Chemotherapy Friends or Foe to Cancer Immunotherapy by Prof. Mohamed L. Salem

Chemotherapy
Friends or Foe to Cancer Immunotherapy
Mohamed Labib Salem, PhD
Prof. of Immunology
Director, Center of Excellence in Cancer Research
Tanta University, Egypt
15TH INTERNATIONAL CONFERENCE ON CHEMISTRY AND ITS
ROLE IN DEVELOPMENT (15TH ICCRD), AUGUST 9, 2021
Faculty of Science, Mansoura University, Egypt

My Current Research Trends
 Escaping mechanisms of cancer cells
 Circulating and cancer stem cells
 Immunosuppressive cells
 Molecular signature (OMICS)
 Cancer Immunotherapy
 Drug Discovery

Agenda of the Talk
1. Cancer Hallmark
2. Chemotherapy as a Foe to cancer
3. Chemotherapy as a friend to immunotherapy
4. Our own data for chemo-Immunotherapy
5. Take home message

• Cancer research is one area in which chemistry can
enhance life and remove misery—as this is recognized
by scientists.
• Chemistry plays the central role in the etiology and
prevention of the most prevalent types of human
cancer.
• Ex: The chemical agents responsible for the initiation
of cancer are the estrogens.
Few words on the role of chemistry in cancer

• Estrogen become carcinogenic when their unbalanced
metabolism in our bodies generates excessive amounts of
estrogen-3,4-quinones.
• Estrogen-3,4-quinones react with DNA, forming
depurinating estrogen-DNA adducts that generate the
mutations leading to the initiation of cancer (breast, ovarian,
and thyroid, and prostate, lymphoma).
• This mechanism can be prevented by the use of natural
compounds such as resveratrol and N-acetylcysteine to block
formation of estrogen-DNA adducts.
Few words on the role of chemistry in cancer

Phase II study
Phase III study
In silco
Preclinical
Studies
Phase I study
Industry
(Market)
BENCH
CLINIC
Phases of Drug Discovery From Bench to
Industry
In vivo
In vitro

Phases
of
drug
discovery
from
bench
to
industry

Vincent T. DeVita, Jr., and Edward Chu Cancer Res 2008;68:8643-8653
Key Advances in The History of Cancer Chemotherapy

Effects
Chemotherapy
Drugs
on
Cell
Cycle
Philipp
et
al.
Cellular
and
Molecular
Life
Sciences,
2016,
73:
2183-2193

TARGETED
CHEMOTHERAPY
Chemo
Therapy
Cancer
Cells
Cancer
Stem
Cells

Cancer Chemotherapy: Friends or
Foes to whom?

Cancer
Chemotherapy:
Friends
or
Foes
to
whom?
Foes Friends
Foes

Cancer Chemotherapy: Friends or Foes to whom?
 Friend to:
 Immune cells to generate anti-tumor immune
responses.
 Foe to:
 Cancer to induce apoptosis, necrosis and necroptosis
 Cancer stem cells to stop their regrowth into new tumor.
 Immune suppressive cells that are induced by chemicals
produced by tumor cells.

Immune Balance
Stimulatory Inhibitory
Chemo
Therapy

The
2
main
types
of
Cancer
Immunotherapy

Our strategy to investigate the role of Chemotherapy in
Immunotherapy
Generation of T
cells in vitro
In vitro
Chemotherapy
Vaccine
In vivo
Chemotherapy
Irradiation
In vivo

Can prior chemotherapy enhances T cell
Therapy?
CD8+ T cells are
specific to the MHC-1
gp10025-33 melanoma
peptide
Donor
Tg Pmel
Culture T cells and stimulate with +
gp10025-33 peptide ± IL12 for 3~5 days
CD44
CD62L
Pept + IL12
(pmelIL12 )
Pept alone
(pmelsham )
PBS
CTX
PBS
CTX
Vaccination
+ Poly (I:C)
Our Model of
Chemotherapy:
Cyclophosphamide
(CTX): 200 mg/kg
(4 mg/mouse)

YES: Chemotherapy before T cell therapy is critical
for expansion of cytotoxic CD8+ T cells

Days after tumor implantation
Tumor
size
(mm
2
)
Yes: Chemotherapy before T cell therapy is critical
for melanoma regression

Yes: Chemotherapy before adoptive T cell therapy
is critical for melanoma regression
A Mouse with s.c. melanoma
after treatment with in vitro
IL-12 activated T cells with
no prior CTX treatment.
A Mouse with s.c. melanoma
after treatment with in vitro
IL-12 activated T cells and
prior treatment with CTX

CTX alone
CTX + Pmel 12
No Tumor
Yes: Chemotherapy before adoptive T cell therapy
is critical for anti-melanoma metastasis

How Chemotherapy
Benefits Immunotherapy

0
2000
4000
6000
8000
10000
0 3 6 9 12 15 18
#
PBL
(10
6
/L)
0
20
40
60
80
100
0 3 6 9 12 15 18
Days post CTX treatment
#
Leucocytes
(10
6
)/organ
Spleen
BM
Blood
Spleen and Bone marrow
Chemotherapy
induces reversible
lymphodepletion
in bone marrow
blood, spleen and
lymph nodes

Chemotherapy Induces expansion of DCs during
restoration phase
CD11c
CD11b
5.6 ± 1.1 3.5 ± 0.9 6.4 ± 0.8 18.7 ± 4.1
25.2 ± 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

Post CTX expanded DCs express the phenotype of
immature myeloid cells
Myeloid DCs (mDCs): CD11chighCD11bhighLy6GlowB220low
Plasmacytoid DCs (pDCs): CD11chighCD11blowLy6GhighB220high
Day 12 post treatment
d4 d14
d0 d2 d10
CD80
4.5% 25% 35% 2.1%
7.2%
Lymphopenic phase Restoration phase
0
5
10
15
20
25
30
35
mDCs pDCs
%
CD11c
+
cells
PBS
CTX

PBS-treated mice CTX-treated mice
Blood from day 12 CTX-treated mice show DC morphology
upon overnight culture

DCs expanded after chemotherapy are functional
in vitro
DCs from
PBS-treated
mice
DCs from
CTX-treated
mice
FITC-labeled dextran
0
50000
100000
150000
200000
250000
CPM
20%
16%
Phagocytosis Antigen Presentation
No
DCs
PBS
DCs
CTX
DCs
Count

Chemotherapy induces inflammatory
microenvironment: Increases IFNs and DC activation
1 4 8 24 48 72 96
Hours post CTX (4 mg) treatment
IFN-a
(pg/ml)
0
10
20
30
40
50
60
70
80
90
100
PBS
CTX
Salem et al. J Immunother 30(1): 40-53 (2007)

Lymphoreplete
Host
Lymphodeplete
Host
No
Chemo
After
Chemo

Induction of
activation of
dendritic cells
Elimination
of
suppressive
cells
Creation of a space “niche”
Induction of
survival
cytokines
How Chemotherapy Benefit Immunotherapy?

(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
Number
of
dendritic
cells
Lymphopenic phase Recovery phase
0
-1
ACT Antigen priming
+ TLR agonists
Antigen boosting
+ TLR agonists
20
DCs
Donor
T cells
Sequential Events in the host after chemotherapy

Agenda of the Talk
1. Cancer Hallmark
2. Chemotherapy as a Foe to cancer
3. Chemotherapy is a friend to immunotherapy
4. Our own data for chemo-Immunotherapy
5. Take home message

Can Chemotherapy enhance anti-cancer
Vaccination Immunotherapy?
Naïve spleen
CD8+ T cells
(500,000)
Transgenic
mice
Tumor
cells
D-2
Vaccine+
Poly(I:C)
D -1 D 0 D 12
D -10
DCs are expanded
T cells can grow
Vaccine+
Poly(I:C)
Chemo
therapy

Yes, Chemotherapy induced lymphopenia enhances expansion
of transferred T cells
0
5
10
15
20
25
3 6 7 8 14 21
%
OT-1
cells
in
PBL
PBS
CTX 1 mg
CTX 4 mg
Days post vaccination
Salem
et
al.
J
Immunother
30(1):
40-53
(2007)
Total
number
(10
6
)
per
spleen
0
10
20
30
40
50
60
70
80
0 6 24 72
**
**
Hr after CTX
0
10
20
30
40
50
60
70
PBS CTX -6 hr CTX -24 hr CTX -48hr
%
OT-1
cells
in
PBL
on
day
7
After vaccination

+
-
+
-
-
-
Poly I:C
+
+
+
+
-
-
gp100
+
+
-
-
+
-
CTX
+
+
+
+
-
-
B16
+
-
+
-
-
-
+
+
+
+
-
-
+
+
-
-
+
-
+
+
+
+
-
-
#
DCs
in
PBL
(10
6
/L)
#
DCs
in
DLNs
(10
6
)
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-1
in
DLNs
(10
6
)
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-1
in
PBL
(10
6
/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%
Yes, Chemotherapy Increases Post-Vaccination DCs and CD8+ T
cell numbers and animal survival
0 10 20 30 40
0
20
40
60
80
100
Days post tumor inoculation
%
Survival
PBS (No pmel-1)
CTX (No pmel-1)
PBS/gp100 + poly I:C d1
CTX/gp100 + poly I:C d1
CTX/gp100 + poly I:C d1 and d12
PBS/gp100 + poly I:C d1 and d12

0
2
4
6
8
10
12
14
16
18
20
PBS CTX
%
OT-1
cells
in
PBL
on
day
3
Yes: Filling the space created by chemotherapy doesn’t prevent
the beneficial effects to T cells
Salem
et
al.
J
Immunother
30(1):
40-53
(2007)
CTX
+50m
CTX
+100m
CTX
+150m

0
1
2
3
4
5
PBS CTX PBS CTX
0
0.2
0.4
0.6
0.8
PBS CTX PBS CTX
#
pmel-1
in
spleen
(10
6
)
#
pmel-1
in
DLNs
(10
6
)
WT DTR Tg WT DTR Tg
1.5%
11.6%
0.8%
4.5%
2.2%
25.2%
0.03% 2.4%
Yes: Depletion of post CTX expanded DCs abrogates
the beneficial effects of chemotherapy

0
50
100
150
200
250
300
350
400
450
12 14 17 20 22 24 26 28 32
Days post tumor inoculation
Tumor
area
(mm
2
)
PBS (No T cells)
CTX
(No T cells)
CTX/Vac + IL-2
CTX/Vac+ poly(I:C)
PBS/Vac + poly(I:C)
Yes, Chemotherapy is critical to induce Post-
Vaccination anti-tumor responses against melanoma

“Lymphodepletion is A bad
cue for good
immunotherapy” Mohamed L Salem, PhD

1. Promote “on-target’
effects: the antigenicity
or adjuvanticity of
malignant cells.
2. Promote ‘off-target’
effects: the activation of
immune effector cells
and/or hampering the
functions of
immunosuppressive
cells).
3. Altering whole-body
physiology: activation
of mechanisms that
ultimately support
immunological
Iinitiation of anticancer immune
responses by chemotherapeutic
agents
Nature
Reviews
Clinical
Oncology
volume
17,
pages725–741

THANK
YOU Chemistry
THANK
YOU Chemists
Mohamed Labib Salem, PhD
Prof. of Immunology, Tanta University, Egypt
Mohamed.labib@science.tanta.edu.eg

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