Molecular Cell Biology

1. Cancer immunotherapy
(nobel prize 2018 in physiology and medicine)
Discovery By : Tasuku Honjo and James P. Allison

2. What is CANCER ?
Cancer is a group of diseases involving abnormal cell
growth with the potential to invade or spread to other
parts of the body. They form a subset of neoplasms.

3. All tumor cells show the six hallmarks of cancer. They
include:
� Cell growth and division absent the proper signals
� Continuous growth and division even given contrary signals
� Avoidance of programmed cell death
� Limitless number of cell divisions
� Promoting blood vessel construction
� Invasion of tissue and formation of metastases

4. HOW can cancer be cured ?
● Surgery - manually the tumour cells are removed
● Chemotherapy - use of medicines
● Radiation therapy - UV rays are used
+
● Immunotherapy - by T cells

5. During treatment, you may
experience a variety of
gastrointestinal,
musculoskeletal or
constitutional symptoms.
the radiation therapy causes
damage to the surrounding
tissues
Nausea, vomiting, loss of
appetite, constipation or
diarrhea. Fever and fatigue
the radiation therapy causes
poor killing of cancer cells in
the areas that do not have a
good oxygen supply
Hair falls out it can not kill the tumor cells
that can not be seen on the
imaging scans.

6. How Immunotherapy Is Used
to Treat Cancer
Immunotherapy is treatment that uses certain parts of a person’s
immune system to fight diseases such as cancer. This can be done in
a couple of ways:
● Stimulating, or boosting, the natural defenses of your immune
system so it works harder or smarter to find and attack cancer
cells
● Making substances in a lab that are just like immune system
components and using them to help restore or improve how your
immune system works to find and attack cancer cells

7. The immune system has a tougher time targeting
cancer cells. This is because cancer starts when
normal, healthy cells become changed or altered and
start to grow out of control. Because cancer cells
actually start in normal cells, the immune system
doesn’t always recognize them as foreign.
Simply put, immunotherapy is the process of Boosting
the Body's Immune System to Fight Cancer

8. James
P.Allison

9. INTRODUCTION :

10. RESEARCH :
James Allison, Ph.D., knows his T cells. For the past 30 years, he's
studied them inside and out, learning what makes them run and
hum.
IN EARLY 1980s :
Allison was one of the first to identify the T cell receptor—the part
of a T cell that binds to antigen and functions as the T cell’s ignition
switch.

11. LATER RESEARCH :
➔ In 1992, a molecule called CD-28 functioned as the T-cell’s gas
pedal.
➔ In 1995, Allison identified the T cell brakes.
➔ Also known as checkpoint blockage.
➔ The antibodies block the action of the braking molecule, called
CTLA-4.

12. HOW CTLA-4 WORKS :

13. IDENTIFICATION OF CTLA-4 AS A NEGATIVE
REGULATOR:
The fundamental property of our immune system is the ability to
discriminate “self” from “non-self” so that invading bacteria,
viruses and other dangers can be attacked and eliminated. T cells, a
type of white blood cell, are key players in this defense. T cells
were shown to have receptors that bind to structures recognized as
non-self and such interactions trigger the immune system to engage
in defense.

14. ACCELERATORS AND BRAKES IN OUR IMMUNE
SYSTEM:
The fundamental property of our immune system is the ability to
discriminate “self” from “non-self” so that invading bacteria,
viruses and other dangers can be attacked and eliminated. T cells, a
type of white blood cell, are key players in this defense. T cells
were shown to have receptors that bind to structures recognized as
non-self and such interactions trigger the immune system to engage
in defense.

15. A NEW PRINCIPLE FOR IMMUNE RESPONSE :
James P. Allison studied the T-cell protein CTLA-4. He was one of
several scientists who had made the observation that CTLA-4
functions as a brake on T cells. Allison, however, had an entirely
different idea. He had already developed an antibody that could
bind to CTLA-4 and block its function. He now set out to investigate
if CTLA-4 blockade could disengage the T-cell brake and unleash
the immune system to attack cancer cells. Mice with cancer had
been cured by treatment with the antibodies that inhibit the brake
and unlock antitumor T-cell activity.

16. INHIBITION OF TUMOR GROWTH BY ANTIBODIES
AGAINST CTLA-4 IN ANIMALS :
He attempted to block the negative effects that CTLA-4 induced,
thereby unleashing an immune response.
Mice that had been transplanted with tumors were treated with
monoclonal antibodies against CTLA-4.

17. ANTI CTLA-4 AGAINST CANCER :

18. BENEFITS :
➔ Didn’t have to study about different antigens for different
tumors .
➔ Blocking CTLA was better.
➔ Strengthen T cell anti- tumor response.
➔ Several different tumor types responded to the same treatment
strategy.

19. Tasuku
Honjo

20. ● Tumor cells can
present antigen to the
T-cell receptor,
resulting in a
stimulatory signal to
the T cell (+).
● Tumor cells may also
express PD-L1, which
interacts with PD-1 on
activated T-cells, and
results in inhibition (−)
of the antitumor T-cell
response
● Tumor cells can
present antigen to the
T-cell receptor,
resulting in a
stimulatory signal to
the T cell (+).
● Tumor cells may also
express PD-L1, which
interacts with PD-1 on
activated T-cells, and
results in inhibition (−)
of the antitumor T-cell
response

21. How Discovered (1990)
1. He found that there was more PD 1 in dying mouse cells.
2. So he aimed to isolate mRNAs that are overexpressed in
these mouse cells.
3. He thought it is involved in some apoptosis
4. So he named this antigen as PD 1
(PD = Programmed cell Death)
Cntd ...

22. In 1996 :
Antibody for PD 1 was made
In 2001 :
● Generated a mice deficient of PD 1
● Tumor cells didn’t proliferate
● So Honjo concluded that PD 1, similar to CTLA 4 acts by
negatively controlling immune responses.
Then : Honjo started a hunt for ligand of PD 1. They named it PD 1
ligand (PD-L1)

23. In 2005 research papers :
Stated that anti PD 1 treatment could :
1. Showed that ligand protects the tumor cells
2. Induce immune responses tumors that didn’t have PD
L1
3. More efficient way than CTLA 4 therapy
4. Leads to less severe autoimmune side effects than
CTLA 4.

24. Responses to anti PD 1
● 20-25% melanoma showed complete tumor regression
In Phase 1 trial of PD antibody
Done on 135 melanoma patients
● Showed +ve results
● 38% patients showed good results, who initially didn’t
respond to anti CTLA 4 treatment

25. therapy in non-small cell lung cancer treated with anti-PD-1
Pseudoprogression at 2 months due to infiltrating immune cells and the reduced
tumor size after 4 months.

27. COMBINATION
THERAPY……..

28. THE START….
●More than fifteen years has passed since the first dose of anti-CTLA4
antibodies was given to a patient.
●The first treatment with anti-PD-1 antibodies was administered twelve years
ago.
Today, there is a solid clinical experience, based not only on mono-treatment
with each antibody, but also on combination treatment.

30. TECHNICAL INFO…
●Outcome of multiple studies suggest that ICIs against PD-1 or its ligand, PD-
L1, yield better treatment effects as compared to anti-CTLA-4, combined
therapy with blockade of both CTLA-4 and PD-1 seems to induce an even
stronger anti-tumor effect in both melanoma and in renal cell carcinoma
possibly because of different mechanisms of action.

32. MECHANISMS IN THE CLINICAL RESPONSE AND
HOW TO PREDICT IT?
●The actual mechanisms whereby the antibodies interfere with negative
regulation are also complex. It has been suggested that temporal and
spatial differences between the CTLA-4 and PD-1 pathways, due to receptor
expression kinetics and ligand expression pattern, lead to different and
complementary roles in the immune response, and consequently,
synergistic effects in combination therapy.

33. INITIAL OBSERVATION
●Initially it was assumed that anti-CTLA-4 antibodies worked by interfering
with intrinsic T cell signaling and mainly acting in lymph nodes to prevent
initial T cell activation.

34. IMPORTANCE OF IMMUNOTHERAPY
It is further debated, and later studies by several groups, including Allison’s,
have provided evidence for at least four different mechanisms .
● 1) Blockade of a direct inhibitory intracellular signaling pathway in effector T
cells
●2) Competition for, or sequestration of, activating ligands on antigen
presenting cells
●3) Interference with the function of regulatory T cells
● 4) Elimination of regulatory T cells.
●the last mechanism may be exerted in the local tumor environment .

35. NOW REGARDING PD-1:
●There is strong evidence that the antibodies act predominantly
●T cell intrinsic signaling, mediated by the ITSM in the cytoplasmic tail of the
molecule
●a major part of the effect occurs intratumorally to counteract exhaustion of
infiltrating T cells.
●cancer cells frequently express PD-L1, and PD-L1 staining of tumor biopsies
has therefore been examined extensively as a predictive marker.

36. CONCLUDING REMARKS…
● new form of immunotherapy unleashes a vigorous, and often durable, immune
response directed against essentially any tumor already recognized by the immune
system.