Cancer Immunotherapy from Bench to Clinic

Cancer Immunotherapy
from Bench to Clinic
Invited by Zoology Dept., Faculty
of Science, Suez Canal University
November 6, 2021
Mohamed Labib Salem, PhD
Prof. of Immunology, Faculty of Science
Director, Center of Excellence in Cancer Research
Tanta University, Egypt mohamedlabibsalem@yahoo.com
Mohamed.labib@science.tanta.edu.eg

Presenter
Prof. Mohamed L Salem
• Prof. of Immunology, Faculty of Science
• Director, Center of Excellence in Cancer Research,
• Asst Prof. MUSC, USA, Visiting Scholar, Japan
• Supervisor, Delta Res Development Center,
Academy of Scientific Res and Technology
• Board Member, Zewail City
• Chair, Council for Scientific Culture & Knowledge
• Chairman, Egy Assoc for Cancer Research
• Editor, Int. J Cancer Biomedical Research
• Grants: 37 (NCI, ASRT, STDF, Tanta University)
• Obada Prize 2021
• Khalifa Prize 2020
• State Medal for Sciences and Arts
• State Esteemed Prize 2019
• State Excellence Prize 2009
• State Incentive Prize 2003
• Tanta University Excellence Prize 2020
• Tanta University Esteemed Prize 2015

Agenda of My Talk
1. History of Cancer
2. Immune killers and immunity
3. History of cancer immunotherapy
a. Coley's toxin
b. Modern immunotherapy to 2018 Nobel Prize
4. Types of cancer immunotherapy
5. Our own preclinical and clinical studies
6. Take-aways
Prof. Mohamed Labib Salem, PhD

1.History of Cancer

Cancer
(Astrology)
Cancer, the Crab
• Although it is one of the constellations of the zodiac, Cancer
plays a relatively smallrole in both sky and sky lore.
• It is a small constellation of faint stars, so it is difficult to find
in the sky.
• In mythology, it forms part of the story of Hercules. While
he wastacklingthe multi-headed monster Hydra, the
goddess Herasent a giant crab to distract the strongman.
Herculescrushed it, then quicklyreturned to hismonster
killing.Hera placed the remains of the crab in the sky, but
gave it only faint stars because of its failure.

Cancer is the Latin name for crab due to the
similarity of crabs to some tumors with swollen
veins

Oldest Descriptions of Cancer
•The oldest description of cancer (although the
word cancer was not used) was discovered in
Egypt and dates back to about 3000 BC.
•It’s called the Edwin Smith Papyrus and is a copy
of part of an ancient Egyptian textbook on
trauma surgery.
•It describes 8 cases of tumors or ulcers of the
breast that were removed by cauterization with a
tool called the fire drill. The writing says about
the disease, “There is no treatment.” Bone cancer

Origin of The Word Cancer
•The origin of the word cancer is credited to the
Greek physician Hippocrates (460-370 BC),
who is considered the “Father of Medicine.”
•Hippocrates used the
terms carcinos and carcinoma to describe non-
ulcer forming and ulcer-forming tumors.
•In Greek, these words refer to a crab, most
likely because the finger-like spreading
projections from a cancer called to mind the
shape of a crab.

Origin of The Word Cancer
•The Roman physician, Celsus (28-50 BC), later
translated the Greek term into cancer, the Latin
word for crab.
•Galen (130-200 AD), another Greek physician,
used the word oncos (Greek for swelling) to
describe tumors.
•Although the crab analogy of Hippocrates and
Celsus is still used to describe malignant
tumors, Galen’s term is now used as a part of
the name for cancer specialists – oncologists.

Cancer in The 16th to 18th
Century
• Autopsies, done by Harvey (1628), led to an understanding
of the circulation of blood through the heart and body that
had until then been a mystery.
• In 1761, Giovanni Morgagni of Padua was the first to do
autopsies to relate the patient’s illness to pathologic findings
after death. This laid the foundation for scientific oncology,
the study of cancer.
• The famous Scottish surgeon John Hunter (1728-1793)
suggested that some cancers might be cured by surgery
others not based on dissemination.
• A century later the development of anesthesia allowed
surgery to flourish and classic cancer operations such as the

Cancer in The 19th Century
•The 19th century saw the birth of scientific
oncology with use of the modern microscope in
studying diseased tissues.
•Rudolf Virchow, often called the founder of
cellular pathology, provided the scientific basis
for the modern pathologic study of cancer.
•As Morgagni had linked autopsy findings seen
with the unaided eye with the clinical course of
illness, so Virchow correlated microscopic
pathology to illness.

Modern science dissected Cancer and Tends the
Surrounding micro-environment
Growth factors = proliferation
Blood vessel
Proteases
Cytokines
Matrix
Fibroblasts,
adipocytes
Cytokines, proteases = migration & invasion

Cancer in The 19th Century
•Microscopic pathology not only allowed a
better understanding of the damage
cancer had done, but also aided the
development of cancer surgery.
•Body tissues removed by the surgeon
could now be examined and a precise
diagnosis could be made.
•The pathologist could also tell the surgeon
whether the operation had completely
removed the cancer.

Cancerous
Cells
are
Dynamic
in
Growth

Anti-cancer therapy
Surgery
Immunotherapy
Radio-
therapy
Chemo-
therapy
Prof. Mohamed Labib Salem

Cancer
Stem
Cell

2.Immune Killers and
Immunity

Immune system is educated to recognize self
from non-self

Cancer
is
Self
cells

22

Dendritic
cells
as
APCs
Immunity
Tolerance
3
Tumor
cells
as
APCs

No
danger
signal
no
anti-tumor
Immunity

Immuno-
Oncolog
y

COVER
Cancer immunotherapy
harnesses the power of
the immune system to kill
tumors. These therapies
aim to activate and
expand T cells, such as
those shown in blue, to
specifically kill tumors
shown in black.

How Cancer Cells
Escape from
Immune Cells!!!

Tug of War Game
“TAG of WAR” Game
Evasion and escape mechanisms
It is the matter of who is
stronger and intelligence !!!
Immune cells
Cancer cells

Intrinsic & Extrinsic Mechanisms Governing
tumor escape from immunity
CTCs
CSCs
Autophagy
Ag editing
MHC-I/II
PD1/PDL-1
Tumorigenic factors
MDSC
Treg cells
NK Reg cells
PD1/PDL-1
Suppressive
mediators

Tumor cells
APCs cells
T cells

Complicated
interaction
between T
cells and
tumor cells.

Clinically
Un-detectable
Localized
Disease
Advanced
Disease
1:10,000 T cells 1:50 T cells 1:2 T cells
Disease
Burden
Causes of Failure of Cancer Immunotherapy High tumor
cells/T cell ratio

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

Prof.
Mohamed
Labib
Salem,
PhD

3.History of Cancer
Immunotherapy

History of Cancer Immunotherapy
•In the writings of the Ebers Papyrus (c 1550 BC),
attributed to the great Egyptian physician Imhotep
(c 2600 BC), the recommended treatment for
tumors (swellings) was a poultice followed by
incision.
•Such a regimen would inevitably lead to an
infection at the tumor site.
•By the 1700 and 1800s AD, crude forms of cancer
immunotherapy became widely known and
accepted.

•Peregrine Laziosi (1265–1345), having been
afflicted with cancer himself, was several
centuries later canonized and named the patron
saint of cancer patients.
•In the course of his untiring work preaching,
converting and reconciling sinners, he noticed a
large growth emerging on his leg.
•The growth on his tibia was pronounced
unanimously by the best physicians of his time
to be malignant.

•Peregrine only option was to have his leg
amputated. The lesion grew to the point where it
broke through the skin and became severely
infected.
•Miraculously, his physician was astonished to
observe that there were no signs of the tumor.
•Saint Peregrine’s cancer never returned.
•Was this spontaneous regression an
isolated event or did the infection play a
part?

• More than 135 years ago the German
physicians Busch and Fehleisen independently
noticed regression of tumors in cancer patients
after accidental infections by the skin bacteria
erysipelas.
• In 1868, Busch was the first to intentionally infect
a cancer patient with erysipelas and he noticed
shrinkage of the malignancy.
• Fehleisen repeated this treatment in 1882 and he
also eventually identified Streptococcus
pyogenes as the causative agent of erysipelas

Coley’s Toxin: Protocol
• Coley’s vaccine was used for sarcomas, carcinomas, lymphomas,
melanomas and myelomas. Several points were considered.
1. First and foremost was to imitate a naturally occurring acute
infection, and thus, inducing a fever was essential.
2. Injections were optimally administered daily (or every other day)
for the first month or two.
3. To avoid immune tolerance to the vaccine, the dosage was
gradually increased over time (depending on patient response).
4. The vaccine was injected directly into the primary tumor and
metastases, when accessible.
5. A minimum six month course of weekly injections was followed to
prevent disease recurrence.

Circa 1920

• Coley’s principles have been shown to be correct, and
the use of bacteria finally found sound justification in 1976
when Morales et al. established the effectiveness of the
bacterium Bacillus Calmette-Guérin (BCG) in the
treatment of superficial bladder cancer.
• This clinical trial was based on an animal study in 1959
by Old et al. showing the anti-tumor effects of BCG in a
mouse model. Besides his work on BCG, Old also was a
discoverer of TNFa in 1975
• Coley and Old have each been referred to as the “Father
of Immunotherapy”,

https://drjohnhwi.medium.com/william-b-coley-father-of-
modern-day-immunotherapy-51c33a77ea33

4.Types of Cancer
Immunotherapy

Brakes
and
Pedals

If inhibitory proteins such
as CTLA4 (arrow) and
PDL1 are expressed early
during T cell priming. T
cell fiction will be
completely blocked.

T cells function are shut down
because of interaction between
PD1 and PDL1

T cells function are functional
after blocking PD1 by ant-PD1
mAb

December
2015

2018

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 R)
• Cixutumumab (insulin-like growth factor 1R [IGF-1R])
• MEDI-575: Platelet-derived growth factor receptor)
• CP 675/tremelimumab (CTL antigen-4)
• RO5323441: Placenta growth factor (PGF)
• HGS1012/mapatumumab: TRAIL-R1).
• GC33 (glypican-3[GPC3]): Ab targeting a HCC-specific tumor
antigen.
•CT-011: Programmed Death-1 (PD-1)

TypesofCancer
Immunotherapy

Different Dendritic Cell Based Anti-
tumor Vaccination

Example of Biotechnology
company for Vaccines

https://immunotherapychina.com/
Example of Biotechnology company
for Vaccines

Growth factors are
increase the numbers
of innate immune
cells: monocytes,
macrophages and
granulocytes that are
critical to attack and
kills microbes.

Non specific
stimulators
Cell specific
stimulators

RBCs
Platelets
Macrophage
Granulocytes
Granulocytes

BCG is a germ that's related to the
one that causes tuberculosis (TB),
but it doesn’t usually cause serious
disease. BCG is put right into the
bladder through a catheter. It
reaches the cancer cells and "turns
on" the immune system.The
immune system cells are attracted to
the bladder and attack the bladder
cancer cells.

5.Our Own
Preclinical &
Clinical Studies

Enhance
stimulation of
dendritic cells
Enhance cytotoxic
CD8 T cells
Target immune
suppressive env.
•In vitro
•In vivo
•IL-12
•CTX
•MDSC
•Treg

Adoptive
T
cell
transfer
therapy

• Creation of a space niche due to the
induced lymphopenia
• Homeostatic proliferation of T cells
• Elimination of regulatory cells
• Elimination of cytokine competition
• Microbial translocation
• Activation of dendritic cells
• Cellular recovery from lymphopenia
• Less 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
Our Tripartite regimen of Immunotherapy

Peptide
Mature DCs
Monocytes
Monocytes
GM-CSF
IL-4
Immature DCs
Tumor
lysate
Viral
vector
MHC class-I
Peptide
complex
Inject dendritic cells
Tumor
CTL
Our Clinical Trial
Pancreatic Cancer Patients
+TLLR3L
+TLLR3L

6.Take-aways

Can Adoptive T cell and dendritic cell
therapy be done in Egypt? YES WE CAN
•There is a long experience with bone marrow
(BM) transplantation in multiple transplantation
centers in Egypt
•Stem cell-based therapy is under clinical trials and
feasible in Egypt
As such, trials can be initiated in centers that have
experience with BM and stem cell based therapy

CECR RESEARCH TEAM

Thank you IMMUNOLOGY
THANKS FOR IMMUNOLOGISTS
Thank you ALL

Cancer Immunotherapy from Bench to Clinic

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