Cancer Immunotherapy from Bench to Clinic_Mohamed Labib Salem ,ppt

Cancer
Immunotherapy from
bench to clinic
Mohamed Labib Salem, PhDMohamed Labib Salem, PhD
Prof. of Immunology, Faculty of Science
Director, Center of Excellence in Cancer
Research
Tanta University, Egypt
cecr@univ.tanta.edu.eg
The 1st
Conference of Society of Pathological Biochemistry
&Hematology, Faculty of Science, Menofia University, Egypt
Feb 16, 2016

Tug of warTug of war Prof. Mohamed Labib Salem

The smart interaction
Immune
cells
Cancer
Cells
Cancer
cellsHost Tumor
microenvironment
Prof. Mohamed Labib Salem

The main focus of my research interest
• Understanding the regulatory mechanisms behind
escape of cancer and virus from immunity:
– myeloid-derived suppressor cells (MDSC)
– CD4 regulatory T cells
– Cancer Stem cell
• Develop new anti-cancer immunotherapeutic
strategies:
– The use of cytokines and TLR agonists to enhance T
cell function
– The use of TLR agonists to enhance dendritic cell
based vaccination

Talk outline
• Cancer Immunotherapy
• Failure of Cancer therapy
• Suppressive cells
• Preclinical data
• Clinical data

Markers of Non-Self
Non-self leukocyte
Antibody
Epitope
Class I MHC protein
Epitope
Antibody
Antigen
Antigen
Bacteria
Non-self nerve cell
SARS virus

The Beginning of Cancerous Growth
Underlying tissue

Conventional anti-cancer therapy
Surgery
Immunotherapy
Radio-
therapy
Chemo-
therapy

Anti-tumor immune responses

Immune surveillance/editing of tumors

Cancer Therapy
In clinic
• Surgery:
Effective but doesn’t cure tumor
metastasis or prevent tumor recurrence
• Radiotherapy/Chemotherapy:
Effective but doesn’t prevent tumor
recurrence besides its serous side
effects

Cancer Therapy
In clinic and clinical trials
• Immunotherapy:
Can cure local and distant tumors
and prevent tumor recurrence
through developing tumor-
specific memory T cell responses

Effectors that can kill Cancer
Antibody
Helper T cell
Natural
killer cell
Macrophage
Cytotoxic T cell
Cancer cells

?
?
?
?
?
Typical Events Essential for Anti-tumor Immunity

Types of Cancer Immunotherapy
• Antibodies
 Cytokines (IL-12, IFN-a)Cytokines (IL-12, IFN-a)
 Adoptive T Cell Therapy inAdoptive T Cell Therapy in
combination withcombination with
chemotherapychemotherapy
 VaccinesVaccines

Adoptive Cell Therapy
“Adoptive= from donor to recipient”
1. Adaptive cell-based therapy
–CD8+ (cytotoxic) T cell therapy
– CD4+ (helper) T cell therapy
– LAK cell therapy
2. Innate cell-based therapy
–Dendritic cell therapy
– NK cell therapy
3. Progenitor cell therapy
– Bone marrow therapy
– Stem cell therapy Prof. Mohamed Labib Salem

s.c./i.d./i.v./i.t.
injection
Dendritic Cell based anti-tumor vaccination

Nature Reviews Immunology 2; 227-238 (2002)

Antibody-based targeted immunotherapy
Antibody
Breast
cancer cell
Growth
factor
Herceptin
blocks
receptor
Growth slows
Radioisotope
Antigen
Lymphoma
cell Lymphoma cell
destroyed
Herceptin

mAb-based therapies against liver cancer
(40 clinical trials on www. ClinicalTrials.gov)
• Bevacizumab/Avastin®: vascular endothelial growth
factor A (VEGF-A)
• Cetuximab/Erbitux®:Epidermal growth factor receptor)
• Cixutumumab (insulin-like growth factor 1 receptor [IGF-
1R])
• MEDI-575: Platelet-derived growth factor receptor)
• CT-011: Programmed Death-1 (PD-1)
• CP 675/tremelimumab (CTL antigen-4)
• RO5323441: Placenta growth factor (PGF)
• HGS1012/mapatumumab: TRAIL-R1).
• GC33 (glypican-3[GPC3]): is the only mAb targeting a
HCC-specific tumor antigen. Prof. Mohamed Labib Salem

T cell
T-Cell Receptor
Gene Transfer
T cell
A tumor-
reactive
T cell
Exogenous
TCR
Endogenous
TCR
Rubinstein MP, Salem ML, et al., J
Immunology 170:1209-17, 2003
Rubinstein MP, Salem ML et al., Cancer Gene
Ther. 2009 Feb;16(2):171-83
Gene therapy

Immuno
-therapy
with TCR-
engineered
T cells

Gene Transfer of Immunostimulatory
molecules

Procedure of Adoptive T cell transfer therapy
Grow T cells
With IL-2
Test T cell
function
Chemo or Irradiation
Before T cell transfer
Infusion
of T cells
+ vaccine
Clonal
expansion of
T cells with
IL-2 & CD3
Tumor excision

29
Cancer Immunotherapy

Why does cancerWhy does cancer
therapy fail?therapy fail?

Causes of Failure of Cancer Immunotherapy
Intrinsic/extrinsic mechanisms

1- Intrinsic mechanisms
• Tumor cells originate from self
(i.e. not foreign)
• Tumor-specific T cells are absent.
• Tumor-reactive immune cells do not
localize to the tumor.
• T cells fail to proliferate and persist in
response to tumors.

Clinically
Un-detectable
Localized
Disease
Advanced
Disease
1:10,000 T cells 1:50 T cells 1:2 T cells
DiseaseBurden
High tumor cells/T cell ratio

0
2
4
6
8
1 3 5 7 10 14 21 30 60 120
CD8+Tcellresponse
Days Post Vaccination
Rapid expansion Rapid
contraction
Low
memory
10
12
Tumor antigen alone
Tumor antigen
+ Danger signal
Rapid contraction of T cells upon vaccination

• Tumor favor expansion of Regulatory cells
that inhibit tumor-specific T-cell activities
• Downregulation of antigen expression in
tumor cells.
• Secretion of immunosuppressive factors.
• Death-receptors such as CD95 and TRAIL
receptor are mutated or lost entirely.
Extrinsic mechanisms

Tumor-induced Immune Dysfunction
MDSC
IL-10
Arginase
ROS, RNS
IDO: depletes L-
tryptophan, results in T
cell unresponsiveness
Inhibitory/
death R:s
Inhibitory/
death receptors:
FasL
TGF-β
PGE2
ROS, RNS:
reactive oxygen
species results in
T cell un-
responsiveness
TGF-β and or IL-10 from
Treg, MDSC, and tumor
cells suppress T cells
Treg
IDO
MDSC/
DC
Arginase: depletes L-
arginine, results in T cell
unresponsiveness

The current Dogma
Every type of myeloid and lymphoid derived
cells can be found in a stimulatory or an
inhibitory (regulatory) status
All depends on the surrounding
microenvironment

Regulatory
immune
cells
Immunity is controlled by the balance
between stimulatory/regulatory cells
Treg
MDSC
NKT cells
B cells
pDCs
Stimulatory
immune
cells
Dendritic cells
CD4+ T cells
CD8+ T cells
NK cells

Suppression of anti-tumor immunity
by myeloid-derived suppressor cells (MDSC)

Mechanisms of the immune-suppressiveMechanisms of the immune-suppressive
effects of MDSCeffects of MDSC
Prof.MohamedLabibSalem

Don’t work hard, work intelligent, and choose your direction

Our strategiesOur strategies
1. Targeting cancer stem cells
2. Blocking regulatory cell expansion
and functions
3. Enhancing T cells survival and
function using IL-12
4. Enhancing dendritic cell expansion
and functions using TLRs.
5. Combination of 2 + 3

ENHANCING T CELL
SURVIVAL AND FUNCTION BY
IL-12
Cancer Immunotherapy

Pmel
Spleen
and LN
Ag ± IL-12 D3 Wash and reculture
+ IL-2
D7
Early Pmelsham
Late Pmelsham
In-vitro culture system and gating strategy
Phenotypic
and functional
analyses
Early Pmel12 Late Pmel12

Days after tumor implantation
Tumorsize(mm2
)
Anti-tumor activity of CD8+
T cells programmed by different
survival cytokines against solid B16 melanoma

Anti-tumor activity of CD8+
T cells programmed by different
survival cytokines against metastasized B16 melanoma

1. Brief conditioning of anti-tumor CD8+ T cells in
vitro with IL-12 enhance their survival phenotype
and function.
2. IL-12-programed CD8+ T cells regress tumor in
absence of vaccination.
3. Preconditioning the recipient hosts with
cyclophopsphamide is a must.
4. IL-12 programs CD8+ T cells to acquire stem cell
phenotype.
5. CD8+ T cells with stem cell phenotype resist
cytotoxic effects of chmotherapy
Conclusion

Understand and optimize
chemo-immunotherapy
Building on the success of IL-12 based immunotherapy

Expansion of DCs during restoration phase from CTX
treatmentCD11c
CD11b
5.6 ± 1.1 3.5 ± 0.9 6.4 ± 0.8 18.7 ± 4.125.2 ± 1.1
Lymphopenic phase Restoration phase
0
200
400
600
800
1000
1200
1400
0 2 6 10 14
Days post CTX treatment
#CD11c
+
CD11b
+
cells(10
6
/L)
Day 0 Day 2 Day 6 Day 9 Day 12

 Is dose-dependent.
 Induction of proliferation of dendritic
cell progenitors in bone marrow.
 Induction of production of myeloid cell
mobilizing factors (GM-CSF, G-CSF,
M-CSF, Flt3L, and chemokines).
 Flt3 and CCR2 signaling pathways are
critical.
Mechanisms of the CTX Induced expansion of
dendritic cells
Salem et al., 2010 J Immunology
Salem et al., 2010 Cell Immunology Prof. Mohamed Labib Salem

Phases post CTX treatment relative to adoptive T
cell therapy (Salem CII 2010)
• Creation of a space niche due to
the induced lymphopenia
• Homeostatic expansion of T cells
• Elimination of regulatory cells
• Elimination of cytokine
competition
• Microbial translocation
• Activation of dendritic cells
• Cellular recovery from lymphopenia
• Less of lymphopenia
• Less homeostatic proliferation of T cells
• Expansion of immature dendritic cells
3 6 9 12 15 18
Days after CTX treatment
Numberofdendriticcells
Lymphopenic phase Recovery phase
0-1
ACT Antigen priming
+ TLR agonists
Antigen boosting
+ TLR agonists
20
DCs
Donor
T cells

Activation of post CTX expanded DCs is essential
for augmenting CD8+
T cell responses
+-+---Poly I:C
++++--gp100
++--+-CTX
++++--B16
+-+---
++++--
++--+-
++++--
#DCsinPBL(106
/L)
#DCsinDLNs(106
)
0
0.03
0.06
0.09
0.12
0.15
0.18
0
250
500
750
1000
1250
1500
0
0.05
0.1
0.15
0.2
0.25
0
500
1000
1500
2000
2500
#pmel-1inDLNs
(106
)
0.02%
3.1% 0.6%
39.4%
0.04%
0.05%
0.1%
0.2%
4.5%
2.1%0.1%
12.5%
#pmel-1inPBL(106
/L)
6.0%
14.9%
7.6%
18.2%
14.6%
6.5%
1.9% 1.7%
3.6%
4.6%
9.1%
2.2%

Vaccination at the peak of post CTX DC expansion
improves survival of tumor-bearing host
0 10 20 30 40 50 60 70 80 90
0
25
50
75
100
Days post tumor challenge
Percentsurvival
PBS
PmelSham
/PBS
PmelIL12
/PBS
PmelSham
/CTX
PmelIL12
/CTX

Vaccination at the peak of post CTX DC expansion
induces effective anti-tumor immunity
0
50
100
150
200
250
300
350
400
450
12 14 17 20 22 24 26 28 32
Days post tumor inoculation
Tumorarea(mm2
)
PBS (No T cells)
CTX
(No T cells)
CTX/Vac + IL-2
CTX/Vac+ poly(I:C)
PBS/Vac + poly(I:C)

T cell responses after CTX/vaccine/poly(I:C)
prevent tumor from growth

Cancer immunotherapy
Combination, Combination, Combination …..
Nature 446, 964-966 (26 April 2007)Prof. Mohamed Labib Salem

Funded agentsFunded agents
• National Cancer Institute (NCI), National
Institute of Health (NIH), USA
• Hollings Cancer Center, Medical
University of South Carolina, USA
• Chain Reaction for Brest Cancer, USA
• Tanta University Research Fund
• Science and Technology Development
Fund (STDF)

ACKNOLWEDGEMENTS
Tanta University, Egypt
Amir A Alkhami, PhD Randa Al-Naggar, PhD Wael Attia, PhD
Sabry EL-Naggar, PhD Sherif Zidane, PhD Said Hamaad, MD
Mohamed Elshanshoory, MD Mohamed Attia, MD Mona Zidan, MSc
Shaima Sobhy, MSs, Asmaa Shaaban, MSc Sohaila Galal, MSc
Suez Canal University, Egypt
Ahmed Khafagy, PhD
Medical University of South Carolina
David J. Cole, MD William Gillanders, MD Mike Nishimura, PhD
Andre Kadima, MD Yian Chen, PhD Osama Naga, DD
Elizabeth Little, BSc Rick Peppler, MS Narender Nath, PhD
Guillermo Rivell, MD Sabry EL-Naggar, PhD Amir A Alkhami, MS
University of Miami, Miller School of Medicine
Marcela Montero, PhD Alberto Montero, MD
University of California in San Diego, USA
Mark Rubstein, PhD

THANK
YOU
Prof. Mohamed Labib Salem, PhDProf. Mohamed Labib Salem, PhD
Tanta University, EgyptTanta University, Egypt

Cancer Immunotherapy from Bench to Clinic_Mohamed Labib Salem ,ppt

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