Immunotherapy

: a new treatment to
fight cancer.

DR. dr. Andhika Rachman, Sp.PD-KHOM, FINASIM

Could the Immune System be an
Important Ally in the Fight Against Cancer?
• The presence of immune cells (such as Tumor
T cells) within a tumor has been
correlated with better clinical outcome in
some tumor types1–3 T cells

– Less advanced stage

– Absence of signs of metastasis
– Increased survival
– Reduced risk of relapse

• When the immune system is suppressed, the risk of developing

certain cancers increases
– HIV patients4
– Transplant patients treated with immunosuppressants5

HIV = human immunodeficiency virus.

1. Hwang WT et al. Gynecol Oncol. 2012;124:192–198. 2. Pages F et al. N Engl J Med. 2005;353:2654–2666. 3. Loi S et al. J Clin Oncol. 2013;31:860–
867. 4. Engels EA et al. Int J Cancer. 2008;123:187–194. 5. Grulich AE et al. Lancet. 2007;370:59–67.
IO therapy differs from conventional anticancer
treatments
Immuno-oncology (IO) therapy, or cancer immunotherapy, differs from chemotherapy and targeted therapy:1,2,3
• Ideally, by modulating the immune system, it can be effective in a broad range of tumors, independent of
tumor histology or driver mutations
• However, these therapies can also effect normal, healthy cells

Cytotoxic Chemotherapy Targeted Therapy IO Therapy

Mitosis M phase
(nuclear Cytokinesis
CAR-T cell
division) (cytoplasmic
division)
M
G2 phase
G2 PD-L2 Tumor
Tumor cell PD-1
Receptor
Interphase PD-L1
CTLA-4
G1 G1 phase T cell Receptor
S phase
M
(DNA replication) B7

• Acts on all rapidly dividing cells, • Targets changes in cancer cells that • Acts on the body’s own immune system
including tumor cells and some normal promote growth, division, and spread to fight cancer5
cells2,3 (often as a result of mutation)4,5 • Modulates immune inhibitory mechanisms
• Prevents cell growth and division2,3 to reactivate antitumor immunity6,7

• References: 1. Emens LA et al. Eur J Cancer. 2017;81:116–129. 2. Molecular Biology of the Cell, sixth edition by Bruce Alberts et al. Copyright © 2015 by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, and Peter Walter. Used by permission of W. W. Norton &
Company, Inc. . National Cancer Institute. Chemotherapy to treat cancer. https://www.cancer.gov/about-cancer/treatment/types/chemotherapy. Accessed on: 14 August 2020. 4. National Cancer Institute. Targeted therapy to treat cancer. https://www.cancer.gov/about-
cancer/treatment/types/targeted-therapies. Accessed on: 14 August 2020. 5. Boolell V et al. Cancers (Basel). 2015;7(3):1815–1846. 6. Pardoll DM. Nat Rev Cancer. 2012;12(4):252–264. 7. Garon EB. Semin Oncol. 2015;42(suppl 2):S11–S18.
 IO therapies, including ICIs, aim to modulate immune responses against cance
cells

The ultimate goal of IO therapy is to create a durable pool of T cells that have potent antitumor activity

Immune Checkpoint Inhibitors (ICIs)

Cancer Vaccines

T-Cell Transfer Therapy

Monoclonal Antibodies and Tumor-Agnostic

Therapies

Other Non-Specific IO Therapy

• Reference: Emens LA et al. Cancer Immunol Res. 2015;3(5)436–444;.

Immune checkpoints like PD-1 and CTLA-4 are found on T cells
and normally act as an “off switch” for immune response1,2

When attached T-cell

• In healthy cells, immune to PD-L1/PD- PD-1 CTLA-4
checkpoints play an L2, PD-1 helps
important role in preventing keep T cells CD28
excessive immune from killing
responses to reduce other cells, T cell When
receptors
injury to healthy cells1,2 including attached to
• Some cancer cells can use cancer cells1,2 Antigens another
inhibitory checkpoint PD-L2 PD-L1 B7 protein
called B7,
pathways (eg, PD-1 and
CTLA-4 helps
CTLA-4) to downregulate Antigen-presenting cell keep
this immune attack3,4
Cancer cell or T cells from
Antigen-presenting cell killing other
cells,
Adapted from Raman R and Vaena D. Biomed Res Int. 2015;2015:367354.
including
cancer cells1

• References: 1. National Cancer Institute. NCI Dictionary of Cancer Terms. https://www.cancer.gov/widgets/termdictionarywidgetenglish. Accessed on: 14 August 2020. 2. Salmaninejad A, Valilou
SF, Shabgah AG, et al. J Cell Physiol. 2019;234(10):16824-16837. 3. May KF Jr et al. In: Prendergast GC, Jaffee EM, eds. Cancer Immunotherapy: Immune Suppression and Tumor Growth. 2nd ed.
Amsterdam, Netherlands; Elsevier: 2013:111–114. 4. Mellman I. Nature. 2011(7378);480:480–489.
Differentiating PD-1 vs CTLA-4 immune checkpoint (1 of 2)

Immune checkpoint inhibitors2

• CTLA-4 is expressed on the T cells, Antigen-presenting cell or T cell
whereas PD-1 is expressed more Tumor cell
broadly on activated
T cells, B cells, and myeloid cells1,2 MHC T cell receptor

• CTLA-4 and PD-1 roles in inhibiting

immune responses, including PD-L1 PD-1
antitumor responses, are largely
distinct:1,2 PD-L2
B7.1

• CTLA-4 inhibits T cells in the early

stages of the immunity cycle primarily PD-L1
in the lymph nodes B7.1
CTLA-4
• PD-1 regulates the immune response
primarily in the peripheral tissues
through binding to its ligands, PD-L1
and PD-L2
Adapted from Soria J-C et al. Clin Cancer Res. 2015 with permission from AACR.

• References: 1. Buchbinder EI, Desai A. Am J Clin Oncol. 2016;39(1):98-106. 2. Soria J-C et al. Clin Cancer Res. 2015;21(10):2256–2262.
Differentiating PD-1 vs CTLA-4 immune checkpoint (2 of 2)

Comparison of CTLA-4 and PD-1

Similarities

Expressed by activated T cells

Level of expression affected by the strength and/or duration of T-cell receptor signaling
Similar negative effects on T-cell activity

CTLA-4 PD-1
Differences

Timing of T-cell • Earlier immune response during the • Later immune response in the
downregulation priming phase effector phase*
Anatomical location • T cells • T cells, B cells, and myeloid cells
Distribution of ligands • Professional APCs, which typically • More widely expressed by antigen-
reside in lymph modes and spleen presenting cells and other immune
cells
• Expressed in the peripheral tissues
CTLA-4, cytotoxic T-lymphocyte-associated antigen 4; PD-1, programmed death protein1; APC, antigen-presenting cell.
*Binding with T cells already engaged in an effector response may result in a more restricted spectrum of T-cell inhibition.

• Reference: Buchbinder EI, Desai A. Am J Clin Oncol. 2016;39(1):98-106.

Immune checkpoint inhibitors (ICIs) act as an “on switch” to reactivate
the anticancer immune response1

Some currently approved ICIs target the PD-1/PD-L1 and CTLA-4 pathways2-5

Inhibition of PD-L1/PD- T cell Inhibition of CTLA-4

PD-1 CTLA-4
L2 to the PD-1 receptor signaling can augment
helps to allow the PD-1 inhibitor
T-cell activation and
immune system to act proliferation to
against cancer cells to
X increase immune
potentially reduce
tumor growth3,4
PD-L2 inhibitor T cell
receptors
X X CTLA-4
inhibitor response against
cancer cells or
Antigens antigen-presenting
PD-L1 inhibitor
PD-L2 PD-L1 B7 cells5

Antigen-presenting cell

Cancer cell or antigen-

presenting cell death Adapted from Raman R and Vaena D. Biomed
Res Int. 2015;2015:367354.

• References: 1. National Cancer Institute. NCI Dictionary of Cancer Terms. https://www.cancer.gov/widgets/termdictionarywidgetenglish. Accessed on: 14 August 2020.. 2. Mellman I. Nature.
2011(7378);480:480–489. 3. Keytruda (pembrolizumab) [prescribing information]. 9-2019. 4. Tecentriq (atezolizumab) [prescribing information]. 12-2019. 5. Yervoy (ipilimumab) [prescribing information].
9-2019. 6. Cole S, Zibelman M, Bertino E, et al. Am Soc Clin Oncol Educ Book. 2019 Jan;39:96-104
Other IO therapies: Cancer vaccines prime the immune system to mount an
attack against cancer cells in the body

Cancer vaccines
• Instead of preventing disease, cancer
Specific CD4 T cell
vaccines are meant to prime the immune
system to elicit immune responses against Dendritic cell Class II
existing tumor cells MHC

• Sipuleucel-T and T-VEC are examples of Intradermal

approved cancer vaccines vaccine protein or
peptide and
• Cancer vaccines can cause flu-like adjuvant
symptoms such as fever, chills, weakness,
dizziness, Class I MHC
nausea or vomiting, fatigue, muscle and joint Antigen uptake
by immature
pain, trouble breathing, low or high blood DC CD8 T cell
pressure,
and headache Activated CD8 T cell

Adapted from Drake CG et al. Nat Rev Clin Oncol. 2014 with permission from Macmillan
Publishers Ltd.

• Reference: NIH National Cancer Institute. Cancer Treatment Vaccines. https://www.cancer.gov/about-cancer/treatment/types/immunotherapy/cancer-treatment-

vaccines. Accessed on 14 August 2020.
Other IO therapies: T-cell transfer therapy adapts a person’s own immune
cells to elicit a more effective immune response against cancer cells1

Adoptive cell transfer (CAR T cell therapy)3

• There are two main types of T-cell transfer therapies:
• Tumor-infiltrating lymphocytes (or TIL) therapy, which Modified CAR T-cell infusion
increases the number of specific tumor-infiltrating 1
Collection of patient
6 along with lymphodepleting
T cells by leukapheresis
lymphocytes that are thought to best recognize the exact chemotherapy
cancer type1
• Chimeric antigen receptor (CAR) T-cell therapy, which
adapts the ability of T cells to attack cancer cells by
engineering a patient's T cells to recognize specific proteins Manufacture of CAR T cells
on cancer cells2
2 T cell activation
• As with other IO therapies, there are risks for serious AEs Antibody-coated Expansion of
beads 4 CAR-expressing
from these treatments (eg, neurotoxicity or cytokine T cells
release syndrome (CRS) associated with CAR T cell
therapy)2,3 5 Isolation
of final
Transduction cell product
3
with CAR
construct

• References: 1. National Cancer Institute. T-cell Transfer Therapy. https://www.cancer.gov/about-cancer/treatment/types/immunotherapy/t-cell-transfer-therapy.

Accessed on: 14 August 2020. 2. American Cancer Society. CAR T-Cell Therapy to Treat Cancer. 2017. 3. Maus MV, June CH. Clin Cancer Res. 2016;22(8):1875–1884.
Other IO therapies: Monoclonal antibodies (mAbs) help the immune system
mount an attack against cancer cells1
• Naked monoclonal antibodies: Boost immune response against Monoclonal antibody therapy1
cancer cells or block antigens that help cancer cells grow or spread2
• Most naked mAbs attach to antigens on cancer cells, but some work by binding to antigens on other,
non-cancerous cells, or even free-floating proteins Monoclonal antibody
• Examples include: trastuzumab, alemtuzumab

• Conjugated monoclonal antibodies: Deliver chemotherapy Antigen (can

drug/radioactive particle to target antigen2 cause immune
response)
• Examples include: brentuximab vedotin, ibritumomab tiuxetan

• Bispecific monoclonal antibodies: Made up of parts of

2 different monoclonal antibodies, therefore they can attach to The monoclonal
antibody locks
Cancer cell
2 different proteins at the same time2 onto the antigen.
This can cause the
• An example includes: Blinatumomab immune system to
attack the cancer
cell.

• References: 1. National Cancer Institute. Monoclonal Antibodies. https://www.cancer.gov/about-cancer/treatment/types/immunotherapy/monoclonal-

antibodies. Accessed on: 14 August 2020. 2. American Cancer Society. Monoclonal antibodies to treat cancer. 2016.
Other IO therapies: Non-specific immune-modulating agents
can enhance the body’s immune response against cancer
Non-specific Immunotherapies
• Stimulate the immune system which may lead to a better immune response against cancer
cells
• May be given by themselves or as adjuvants (along with a main treatment)
• Non-specific immunotherapies include:
• Cytokines such as interleukins and interferons
• Immunomodulating drugs (or IMiDs) such as thalidomide, lenalidomide, and pomalidomide
• Thought to work in a general way by boosting the immune system, however the
mechanism
of action is unknown
• Bacille Calmette-Guérin (BCG)
• A weakened form of the bacteria that can infect human tissues and help activate the
immune system to attack certain cancer cells
• Imiquimod
• Topical medication that stimulates a local immune response against very early stage
skin cancers (or pre-cancers)

• Reference: American Cancer Society. Non-specific cancer immunotherapies and adjuvants. 2016.
What Have We Learned About the Role of the
Immune System in Oncology?
Burnet and Thomas: The Reports of tumor regression
theory of in patients administered LAK
immunosurveillance2: The with IL-2.4 Regulators of T-cell activity,
immune system patrols spurring research into the
Coley reports cases of The immune response
the body to detect and role of immune checkpoints
tumor regression remains an active
destroy nascent tumor in cancer are elucidated.6
following inoculation focus of cancer
with erysipelas cells.
research.9
infection.1

1890s 1909 Late 1950s 1980s 1985 1990s 1995 2000s Present

Paul Ehrlich proposed a role

for the immune system Tumors are found to Increased
against cancer.2 express antigens that tumorigenesis in
Beginning in the 1980s, can elicit a T cell– immunodeficient mice
immunosuppressed HIV mediated immune lacking T-, B- 7,8
patients were shown to be at response.5 and NKT cells.
increased risk of certain
cancers.3

HIV = human immunodeficiency virus; LAK = lymphokine-activated killer; IL-2 = interleukin-2; NKT = natural killer T.
1. Coley WB. Am J Med Sci. 1893;105:487–511. 2. Ichim CV. J Transl Med. 20058;3:8. 3. Levine AM et al. Curr Probl Cancer. 1987;11:209–55. 4.
Rosenberg SA et al. N Engl J Med. 1985;313:1485–1492. 5. van der Bruggen P et al. Science. 1991;254:1643–1647. 6. Tivol EA. et al. Immunity.
1995;3:541–547. 7. Vesely MD et al. Annu Rev Immunol. 2011;29:235–271. 8. Shankaran V. et al. Nature. 2001;410:1107–1111. 9. Drake CG et al. Nat. Rev. Clin. Oncol. 2014;11:124–37.
The Immune System Can Fight Tumors Via A Variety of
Functionally Specialized Cells1

Dendritic cells
T cells
Myeloid- Lymphoid-
derived cells derived cells
Hematopoietic
Present antigens Eradicate
derived from Stem cell pathogens and
pathogens and nascent tumor cells
nascent tumor cells to B cells through their
immune cells, response to
including T cells, B antigens that are
cells, and not expressed in
Macrophages
NK cells normal tissue
NK cells

NK = natural killer.
1. Norvell A. In: Prendergast GC et al. Cancer Immunotherapy. 2nd ed. Elsevier; 2013:11–24.
Some Tumor Cells Express Multiple Antigens That Are Not
Expressed by Normal Cells1
Tumor cells release differentially
Normal cells release molecules that are
expressed antigens that cause them to
captured by antigen-presenting cells, but
be recognized as foreign entities and
they don’t elicit an immune response.
therefore elicit an immune response.

NORMAL TUMOR
CELL CELL

1. Finn OJ. N Engl J Med. 2008;358:2704–2715.

T cells Are Important in the Ability of the Immune System to Detect
and Destroy Tumor Cells1

1. Antigens are released by tumor cells and

captured by dendritic cells.
Dendritic cell

TUMOR

1. May KF Jr et al. In: Prendergast GC et al. Cancer Immunotherapy. 2nd ed. Elsevier; 2013:101–113.
T cells Are Important in the Ability of the Immune System to Detect
and Destroy Tumor Cells1

1. Antigens are released by tumor cells and

captured by dendritic cells.
Dendritic cell

Naive T cell

TUMOR 2. Dendritic cells activate

naive T cells in lymph
nodes.

LYMPH
NODE

1. May KF Jr et al. In: Prendergast GC et al. Cancer Immunotherapy. 2nd ed. Elsevier; 2013:101–113.
1
T cells Are Important in the Ability of the Immune System to Detect
and Destroy Tumor Cells1

1. Antigens are released by tumor cells and

captured by dendritic cells.
Dendritic cell

Naive T cell

TUMOR 2. Dendritic cells activate

naive T cells in lymph
nodes.

LYMPH
NODE

Activated
T cell

3. Activated T cells migrate back to the

tumor.

1. May KF Jr et al. In: Prendergast GC et al. Cancer Immunotherapy. 2nd ed. Elsevier; 2013:101–113.
T cells Are Important in the Ability of the Immune System to Detect
and Destroy Tumor Cells1

1. Antigens are released by tumor cells and

captured by dendritic cells.
Dendritic cell

Naive T cell

TUMOR 2. Dendritic cells activate

naive T cells in lymph
nodes.

LYMPH
NODE

Activated
4. T cells kill tumor cells through T cell
the release of lytic enzymes or
induction of apoptosis.

3. Activated T cells migrate back to the

tumor.

1. May KF Jr et al. In: Prendergast GC et al. Cancer Immunotherapy. 2nd ed. Elsevier; 2013:101–113.
1
 T-Cell Activity Is Regulated By Immune
Checkpoints to Limit Autoimmunity1
Dendritic cell

Inactivated
T cell
TUMOR

Inactivated - Checkpoints
Checkpoints - LYMPH
T cell NODE

Immune checkpoints, such as

CTLA-4, PD-1, LAG-3, and TIM-3
function at different phases in Activated
T cell
the immune response to
regulate the duration and level
of the T-cell response.

CTLA-4 = cytotoxic T-lymphocyte antigen 4; PD-1 = programmed cell death protein 1; LAG-3 = lymphocyte activation gene 3;
TIM-3 = T-cell immunoglobulin and mucin protein 3.
1. Pardoll DM. Nat Rev Cancer. 2012;12:252–264.
2
How Do Tumors Evade the
Immune Response?
 Escape From Immune Surveillance Is an Emerging
Hallmark of Cancer
• Avoiding immune surveillance is an emerging Hallmarks of cancer
hallmark of cancer that allows cancer cells to
evade immunologic destruction by disabling Emerging Hallmarks
components of the immune system (eg, T
and B lymphocytes, macrophages, and Activated Tumor cells can evade
natural killer cells) that have been Tumor cells can reprogram T cells detection and
dispatched to eliminate them1 cellular metabolism to gain
destruction by the
energy
immune system

Tumor cells divide TUMOR Tumor cells invade and

without control metastasize to other tissues

Tumor cells sustain

Tumor cells encourage
proliferative signaling
Tumor cells evade growth of new blood vessels
Tumor cells resist
growth suppressors
cell death

Established Hallmarks

1. Image adapted from Hanahan D, Weinberg RA. Cell. 2011;144(5):646–674.

 Tumor Cells Can Evade the Body’s Immune
Response Via Different Mechanisms

1. Loss of antigen expression1

2. Secreting immunosuppressive cytokines and recruiting
immunosuppressive cells2,3
3. Exploiting immune checkpoint pathways, such as the
PD-1 pathway4

PD-1 = programmed cell death protein 1.

1. Ahmad M et al. Cancer Immunol Immunother. 2004;53:844–854; 2. Zou W. Nat Rev Immunol. 2006;6:295–307;
3. Finn OJ. N Engl J Med. 2008;358:2704–2715; 4. Pardoll DM. Nat Rev Cancer. 2012;12:252–264.
2
 1. Loss of Antigen Expression

Dendritic cells

• In the adaptive immune

response, the first step of
tumor cell detection is
antigen capture and
presentation by dendritic
TUMOR cells1
• Tumors can escape
detection by decreasing or
completely shutting down
antigen expression2

1. Pinzon-Charry A et al. Immunol Cell Biol. 2005;83:451–461.

2. Ahmad M et al. Cancer Immunol Immunother. 2004;53:844–854.
 2. Secreting Immunosuppressive Cytokines
and Recruiting Immunosuppressive Cells

• Tumor cells can secrete MDSC

cytokines (TGF-β, IL-10,
VEGF) that have an
Treg
inhibitory effect on T and
NK cell function1
Inactivated
• Tumor cells can be T cell
Cytokines
infiltrated by
immunosuppressive cells
that can inhibit T cell Inactivated

function2: TUMOR NK cell

– Treg cells
– MDSCs

TGF-b = transforming growth factor b; IL-10 = interleukin10; VEGF = vascular endothelial growth factor; NK = natural killer;
Treg = T regulatory; MDSCs = myeloid-derived suppressor cells.
1. Zou W. Nat Rev Immunol. 2006;6:295–307; 2. Finn OJ. N Engl J Med. 2008;358:2704–2715.
 3. Exploiting the PD-1 Immune Checkpoint Pathway1
Priming Phase of Effector Phase
Activation
Dendritic cell Naïve T cell Activated T cell Tumor cell

• Emerging research has

PD-1 identified PD-1 as an
immune checkpoint
pathway that tumor cells
may exploit to evade
Antigen
immune surveillance
• Tumor cells may block
immune responses via the
TCR MHC
PD-1 immune checkpoint
pathway by expressing the
dual PD-1 ligands, PD-L1
and PD-L2
PD-L1

PD-1
Adapted with permission from Pardoll DM.1 PD-L2
PD-1 = programmed cell death protein 1; TCR = T-cell receptor; MHC = major histocompatibility complex; PD-L1 = programmed
cell death ligand 1; PD-L2 = programmed cell death ligand 2.
1. Pardoll DM. Nat Rev Cancer. 2012;12:252–64.
 3. Exploiting the PD-1 Immune Checkpoint Pathway1
Priming Phase of Effector Phase
Activation
Dendritic cell Naïve T cell Inactivated T cell Tumor cell

• PD-1 is upregulated on
PD-1 activated T cells during

-
the effector phase of the
immune response

Antigen • PD-L1 and PD-L2

engage the PD-1
TCR MHC receptor on T cells to
downregulate T-cell
activity in the effector
PD-L1 phase

- PD-1

PD-L2

T cell Tumor cells

Adapted with permission from Pardoll DM.1 Inactivation evade destruction
PD-1 = programmed cell death protein 1; PD-L1 = programmed cell death ligand 1; PD-L2 = programmed cell death ligand 2.
1. Pardoll DM. Nat Rev Cancer. 2012;12:252–264.
 Targeting the PD-1 Pathway Involved in Tumor Immunosuppression Is a
Promising Therapeutic Approach
Effector phase
• PD-1 receptors are normally expressed on various immune cells, including
inactivated T cells1 Inactivated T cell Tumor cell

• Activated (primed) T cells upregulate PD-L11 PD-L1

• Tumor cells can express the PD-1 ligands,
PD-L1 and PD-L21
PD-1 PD-L2
• PD-L1 and PD-L2 bind to the PD-1 receptors to inhibit the activated T cells
and allow tumor cells
to evade the immune response1
• Studies have demonstrated significant correlations between impaired
survival and tumor expression of PD-L1 and PD-L22
• Anti–PD-1 antibodies block PD-L1 and PD-L2 from binding to PD-1 in the
tumor microenvironment3

Activated
Anti–PD-1 Tumor cell
T cell
Image adapted from Pardoll DM. Nat Rev Cancer. 2012;12(4):252–264.
PD-1 = programmed death receptor-1; PD-L1 = programmed death ligand 1; PD-L2 = programmed death ligand 2; MHC = major histocompatibility complex; TCR = T-cell receptor.
1. Pardoll DM. Nat Rev Cancer. 2012;12(4):252–264. 2. Khan H et al. J Oncol. 2015;2015:847383. 3. McDermott DF, Atkins MB. Cancer Med. 2013;2(5):662–673.
 PD-1 Receptor Inhibition May Provide More Complete
Pathway Blockade Than Targeting a Single Ligand
1 1
PD-1 Receptor Inhibition PD-L1 Ligand Inhibition
• PD-1 is a receptor located on T cells • PD-L1 and PD-L2 are ligands located on tumor cells
• Antibodies directed against the PD-1 receptor on T cells block the binding of both PD-L1 and PD-L2 • Antibodies targeting the PD-L1 ligand on tumor cells only block the binding of PD-L1 to the PD-1
• Signaling activities of both PD-L1 and PD-L2 are inhibited
receptor

• PD-L2 is expressed in bladder cancer and may be an essential part of its immuno-biology • Signaling activities of PD-L2 are not inhibited

Antigen

MHC
TCR

Anti-PD-1

PD-1
PD-L1

Activated PD-L2
cytotoxic T cell Tumor cell

PD-1 = programmed death receptor-1; PD-L1 = programmed death ligand 1; PD-L2 = programmed death ligand 2.
1. McDermott DF, Atkins MB. Cancer Med. 2013;2(5):662–673. Figure: Pardoll DM. Nat Rev Cancer. 2012;12:252–264.
 PD-1 Pathway and Pembrolizumab

• PD-1 is a negative co-stimulatory receptor

expressed primarily on activated T cells1
• Binding of PD-1 to its ligands
PD-L1 and PD-L2 inhibits effector
T-cell function1
• PD-L1 expression on tumor cells and
macrophages suppresses immune surveillance
and permits neoplastic growth2
• Pembrolizumab is a humanized monoclonal
IgG4 antibody
• Binds to PD-1 with high affinity
• Prevents PD-1 from binding to PD-L1 and PD-L2
• Robust antitumor activity and manageable in
multiple advanced malignanciesa

aFDA-approved for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation

positive, a BRAF inhibitor.

1. Keir ME et al. Annu Rev Immunol. 2008;26:677-704; 2. Pardoll DM. Nat Rev Cancer. 2012;12:252-64.
Mechanism of action – Immunotherapy in combination
with Chemotherapy

31
 Chemotherapy Can Induce Immunogenic Cell Death (ICD): A Robust Mechanism
for Enhancing Immunogenicity Of Cold
PD-L1 negative tumors
Dying tumor cells emit a panel of DAMPs, which can activate innate and ICD is independent of
ICD is involved in the antitumor activity of adaptive immune responses.1 other mechanisms of
chemotherapies including anthracyclines,
cyclophosphamide, oxaliplatin, and
tumor cell death mediated
bortezomib.1 by cytotoxic agents, such
Calreticulin acts as an “eat me”
Therapy-induced ER stress
signal, leading to engulfment of as the DNA-binding effects
leads to exposure of calreticulin
1
Oxaliplatin
on the plasma membrane the tumor cell by DCs of platinum-based
chemotherapy2
Preapoptotic/early apoptotic cell

ATP acts as a chemoattractant,

Induction of apoptosis leads leading to the recruitment of DCs
2 to release of ATP from the to the tumor site and inducing
dying cell DC maturation

Cancer cell Apoptotic cell

Calreticulin

HMGB-1 HMGB-1 is recognized by TLR4

During secondary necrosis, the cell
3 on DCs, leading to enhanced
ATP membrane becomes
activation and cross-presentation
permeabilized, leading to release of
by DCs
HMGB-1

Necrotic cell

1. Fournier C et al. Curr Opin Pharmacol. 2017;35:83–88. 2. Hato SV et al. Clin Cancer Res. 2014;20(11):2831–2837. Reprinted with permission of AACR: Hato SV et al. Clin Cancer Res. 2014;20(11):2831–2837.
 Response to I-O Therapy Is a Multistep Process That May Impact Response
Kinetics
The response to I-O therapies that modulate T-cell activity may be characterized as a multistep process1

Start Days to Weeks Weeks to Months Several Months

Initial I-O therapy Immune cell activation
Effect on tumor2 Effect on survival2
administration2 and proliferation2

I-O, immuno-oncology.
1. Hoos A, Britten CM. OncoImmunology. 2012;1:334-339.
2. Hoos A et al. J Natl Cancer Inst. 2010;102:1388-1397.
 Non-Conventional Response and I-O Therapy
Apparent progression upon radiographic imaging after initial I-O therapy can actually be a sign of non-
conventional response to I-O therapy. This response may occur when T cells infiltrate the tumor site and
1,2
cause tumors to flare or appearance of new lesions upon imaging.

I-O therapy

T cells
infiltrating the
Tumor cells
tumor site
Appearance of new
lesions upon imaging

I-O, immuno-oncology.
1. Wolchok JD et al. Clin Cancer Res. 2009;15:7412-7420.
2. Ribas A et al. Clin Cancer Res. 2009;15:7116-7118.
34
 Potential Patterns of Response to I-O Therapy
Therapies that affect the immune system may not induce a measurable impact on tumor growth immediately after
administration. Potential effects may be seen weeks to months after initial administration. The potential patterns of response to I-
O therapies that modulate T-cell activity are1,2:

Immediate response3

Lack of tumor shrinkage but a slowing

of tumor progression3

Early but clinically insignificant progression3

Tumor regression after early radiographical

progression that may be caused by T cells
infiltrating the tumor site or appearance of
new lesions upon imaging3,4

There is also the potential that patients may not respond to therapy.

I-O, immuno-oncology.
1. Hoos A et al. OncoImmunol. 2012;1:334-339. 2. Aarntzen EHJG et al. Cell Mol Life Sci. 2013;70:2237-2257. 35
3. Wolchok JD et al. Clin Cancer Res. 2009;15:7412-7420. 4. Ribas A et al. Clin Cancer Res. 2009;15:7116-7118.
 Time to Response1,a

CR or PR
PD or death
Pembrolizumab
(n=57) Treatment
ongoing

Median time to response:

2.1 months (range, 1.4–6.3)

Chemotherapy
(n=30) Median time to response:
2.1 months (range, 1.7–4.9)

Weeks

aFor patients who achieved a complete or partial response.

Data cutoff date: January 18, 2017.

CR = complete response; PD = progressive disease; PR = partial response.
1. Bajorin DF, et al. Presented at ASCO 2017; Abstract 4501.
Summary
• The body’s immune system can detect and destroy tumor
cells through T-cell activity1
• T-cell activity is regulated by various immune checkpoints in order to
limit collateral tissue damage during the immune response2
• One way tumor cells may evade the body’s immune response is
by exploiting the PD-1 immune checkpoint pathway2

PD-L1 = programmed cell death ligand 1.

1. Finn OJ. Ann Oncol. 2012;23 (suppl 8): viii6–vii9; 2. Pardoll DM. Nat Rev Cancer. 2012;12:252–264.