12-dependent classical
mechanism

Clinical response to
dendritic cell
vaccination in a
patient with non-
Hodgkin.s
lymphoma.
Prevaccine CT scan
images demonstrate
(a) periaortic lymph
nodes and
(c) a paracardial
mass.
(b) and (d)
demonstrate
complete resolution
of tumors 10 months
following
vaccination with
dendritic cells.
Clinical response to
dendritic cell
vaccination in a
patient with non-
Hodgkin.s
lymphoma.
Prevaccine CT scan
images demonstrate
(a) periaortic lymph
nodes and
(c) a paracardial
mass.
(b) and (d)
demonstrate
complete resolution
of tumors 10 months
following
vaccination with
dendritic cells.

Ab therapy for cancer
has become established
over the past 15 years &
is now one of the most
successful & important
strategies for treating
patients with
haematological
malignancies & solid
tumours
Ab therapy for cancer
has become established
over the past 15 years &
is now one of the most
successful & important
strategies for treating
patients with
haematological
malignancies & solid
tumours
The Magic BulletsCirrhosis.pptx by Arun Viswanthan is licensed under a Creative Commons Attribution 4.0 International License.

• Ab therapy targets cancer antigents or Neoantigents
• Ideally, the target antigen should be abundant and
accessible & should be expressed homogeneously,
consistently and exclusively on the surface of cancer
cells.
• Mainly kills cells by complement-dependent cytotoxicity
(CDC), antibody-dependent cellular cytotoxicity (ADCC)
• Killing can result from direct action of the antibody,
immune-mediated cell killing mechanisms, payload
delivery, and specific effects of an antibody on the
tumour vasculature and stroma
Antibody Therapy
• Ab therapy targets cancer antigents or Neoantigents
• Ideally, the target antigen should be abundant and
accessible & should be expressed homogeneously,
consistently and exclusively on the surface of cancer
cells.
• Mainly kills cells by complement-dependent cytotoxicity
(CDC), antibody-dependent cellular cytotoxicity (ADCC)
• Killing can result from direct action of the antibody,
immune-mediated cell killing mechanisms, payload
delivery, and specific effects of an antibody on the
tumour vasculature and stroma

Ab Therapy
• Naked monoclonal Abs
– Antibodies without modification. Most
of the currently used antibodies
therapies are naked.
• Conjugated monoclonal Abs
– Abs are conjugated with toxins or
radioactive compounds to properly
deliver the conjugant
Types of antibodies
Two types of monoclonal antibodies used in therapy :
Four types of monoclonal antibodies based on source:
• Naked monoclonal Abs
– Antibodies without modification. Most
of the currently used antibodies
therapies are naked.
• Conjugated monoclonal Abs
– Abs are conjugated with toxins or
radioactive compounds to properly
deliver the conjugant
• Murine : antibodies were the first to be produced, and carry a great risk of immune
reaction, because the antibodies are from a different species
• Chimeric : the first attempt to reduce the immunogenicity. murine Abs with a specific
constant region replaced with the corresponding human counterpart
• Humanized : almost completely human; only the complementarity determining regions
of the variable regions are derived from murine
• Human antibodies have completely human origin

Ab Therapy
• Haematopoietic differentiation
antigens
– CD20, CD30, CD33, CD52
• Glycoproteins expressed by solid
tumours
– Mucins , EpCAM-epithelial cell
adhesion molecule
• Glycolipids
– Gangliosides such as GD2, GD3 and
GM2
• Carbohydrates
– Lewis Y Ag expressed by 42%
squamous cell lung carcinoma, 80%
lung adenocarcinoma, 25% ovarian
carcinoma, colorectal
adenocarcinoma*
• Targets of anti-angiogenic mAbs
– Integrin α5β1 , VEGFR, VEGF
• Growth and differentiation
signalling
– EGFR, ERBB2, ERBB3
• Stromal and extracellular matrix
antigens
– FAP-fibroblast activation protein
Targets in Human Cancers
• Haematopoietic differentiation
antigens
– CD20, CD30, CD33, CD52
• Glycoproteins expressed by solid
tumours
– Mucins , EpCAM-epithelial cell
adhesion molecule
• Glycolipids
– Gangliosides such as GD2, GD3 and
GM2
• Carbohydrates
– Lewis Y Ag expressed by 42%
squamous cell lung carcinoma, 80%
lung adenocarcinoma, 25% ovarian
carcinoma, colorectal
adenocarcinoma*
• Targets of anti-angiogenic mAbs
– Integrin α5β1 , VEGFR, VEGF
• Growth and differentiation
signalling
– EGFR, ERBB2, ERBB3
• Stromal and extracellular matrix
antigens
– FAP-fibroblast activation protein
*The Lewis-Y carbohydrate antigen is expressed by many human tumors and can serve as a target for genetically redirected T cells despite the presence of soluble
antigen in serum. Westwood.J.A Et.al 2009 Apr;32(3):292-301. doi: 10.1097/CJI.0b013e31819b7c8e.

Ab Therapy Mechanism of action
• elicited by receptor agonist activity:- Ab
binding to a tumour cell surface receptor
and activating it, leading to apoptosis
(represented by the mitochondrion).
• by receptor antagonist activity:- Ab
binding to a cell surface receptor and
blocking dimerization, kinase activation and
downstream signalling, leading to reduced
proliferation and apoptosis.
• An antibody binding to an enzyme can
lead to neutralization, signalling abrogation
& cell death,
• conjugated antibodies can be used to
deliver a payload (such as a drug, toxin,
small interfering RNA or radioisotope) to a
tumour cell.
Direct Tumor cell Killing • elicited by receptor agonist activity:- Ab
binding to a tumour cell surface receptor
and activating it, leading to apoptosis
(represented by the mitochondrion).
• by receptor antagonist activity:- Ab
binding to a cell surface receptor and
blocking dimerization, kinase activation and
downstream signalling, leading to reduced
proliferation and apoptosis.
• An antibody binding to an enzyme can
lead to neutralization, signalling abrogation
& cell death,
• conjugated antibodies can be used to
deliver a payload (such as a drug, toxin,
small interfering RNA or radioisotope) to a
tumour cell.

• can be carried out by the induction of
•Phagocytosis;
•Complement activation
• Antibody-dependent cellular
cytotoxicity (ADCC)
• Genetically modified T cells being
targeted to the tumour by single-chain
variable fragment (scFv); T cells being
activated by antibody-mediated cross-
presentation of antigen to dendritic
cells; and inhibition of T cell inhibitory
receptors, such as cytotoxic T
lymphocyte-associated antigen 4
(CTLA4).
Immune – mediated killing
• can be carried out by the induction of
•Phagocytosis;
•Complement activation
• Antibody-dependent cellular
cytotoxicity (ADCC)
• Genetically modified T cells being
targeted to the tumour by single-chain
variable fragment (scFv); T cells being
activated by antibody-mediated cross-
presentation of antigen to dendritic
cells; and inhibition of T cell inhibitory
receptors, such as cytotoxic T
lymphocyte-associated antigen 4
(CTLA4).

• Vascular and stromal cell ablation can
be induced by
•vasculature receptor antagonism
or ligand trapping
• stromal cell inhibition
• delivery of a toxin to stromal cells
• delivery of a toxin to the
vasculature
Vascular and stromal cell ablation
• Vascular and stromal cell ablation can
be induced by
•vasculature receptor antagonism
or ligand trapping
• stromal cell inhibition
• delivery of a toxin to stromal cells
• delivery of a toxin to the
vasculature

Ab Therapy
• A human IgG4 anti-PD-1 monoclonal antibody developed by Ono
Pharmaceutical and Medarex
• inhibitory ligand blocking antibody against the programmed death
receptor
• PD-1 is a protein on the surface of activated T cells. If its is ligand
PD-L1 or PD-L2, binds to PD-1, the T cell becomes inactive.
• This is one way that the body regulates the immune system, to
avoid an overreaction.
• Many cancer cells make PD-L1, which inhibits T cells from attacking
the tumor
• nivolumab acts by blocking PD-1 of T-cell activation and response
thus allowing the immune system to attack the tumor
• Uses: Metastatic melanoma, Lung cancer, Hodgkin's lymphoma,
Kidney cancer
Examples | Nivolumab
• A human IgG4 anti-PD-1 monoclonal antibody developed by Ono
Pharmaceutical and Medarex
• inhibitory ligand blocking antibody against the programmed death
receptor
• PD-1 is a protein on the surface of activated T cells. If its is ligand
PD-L1 or PD-L2, binds to PD-1, the T cell becomes inactive.
• This is one way that the body regulates the immune system, to
avoid an overreaction.
• Many cancer cells make PD-L1, which inhibits T cells from attacking
the tumor
• nivolumab acts by blocking PD-1 of T-cell activation and response
thus allowing the immune system to attack the tumor
• Uses: Metastatic melanoma, Lung cancer, Hodgkin's lymphoma,
Kidney cancer

Ab Therapy Examples | Nivolumab

Ab Therapy
• a chimeric monoclonal antibody against the protein CD20
• used to treat diseases which are characterized by excessive
numbers of B cells, overactive B cells, or dysfunctional B cells.
• Ex:- lymphomas, leukemias, transplant rejection, and autoimmune
disorders.
• CD20 is widely expressed on B cells, from early pre-B cells to later
in differentiation, but it is absent on terminally differentiated
plasma cells. CD20 does not shed, modulate or internalise.
Although the function of CD20 is unknown, it may play a role in
Ca2+ influx across plasma membranes, maintaining intracellular
Ca2+ concentration and allowing activation of B cells.
Examples | Rituximab
• a chimeric monoclonal antibody against the protein CD20
• used to treat diseases which are characterized by excessive
numbers of B cells, overactive B cells, or dysfunctional B cells.
• Ex:- lymphomas, leukemias, transplant rejection, and autoimmune
disorders.
• CD20 is widely expressed on B cells, from early pre-B cells to later
in differentiation, but it is absent on terminally differentiated
plasma cells. CD20 does not shed, modulate or internalise.
Although the function of CD20 is unknown, it may play a role in
Ca2+ influx across plasma membranes, maintaining intracellular
Ca2+ concentration and allowing activation of B cells.

Ab Therapy
The following effects have been found:
• The Fc portion of rituximab mediates ADCC and CDC
• It increases MHC II and adhesion molecules LFA-1 and LFA-3
(lymphocyte function-associated antigen).
• It elicits shedding of CD23.
• It downregulates the B cell receptor.
• It induces apoptosis of CD20+ cells.
• The combined effect results in the elimination of B cells and allow
production of healthy cells
Examples | Rituximab
The following effects have been found:
• The Fc portion of rituximab mediates ADCC and CDC
• It increases MHC II and adhesion molecules LFA-1 and LFA-3
(lymphocyte function-associated antigen).
• It elicits shedding of CD23.
• It downregulates the B cell receptor.
• It induces apoptosis of CD20+ cells.
• The combined effect results in the elimination of B cells and allow
production of healthy cells

PET-CT scan showing
localisation of 124I-
labelled cG250 (carbonic
anhydrase IX (CAIX)-
specific) monoclonal
antibody, obtained 5 days
after antibody infusion.
The specific uptake of the
antibody can be seen in
the left renal tumour
(arrow), which is
expressing CAIX antigen.
PET-CT scan showing
localisation of 124I-
labelled cG250 (carbonic
anhydrase IX (CAIX)-
specific) monoclonal
antibody, obtained 5 days
after antibody infusion.
The specific uptake of the
antibody can be seen in
the left renal tumour
(arrow), which is
expressing CAIX antigen.

Cytokines, secreted
proteins with
immunemodulating
properties, can be
delivered systemically
to activate antitumor
immunity
Cytokine Therapy
Cytokines, secreted
proteins with
immunemodulating
properties, can be
delivered systemically
to activate antitumor
immunity

• Cytokines are secreted or membrane-bound
proteins
• Significance in immuno survialence:- higher
frequency of spontaneous cancers seen in mice
genetically deficient in type I or II IFN receptors
or elements of downstream IFN receptor signal
transduction
• IL-2 & IFN-α have been used to treat advanced
melanoma & renal cell
Cytokine Therapy
• Cytokines are secreted or membrane-bound
proteins
• Significance in immuno survialence:- higher
frequency of spontaneous cancers seen in mice
genetically deficient in type I or II IFN receptors
or elements of downstream IFN receptor signal
transduction
• IL-2 & IFN-α have been used to treat advanced
melanoma & renal cell

• secreted by nearly every cell in the body and involved in
cellular immune responses against viral infections
• Type I-IFNs induce expression of MHC class I molecules on
tumor cells and mediate the maturation of a subset of DC
• can also activate CTLs, NK cells and macrophages
• IFN- α is the only currently approved adjuvant therapy for
patients with high-risk Stage II or Stage III melanoma
• Also approved for the treatment of some hematologic
malignancies, AIDS-related Kaposi’s sarcoma, and as a
component in an anti-angiogenic combination regimen with
bevacizumab for advanced renal cancer
• IFN-α has dose related toxicity, can leads to depression,
confusion, mania and other neuropsychiatric diseases. High
doasages may coause permanaent alternation of immune
system causing vitiligo and hypothyroidism
Cytokine Therapy Type I Interferons
IFN-α
• secreted by nearly every cell in the body and involved in
cellular immune responses against viral infections
• Type I-IFNs induce expression of MHC class I molecules on
tumor cells and mediate the maturation of a subset of DC
• can also activate CTLs, NK cells and macrophages
• IFN- α is the only currently approved adjuvant therapy for
patients with high-risk Stage II or Stage III melanoma
• Also approved for the treatment of some hematologic
malignancies, AIDS-related Kaposi’s sarcoma, and as a
component in an anti-angiogenic combination regimen with
bevacizumab for advanced renal cancer
• IFN-α has dose related toxicity, can leads to depression,
confusion, mania and other neuropsychiatric diseases. High
doasages may coause permanaent alternation of immune
system causing vitiligo and hypothyroidism

• produced by leukocytes but also by some
tumors
• comparatively, IFN-β is more potent than IFN- α
in inducing antiproliferative effects in cancer
models
• Usage is limitted due to substantial side effects
Cytokine Therapy Type I Interferons
IFN-β
• produced by leukocytes but also by some
tumors
• comparatively, IFN-β is more potent than IFN- α
in inducing antiproliferative effects in cancer
models
• Usage is limitted due to substantial side effects

• only member of this family is IFN-γ
• role in immunosurveillance :mice with targeted
deletion of IFN or the Type II IFN receptor have
an increased risk of spontaneous and
chemically-induced tumors compared to
controls
• cytotoxic to some malignant cells and has
modest anti-angiogenic activity
• IFN- has demonstrated very limited clinical
utility in cancer therapy
Cytokine Therapy Type II Interferons
• only member of this family is IFN-γ
• role in immunosurveillance :mice with targeted
deletion of IFN or the Type II IFN receptor have
an increased risk of spontaneous and
chemically-induced tumors compared to
controls
• cytotoxic to some malignant cells and has
modest anti-angiogenic activity
• IFN- has demonstrated very limited clinical
utility in cancer therapy

• IL-2 plays a pivotal role in the treatment of patients with
metastatic melanoma and renal cell carcinoma.
• National Cancer Institute found that adoptively
transferred IL-2-activated peripheral blood mononuclear
cells with administration of IL-2 in high doses, resulted in
significant tumor regression in patients
• it promotes both effector T cells and T-reg cells, but its
exact mechanism in the treatment of cancer is unknown
• Side effects: capillary leak syndrome, which is
characterized by hypotension, tachycardia and peripheral
edema secondary to third space fluid accumulation.
• fever, chill and fatigue, gastrointestinal side effects such
as nausea, vomiting, anorexia, cholestasis and diarrhea
• IL-2 reported a 2% mortality rate
Cytokine Therapy Interleukin-2
• IL-2 plays a pivotal role in the treatment of patients with
metastatic melanoma and renal cell carcinoma.
• National Cancer Institute found that adoptively
transferred IL-2-activated peripheral blood mononuclear
cells with administration of IL-2 in high doses, resulted in
significant tumor regression in patients
• it promotes both effector T cells and T-reg cells, but its
exact mechanism in the treatment of cancer is unknown
• Side effects: capillary leak syndrome, which is
characterized by hypotension, tachycardia and peripheral
edema secondary to third space fluid accumulation.
• fever, chill and fatigue, gastrointestinal side effects such
as nausea, vomiting, anorexia, cholestasis and diarrhea
• IL-2 reported a 2% mortality rate

• When combined with vaccines, cytokines can boost
immune responses through recruitment and maturation
of a wider variety of immune effector cells
• Ex:- GM-CSF primarily acts on myeloid cells, functions to
recruit DCs
• GVAX is a granulocyte-macrophage colony-stimulating
factor (GM-CSF) gene-transfected tumor cell vaccine
• GM-CSF gene transfected into tumor cells and used as a
vaccine (GVAX). Tumor regression and prolonged survival
was demonstrated in animal models. Toxicology with
GVAX indicated no adverse effects, which enabled
further testing in cancer patients.
• GVAX a vaccines based on cytokine is currently in Phase II
in pancreatic cancer, Aduro Biotech, a private company is
also trialing a combination of GVAX with a PD-1 inhibitor
Cytokine Based Tumor Cell Therapy
• When combined with vaccines, cytokines can boost
immune responses through recruitment and maturation
of a wider variety of immune effector cells
• Ex:- GM-CSF primarily acts on myeloid cells, functions to
recruit DCs
• GVAX is a granulocyte-macrophage colony-stimulating
factor (GM-CSF) gene-transfected tumor cell vaccine
• GM-CSF gene transfected into tumor cells and used as a
vaccine (GVAX). Tumor regression and prolonged survival
was demonstrated in animal models. Toxicology with
GVAX indicated no adverse effects, which enabled
further testing in cancer patients.
• GVAX a vaccines based on cytokine is currently in Phase II
in pancreatic cancer, Aduro Biotech, a private company is
also trialing a combination of GVAX with a PD-1 inhibitor

Adaptive T cell therapy
The initial T-cell based
therapy was reported by
Rosenberg in 1988

• isolate antigen-specific T cells from a cancer
patient, expand them to large numbers in a test-
tube, and re-infuse them back into the patient to
kill off the remaining tumor cells
• Cells are Harvested from a variety of sites, including
peripheral blood, malignant effusions, resected
lymph nodes, and tumor biopsies
• tumor-infiltrating lymphocytes (TILs) obtained from
biopsies may contain a higher frequency of tumor-
reactive cells
• T cells can be expanded through polyclonal
stimulation with activating antibodies or through
exposure to specific tumor antigens
Adoptive T cell therapy
• isolate antigen-specific T cells from a cancer
patient, expand them to large numbers in a test-
tube, and re-infuse them back into the patient to
kill off the remaining tumor cells
• Cells are Harvested from a variety of sites, including
peripheral blood, malignant effusions, resected
lymph nodes, and tumor biopsies
• tumor-infiltrating lymphocytes (TILs) obtained from
biopsies may contain a higher frequency of tumor-
reactive cells
• T cells can be expanded through polyclonal
stimulation with activating antibodies or through
exposure to specific tumor antigens

• Such infusions are short lived because immune
system where not able to provide co-stimulatory
signals to sudden large increase of CTLs
• Also requires the identification of relevant targets
• This can be overcome by treating the culture with
co stimulatory molecules
• CTL lines have cultured in medium containing IL-2
support T cell survival and proliferation
• cytokines such as IL-7, IL-12, IL-15, and IL-21 have
also proven crucial for the reactivation, survival,
and expansion of tumor specific T cells in vitro
• A second approach is by using genetic enginneering
• Such infusions are short lived because immune
system where not able to provide co-stimulatory
signals to sudden large increase of CTLs
• Also requires the identification of relevant targets
• This can be overcome by treating the culture with
co stimulatory molecules
• CTL lines have cultured in medium containing IL-2
support T cell survival and proliferation
• cytokines such as IL-7, IL-12, IL-15, and IL-21 have
also proven crucial for the reactivation, survival,
and expansion of tumor specific T cells in vitro
• A second approach is by using genetic enginneering

• T cells harvested from the peripheral blood can be
engineered to express TCRs that have been selected for
tumor recognition - tested in metastatic melanoma
• because TCR recognition of antigen is MHC restricted,
each engineered TCR can only be used in patients with
the required MHC allele
• This can be bypassed by engineering T cells to express
novel chimeric fusion proteins, “T-bodies” that link the
antigen-binding domain of the B cell receptor with the
signaling component of the TCR complex.
• T-bodies can directly bind tumor antigens, leading to T
cell activation
• tested in ovarian carcinoma, and pediatric
neuroblastoma
• T cells harvested from the peripheral blood can be
engineered to express TCRs that have been selected for
tumor recognition - tested in metastatic melanoma
• because TCR recognition of antigen is MHC restricted,
each engineered TCR can only be used in patients with
the required MHC allele
• This can be bypassed by engineering T cells to express
novel chimeric fusion proteins, “T-bodies” that link the
antigen-binding domain of the B cell receptor with the
signaling component of the TCR complex.
• T-bodies can directly bind tumor antigens, leading to T
cell activation
• tested in ovarian carcinoma, and pediatric
neuroblastoma

Adoptive T cell therapy Different approaches

Before
treatment
Complete Regression of Metastatic Cervical Cancer After Treatment With Human
Papillomavirus–Targeted Tumor-Infiltrating T Cells (HPV-TILs)
May 10, 2015
After 22
months of
treatment

Blockade of immune
system inhibitory
checkpoints to activates
immune system
function.
Immune checkpoint blockade

• A particularly important immune-checkpoint receptor is cytotoxic
T-lymphocyte-associated antigen 4 (CTLA4), which downmodulates
the amplitude of T cell activation. Antibody blockade of CTLA4 in
mouse models of cancer induced antitumour immunity.
• Clinical studies using antagonistic CTLA4 antibodies demonstrated
activity in melanoma. Despite a high frequency of immune-related
toxicity, this therapy enhanced survival in two randomized Phase III
trials.
• Anti-CTLA4 therapy was the first agent to demonstrate a survival
benefit in patients with advanced melanoma and was approved by the
US Food and Drug Administration (FDA) in 2010.
• Nivolumab has been approved in 2014. Pembrolizumab was also
approved by the FDA in 2014.
• The first monoclonal antibody approved by the FDA for immune
checkpoint blockade was ipilimumab, approved in 2011. Ipilimumab
blocks the inhibitory immune checkpoint CTLA-4.
Immune checkpoint blockade
• A particularly important immune-checkpoint receptor is cytotoxic
T-lymphocyte-associated antigen 4 (CTLA4), which downmodulates
the amplitude of T cell activation. Antibody blockade of CTLA4 in
mouse models of cancer induced antitumour immunity.
• Clinical studies using antagonistic CTLA4 antibodies demonstrated
activity in melanoma. Despite a high frequency of immune-related
toxicity, this therapy enhanced survival in two randomized Phase III
trials.
• Anti-CTLA4 therapy was the first agent to demonstrate a survival
benefit in patients with advanced melanoma and was approved by the
US Food and Drug Administration (FDA) in 2010.
• Nivolumab has been approved in 2014. Pembrolizumab was also
approved by the FDA in 2014.
• The first monoclonal antibody approved by the FDA for immune
checkpoint blockade was ipilimumab, approved in 2011. Ipilimumab
blocks the inhibitory immune checkpoint CTLA-4.

Regressions of lung (top two
panels) and brain (lower panel)
metastases in a patient with
melanoma who was treated
with ipilimumab. 25–30% of
patients treated with extended
doses of anti-CTLA4 therapy
can develop immune-related
‘on-target’ toxicities. However,
the frequency of severe
adverse toxicities was lower
(10–15%) with the short course
that was used in the Phase III
trial that led to the approval of
ipilimumab. This short-course
regimen (4 doses at a cost of
US$30,000 per dose) was
recommended by the US Food
and Drug Administration (FDA).
Regressions of lung (top two
panels) and brain (lower panel)
metastases in a patient with
melanoma who was treated
with ipilimumab. 25–30% of
patients treated with extended
doses of anti-CTLA4 therapy
can develop immune-related
‘on-target’ toxicities. However,
the frequency of severe
adverse toxicities was lower
(10–15%) with the short course
that was used in the Phase III
trial that led to the approval of
ipilimumab. This short-course
regimen (4 doses at a cost of
US$30,000 per dose) was
recommended by the US Food
and Drug Administration (FDA).

efficacy might be
improved by
combining
[targeted]
therapies with
immune-
stimulating
agents
Combined Therapy
efficacy might be
improved by
combining
[targeted]
therapies with
immune-
stimulating
agents

• monoclonal antibody trastuzumab targets ERBB2 in
breast cancer and expose them to ADCC which depends
on NK cells
• Ronald Levy and colleagues investigated whether
activation of the co-stimulatory molecule CD137 (also
known as TNFRSF9 and 4-1BB) in NK cells could improve
trastuzumab efficacy.
• In vitro studies showed that co-incubation of
ERBB2-expressing breast cancer cell lines and purified
human NK cells with trastuzumab upregulated CD137 on
the NK cells.
• These activated NK cells were able to kill trastuzumab-
coated ERBB2-expressing breast cancer cell lines through
ADCC, and this was enhanced by a CD137 agonistic
antibody.
Combination of therapy
• monoclonal antibody trastuzumab targets ERBB2 in
breast cancer and expose them to ADCC which depends
on NK cells
• Ronald Levy and colleagues investigated whether
activation of the co-stimulatory molecule CD137 (also
known as TNFRSF9 and 4-1BB) in NK cells could improve
trastuzumab efficacy.
• In vitro studies showed that co-incubation of
ERBB2-expressing breast cancer cell lines and purified
human NK cells with trastuzumab upregulated CD137 on
the NK cells.
• These activated NK cells were able to kill trastuzumab-
coated ERBB2-expressing breast cancer cell lines through
ADCC, and this was enhanced by a CD137 agonistic
antibody.

Combining PROSTVAC With ipilimumab

Combining PROSTVAC With radiotherapy
Exposure of prostate
cancer cell lines to
153Sm results in
increased
susceptibility to killing
by cytotoxic T
lymphocytes (CTLs),
establishing a
potential rationale for
the combination of
active
immunotherapy with
PROSTVAC and
radiotherapy with
153Sm. Early clinical
evidence is suggestive
of potential clinical
benefit with this
combination.
Exposure of prostate
cancer cell lines to
153Sm results in
increased
susceptibility to killing
by cytotoxic T
lymphocytes (CTLs),
establishing a
potential rationale for
the combination of
active
immunotherapy with
PROSTVAC and
radiotherapy with
153Sm. Early clinical
evidence is suggestive
of potential clinical
benefit with this
combination.

Reference
• Cancer immunotherapy via dendritic cells, Karolina.P and Jacques.B, Focus on
tumour immunology & immunotherapy, Nature reviews, cancer vol12, April 2012,
p265-277© 2012 Macmillan Publishers Limited
• Antibody therapy of cancer Andrew M. Scott1, Jedd D. Wolchok and Lloyd J. Old
Nature Reviews, April 2012, Vol 12, p278-287 © 2012 Macmillan Publishers
Limited. All rights reserved
• Cytokines in Cancer Immunotherapy, Sylvia. L and Kim.M, Cancers 2011, Vol3,
3856-3893; doi:10.3390/cancers3043856, ISSN 2072-6694,
www.mdpi.com/journal/cancers
• Vaccines in cancer: GVAX, a GM-CSF gene vaccine, Nemunaitis J, Expert Rev
Vaccines. 2005 Jun;4(3):259-74
• Complete Regression of Metastatic Cervical Cancer After Treatment With Human
Papillomavirus–Targeted Tumor-Infiltrating T Cells , Sanja Stevanović et al,
American Society of Clinical Oncology, May 10, 2015 vol. 33 no. 14 1543-1550 ,
doi: 10.1200/JCO.2014.58.9093
• Combinations that work, Sarah Seton-Rogers, Research Highlights Nature Reviews,
Cancer Vol12, APRIL 2012
• Cancer immunotherapy via dendritic cells, Karolina.P and Jacques.B, Focus on
tumour immunology & immunotherapy, Nature reviews, cancer vol12, April 2012,
p265-277© 2012 Macmillan Publishers Limited
• Antibody therapy of cancer Andrew M. Scott1, Jedd D. Wolchok and Lloyd J. Old
Nature Reviews, April 2012, Vol 12, p278-287 © 2012 Macmillan Publishers
Limited. All rights reserved
• Cytokines in Cancer Immunotherapy, Sylvia. L and Kim.M, Cancers 2011, Vol3,
3856-3893; doi:10.3390/cancers3043856, ISSN 2072-6694,
www.mdpi.com/journal/cancers
• Vaccines in cancer: GVAX, a GM-CSF gene vaccine, Nemunaitis J, Expert Rev
Vaccines. 2005 Jun;4(3):259-74
• Complete Regression of Metastatic Cervical Cancer After Treatment With Human
Papillomavirus–Targeted Tumor-Infiltrating T Cells , Sanja Stevanović et al,
American Society of Clinical Oncology, May 10, 2015 vol. 33 no. 14 1543-1550 ,
doi: 10.1200/JCO.2014.58.9093
• Combinations that work, Sarah Seton-Rogers, Research Highlights Nature Reviews,
Cancer Vol12, APRIL 2012

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