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
