Cancer Immunotherapy

Dra. Cristina Nadal

Oncologia Medica
Hospital Clinic Barcelona
 What is Immunotherapy?

Treatment to boost or restore the ability of the

immune system to fight cancer, infections, and
other diseases

National Cancer Institute, 2014

 Cancer Capabilities
Sustained proliferative Evading growth
signalling suppressors

Deregulating cellular
energetics Avoiding immune
destruction

Resisting cell Enabling replicative

death immortality

Genome instability and

Tumour-promoting
mutation
inflammation

Inducing angiogenesis Activating

invasion and
metastasis

Hanahan & Weinberg. Cell 2011

 tumor cells and system attack.
normal cells, Immunotherapy seeks to reverse this
tolerance, to once again identify the
the tumor cells
may be able What is Immunotherapy? cancer cells as a threat and a target for
destruction.
to hide.

FIGURE 5
HOW THEIMMUNESYSTEM ATTACKS CANCER

Tumor Tumor APC Naïve T cell Activated T cell Activated Destroyed

cell antigens T cell tumor cell

Tumor
cell

Tumor cells release APCs gather tumor T cells are Activated T cells find the tumor
tumor antigens. antigens and prepare to activated by cells with the same tumor
present to naïve T cells. the APC. antigens and destroy them.
©Patient Resource LLC

Pat i ent Resource.com 3

PatientResource.com
 History of Immunotherapy
In 1796 Dr. Edward Jenner realized cowpox
protected against smallpox
• Introduced the practice of vaccination
 History of Cancer Immunotherapy

PatientResource.com
 History of Cancer Immunotherapy
PatientResource.com
Immunotherapy in Cancer
 Immunotherapy in Cancer

Therapeutic Antibodies

Immune Checkpoints Modulators

Immune Cell Therapy

Cancer Treatment Vaccines

Immune System Modulators

 Immunotherapy in Cancer

Therapeutic Antibodies

Immune Checkpoints Modulators

Immune Cell Therapy

Cancer Treatment Vaccines

Immune System Modulators

Therapeutic Antibodies
Therapeutic Antibodies
Therapeutic Antibodies
 Therapeutic Antibodies
Tumor cell
AkT
EGFR mTOR
PI3K
HER2
Hypoxia
HER3 RAS
Cyclin D1
HIFa
HER4
MAPK Normoxia

pVHL
VEGF

EGFR MaB Proteasome

inhibitors

P P P P
P P P P
VEGFR-1 VEGFR-2
Endothelial cell
Therapeutic Antibodies

ADCC

Halim N. Monoclonal antibodies: a 25-year roller coaster ride. 2000.

 Therapeutic Antibodies

Secondary Effects
Therapeutic Antibodies

Weiner LM. Nat Rev Immunol, 2010

Therapeutic Antibodies
 Therapeutic Antibodies

IMMUNOCONJUGATES
Denileukin-Diftitox CD25 Skin Lymphoma
Gemtuzumab-Ozogamicin CD33 Acute Myelogenous
Leukaemia
Ibritumomab-Tiuxetan CD20 Lymphoma
Tositumumab-I131 CD20 Lymphoma
Trastuzumab-Emtansina HER2 Breast
(TDM1)
Brentuximab-Vetodina CD30 Lymphoma

Weiner, Nat Rev Immunology, 2010

 Therapeutic Antibodies
Bispecific Antibodies

Rouet, Nature Biotech, 2014

 Immunotherapy in Cancer

Therapeutic Antibodies

Immune Checkpoints Modulators

Immune Cell Therapy

Cancer Treatment Vaccines

Immune System Modulators

 Immune Checkpoints Modulators

Co-stimulatory molecules
TNF receptor or B7 superfamilies Mellman, Nature, Dec 2011
Immune Checkpoints Modulators
Immune Checkpoints Modulators
CTLA-4: Negatively Modulates the Immune Response

Pardoll, Nature Rev Cancer, 2012

 Immune Checkpoints Modulators

B7 costimulatory molecules (CD80, CD86) Mellman, Nature, Dec 2011

Immune Checkpoints Modulators
PD1-PDL1/L2 Pathway

Fase Efectora o de Fase de “Priming” de linfocitos por

Reconocimiento periférico células presentadoras de antígenos
de tumor por células T
 Immune Checkpoints Modulators
IFN--mediated up-regulation PD-L1/PD-1-mediated inhibition
of tumour PD-L1 Tumour of tumour cell killing
cell

IFN-R

Stromal PD-L1
Dendritic
modulation of T cells cell
PD-L1/B7.1
Tumour-associated immunosuppression
fibroblast of T cells
CD8+ CTL

PD-L1/PD-1 inhibits
priming and activation
PD-L2 PD-1 of T cells
CD28 B7.1 Macrophage

PD-L1 PD-1
Treg
Immune modulation
PD-L1 B7.1 cell of Treg cells
Th2
MHC I TCR T cell

PD-L2/PD-1-mediated
inhibition of Th2 T cells
Chen, Clin Cancer Res, 2012
PD1: APCs, linfocitos T y B activados Keir, Ann Rev Immunol, 2008
PDL1: APCs, linfocitos T y B activados & células tumorales, CAFs Merelli, Crit Rev Oncol Haematol, 2014
PDL2: APCs, células tumorales Pardoll. Nature Rev Cancer ,2012
Immune Checkpoints Modulators

Atezolizumab

www.cancernetwork.com
 Immune Checkpoints Modulators
PD-1 or PD-L1 Blockade
Anti-PD1 Anti-PDL1

PD-1 PD-1
PD-L1 T cell PD-L1 T cell

B7.1 B7.1
Tumour Tumour
B7.1 PD-1 B7.1 PD-1
cell cell

PD-L1 PD-L2 PD-L1 PD-L2

PD-L1 PD-L1

Macrophage Stromal Macrophage

Stromal
cell cell

Chen, Clin Cancer Res, 2012

Paterson, J Immunol, 2011
Yang, J Immunol, 2011
Brahmer, N Engl J Med, 2012
Immune Checkpoints Modulators
T cell targets for immunoregulatory antibody therapy

Mellman Nature: 480-489, 2011

 Immune Checkpoints Modulators
Combinations to Overcome Primary and Acquired Resistance
Presence of PD-L1 or TILs1
PD-L1/TIL PD-L1+/TIL+ PD-L1 /TIL+ PD-L1+/TIL

Potential Immune-related combinations3

45% 17% 26% 12%

Type 1 Type 2 Type 3 Type 4

Mutational Burden2

1Unpublished Data: Rimm, Chen, Schalper et al.(Yale Pathology); 2Rizvi et al.,

Science 3 April 2015: Vol. 348 no. 6230 pp. 124-128. 3Mellman I et al. Nature 2011
Dec 21;480(7378):480-9.
 Immune Checkpoints Modulators
Anti-CTLA-4 and Anti-PD-1
APC – T-cell Interaction Tumor Microenvironment

Activation
(cytokine secretion, lysis,
proliferation, migration to tumor)

MHC
TCR TCR MHC
Dendritic
+++ +++
cell B7 CD28 T cell T cell Tumor cell
+++ PD-1 PD-L1
B7 CTLA-4 ---
--- anti-PD-1
anti-CTLA-4 PD-1 PD-L2
---
anti-PD-1

CTLA-4 Blockade (Ipilimumab) PD-1 Blockade (Nivolumab)

• CTLA4 is expressed on T-cells and inhibits T-cell activation7

• Ipilimumab disrupts the CTLA-4 pathway, thus inducing anti-tumor immunity7
• PD-1 expression on tumor-infiltrating lymphocytes is associated with decreased cytokine
production and effector function. Nivolumab disrupts PD-1 pathway signaling and restores
antitumor T-cell function7-12
 Immunotherapy in Cancer

Therapeutic Antibodies

Immune Checkpoints Modulators

Immune Cell Therapy

Cancer Treatment Vaccines

Immune System Modulators

Immune Cell Therapy

Population
expansion
or

T cell
engineering
 Immune Cell Therapy
Expanded ex vivo: can kill Engineered T cell therapy
tumor cells directly

Adapted from Wang J and Wang X. Mol Biol Rep 2014

 Immune Cell Therapy
Tumor infiltrating lymphocytes (TILs)

N=131

TIL
Infusion 6-
8 weeks
after
surgery
with IL-2
support

Abbas, Basic Immunol, Crystal

2011Ma
Ratto GB et al. Cancer 1996
 Immune Cell Therapy
Υδ T cells Therapy
• Comprise 1–5 % of the peripheral blood T cells
• Could recognize antigens in a MHC unrestricted manner, and they could bind
tumor-expressed ligands, however, not by conventional ab T cells
• Most γδ T cells lack cell surface expression of CD4 or CD8
• Activated γδ T cells display strong cytotoxic effector activity and produce various
cytokines have recently stimulated great interest in the development of γδ T cell-
based immunotherapies in some type of tumors

Sakamoto M. et al J Immunother 2011

 Immune Cell Therapy
NK cell Therapy

• Large granular
lymphocytes critical
effector cells in the early
innate immune
response to pathogens
and cancer
• 10-15% of the
peripheral blood
lymphocytes
• CD56+CD3–
• Are able to kill tumor
cells without the need
to recognize a tumor
specific Ag

Iliopoulou EG et al. Cancer Immunol Immunother 2010

 Immune Cell Therapy
CIK cell Therapy
• Unique population
of cytotoxic T
lymphocytes with a
characteristic
CD3+CD56+
phenotype
• CIK cells are
expanded from
peripheral blood
mononuclear cells
(PBMCs) cultured
with the timed
addition of IFN-γ,
anti-CD3 Ab, and IL-2

Liu L et al. Cancer Lett 316(1):1–5; 2012

 Immune Cell Therapy
Engineered T cell therapy
• T cells isolated from the blood of patients are reactive against tumors and
are generated using genetic engineering
• Involves introducing the T cell gene encoding cell surface receptors that
are able to recognize tumor associated antigens (TAAs).
• Receptors could be T-cell receptors (TCRs) derived from responding
patients or chimeric antigen receptors (CARs), which are generated using a
molecular biology technique
TCRs CARs

Kershaw, Nature Rev Cancer, 2013

 Immune Cell Therapy
Engineered T cell therapy

TCRs
TCRs

Kershaw, Nature Rev Cancer, 2013

 Immune Cell Therapy
Engineered T cell therapy

CAR Ts
CARs

Kershaw, Nature Rev Cancer, 2013

Immune Cell Therapy
Engineered T cell therapy

Crystal Mackall et al. 2012 Clin Cancer Res.

Mackall, Clin Cancer Res, 2012
Immune Cell Therapy
Engineered T cell therapy
 Immune Cell Therapy
Engineered T cell therapy
Normal T TCRs CARs

32 Longo DL, N Engl J Med, 2011

Dan L. Longo et al. 2011 NEJM.
Immune Cell Therapy
Engineered T cell therapy
 Immunotherapy in Cancer

Therapeutic Antibodies

Immune Checkpoints Modulators

Immune Cell Therapy

Cancer Treatment Vaccines

Immune System Modulators

Cancer Treatment Vaccines
Cancer Treatment Vaccines
 Cancer Treatment Vaccines
Tumor Cell Vaccines
 Cancer Treatment Vaccines
Antigen Vaccines
 Cancer Treatment Vaccines
Anti-idiotype Vaccines
 Cancer Treatment Vaccines
Vector Vaccines
 Cancer Treatment Vaccines
Sipuleucel-T
DendriticFDA
cell(Provenge
Vaccines
®)(Dendreon)
approved on April 29, 2010.

Sipuleucel-T
An autologous vaccine
approved for metastatic
prostate cancer

Philip W. Kantoff et al. 2011 Nat Rev Clin Oncol. Kantoff, Nat Rev Clin Oncol, 2011
 Cancer Treatment Vaccines
Promoting Promoting
antigen production
presentation of
functions of DCs protective
T cell
responses

Overcoming
immunosuppres
sion in the
tumor bed

Mellman, Nature, Dec 2011

 Immunotherapy in Cancer

Therapeutic Antibodies

Immune Checkpoints Modulators

Immune Cell Therapy

Cancer Treatment Vaccines

Immune System Modulators

 Immune System Modulators
Cytokines

• Heterogeneous group of secreted proteins produced by multiple cells

• Mediates and regulates all aspects of innate and adaptive immunity

• Interleukins
• Interferons
• Tumor necrosis factors
• Colony-stimulating factors
• Chemokines

15
 Immune System Modulators
Cytokines
Cytokines --IL-2
IL-2
Cytokines - IL2

Thomas A. Waldmann 2006 Nat Rev Immunol.

Thomas A. Waldmann 2006 Nat Rev Immunol.

17 Waldmann, Nat Rev Immunol, 2006

 Cytokines
Immune - Interferon
System Modulators
Cytokines - IFN

: IFN-α-2b (Merck)
proved for: IFN-α-2b
S-related Kaposi sarcoma
Pegylated IFN-α-2b
y cell leukemia IFN-α-2a
noma Pegylated-IFN-α-2ª
Hodgkin’s lymphoma.
ron: pegylated IFN-α-2b (Merck)

on: IFN-α-2a (Roche)

ys: Pegylated IFN-α-2a (Roche)

Robert D. Schreiber et al. 2006 Nat Rev Immunol.

Schreiber, Nat Rev Immunol, 2006
 Immune System Modulators
BCG therapy
 Immune System Modulators
Toll-like receptor agonists - Imiquimod
 Immune System Modulators
Immunomodulating Drugs (IMIDs)-

• Known as immunomodulating drugs

(IMiDs), and include:
• Thalidomide
• Lenalidomide
• Pomalidomide
• Thought to work by boosting
immune system
• Not exactly clear how
• Used to treat multiple myeloma
and some other cancers
 Immune System Modulators
Oncolytic Viruses