The nobel prize in physiology or medicine was awarded to James P. Allison and Tasuku Hanjo for their pioneering work in cancer therapy by inhibition of negative immune regulations. Allison discovered that the protein CTLA-4 functions as a brake on T cells, inhibiting their immune response. He developed an antibody to block CTLA-4's function and unleash anti-tumor immune responses in mice. This led to the first successful clinical trial in 2010 treating advanced melanoma patients, with signs of cancer disappearing in multiple patients. Their work established checkpoint inhibition as a new therapeutic approach in cancer treatment by releasing brakes on the immune system.

1. The nobel prize in physiology or medicine was awarded to James P. Allison and Tasuku Hanjo for their pioneering work in cancer
therapy by the inhibition of negative immune regulations.
Cancer is a disease of uncontrolled proliferation of cell division. When changes occur in cell cycle regulators for
instance, when they are overactive, or underactive such changes are known to have direct correlation to the
development of tumour cells. These alterations in activity are due to mutations in genes that are known to encode
cell cycle regulator proteins.
Cancer cells have replicative immortality. They can proliferate indefinitely unlike the proliferation of normal
somatic cells, which have a set number of cell divisions.
Normal functioning cells enter a state of replicative senescence in which they can no longer proliferate however
remain metabolically active. one of the triggers of senescence state is exposed telomerase. Telomeres are
nucleoproteins structures that cap the end of chromosomes and maintain genome stability. They protect the
genome from nucleolytic degradation , unrequired repair , recombination and intrachromosomal fusion.
.

2. The immune system is made up of convoluted network of cells, tissues & organs
that work together to protect the body from pathogens and other harmful
substances.
James p. Allison illustrated that antibodies directed against a cell surface
molecule on T cells known as CTLA – can unleash immune response, which
eradicated tumours from mice.
PD1 was identified to act as a brake on T cells , which prevented them from killing
cancer cells. The concept of anti –CTLA was developed for patients with
advanced forms of melanoma.
CTLA-4 this act as a brake on T cell so they no longer kill tumour cells. Blocking
the binding of B7-1/B7-2 to CTLA-4 with an anti-CTLA antibody enables T cells to
be activate and therefore eradicate tumour cells. ("The Nobel Prize in Physiology
or Medicine 2018", 2020)
Inhibition of these molecules have led to an increased activation of immune
system.

3. Immune
system
By Cara-louise Barker

4. Introduction to
Immune system
• Crucial for our survival, without it minor infections can be
fatal.
• Main function is to protect body from infectious diseases.
• Works by invading microorganisms building up its strongest
response .
• Most microorganisms are smaller than a single human cell
(Parham, 2012, pp. 1-2).
• The first mechanism against invading microorganisms are
physical barriers and any viruses, bacteria or parasites must
first break through this barrier to be able to cause any
problems.
• If the invaders successfully invade the first physical barrier it
first encounters the innate immune system (The second
defence) (Sompayrac, 2019, pp. 1–2).

5. Innate immune system
• Cuts, wounds and abrasions are entries for pathogens to enter the body, as well as
touching and picking the eyes, nose or mouth which helps break the surface.
• Infections are normally localised and stamped out within a few days before signs of
becoming ill appear.
• The innate response firstly acknowledges the fact that a pathogen is present via
cell surface receptors binding to either the pathogen or a human cell, or serum
proteins which are altered in pathogens existence.
• The effector mechanisms then eliminate the pathogens in the second stage, these
effector cells kill virus infected cells and engulf bacteria or attack protozoan
parasites.
• Complement proteins attack pathogens while also marking them with molecular
flags, helping the effectors (Parham, 2012, pp. 8-9).
• Redness and swelling around a wound are indicators that your innate immune
system has kicked in.
• Macrophages are the most known defender cell in the innate immune system, fats
and carbohydrates that are present in bacteria membranes provide signals to the
macrophages, picked up by its antenna like receptors which in turn recognise
danger molecules (Sompayrac, 2019, pp. 2-3).

6. Innate immune system
• Cuts, wounds and abrasions are entries for pathogens to enter the body, as well as
touching and picking the eyes, nose or mouth which helps break the surface.
• Infections are normally localised and stamped out within a few days before signs of
becoming ill appear.
• The innate response firstly acknowledges the fact that a pathogen is present via
cell surface receptors binding to either the pathogen or a human cell, or serum
proteins which are altered in pathogens existence.
• The effector mechanisms then eliminate the pathogens in the second stage, these
effector cells kill virus infected cells and engulf bacteria or attack protozoan
parasites.
• Complement proteins attack pathogens while also marking them with molecular
flags, helping the effectors (Parham, 2012, pp. 8-9).
• Redness and swelling around a wound are indicators that your innate immune
system has kicked in.
• Macrophages are the most known defender cell in the innate immune system, fats
and carbohydrates that are present in bacteria membranes provide signals to the
macrophages, picked up by its antenna like receptors which in turn recognise
danger molecules (Sompayrac, 2019, pp. 2-3).

7. Adaptive immune system
• Most of us get through life fine with our natural barriers
and our innate immune system, however we have the
adaptive immune system which protect us from nearly all
other invaders. If the immune system has enough time to
prepare it can produce equipment to fight intruders that it
hasn’t encountered before (Sompayrac, 2019, pp. 4-5).

8. Antibodies and B cells
• Immunoglobin G (igG) makes up around 75% of antibodies in the blood and is made up of 2 proteins,
the heavy chain and the light chain, resulting in igG having two identical hands known as fab regions
which are able to bind to antigens
• igA, igD and igM are also other types of antibodies which are manufactured via the white blood cells
produced in bone marrow, known as B cells which go on to mature into plasma B cells.
• A constant region (Fc) is a tail which is found on the antibody molecule, this can bind to Fc receptors
such as macrophages. The structure of the Fc regions decides its call for examples igG, plus which
immune system cells it will bind to and how it functions.
• Different antibody molecules are needed to obtain antibodies that can combine to different antigens.
Antibodies are important in fighting invaders, although they don’t actually kill anything, they flag it to
be destructed.
• We have enough B cells to attack any invaders, although we don’t have many of one type, so when
invaded the appropriate B cell must be produced via clonal selection where B cell receptors (BCR’s)
move to the surface of the cell which their antigen body receptors facing out acting as bait to grasp
their associated antigen, if this occurs the B cell doubles in size and divides into 2 daughter cells
(proliferation)
• The daughter cells divide into 4 cells and eventually after a week of proliferation there are enough B
cells to prepare a real defence.
• These antibodies produced by specially selected B cells do not have anchors to attach them to B cells,
so move into the blood stream.
• 2000 antibody molecules per second are produced by one B cell, but only survive for 1 week
preventing us from filling up with B cells which where only needed for one previous invader
(Sompayrac, 2019, pp. 5-7).

9. T cells
• If a virus enters a cell, antibodies cant then get to it, so the virus is able to make 1000’s of copies
of itself.
• Part of the adaptive immune system, any one person has around 300 billion of them at one time
• T cells and B cells together are hard to tell apart from the surface.
• Produced in bone marrow and display T cell receptors (TCR’s) which are as assorted B cell
receptors.
• Also use clonal selection, TCR’s receptors mould with associated antigen, and the T cell generates
a clone of T cells with the same precision.
• Prefoliation stage takes around a week, with receptors staying glued to its surface.
• Mature in the Thymus, and specialise in recognising protein antigens presented by another cell.
• Cytotoxic Lymphocytes (CTL’s), helper and regulatory are the 3 main types. CTL destroys an
infected cell by connecting with it and forcing it to kill itself, a helper T cell is a Cytokine factor
which have affects on other immune system cells, helping them become fully activated effector
cells, and regulatory T cells help stop immune system from over reacting or acting inappropriate
e.g. preventing unnecessary tissue damage. (Parham, 2012, pp. 16-18)

14. Introduction to
Immune system
• Crucial for our survival, without it minor infections can be
fatal.
• Main function is to protect body from infectious diseases.
• Works by invading microorganisms building up its strongest
response .
• Most microorganisms are smaller than a single human cell
(Parham, 2012, pp. 1-2).
• The first mechanism against invading microorganisms are
physical barriers and any viruses, bacteria or parasites must
first break through this barrier to be able to cause any
problems.
• If the invaders successfully invade the first physical barrier it
first encounters the innate immune system (The second
defence) (Sompayrac, 2019, pp. 1–2).

16. Alberola-Ila, J. Hogquiest, K. A. Swan, K. A. Bevan M. J. Perlmutter,
R. M. (1996). Positive and negative selection invoke distinct signaling
pathways. Retrieved from: https://doi.org/10.1084/jem.184.1.9
Kasyanyuk, V. (n.d.) Anatomy of the thymusgland. Retrieved from: Anatomy Of The
Thymus Gland. Stock Vector - Illustration of immunity, capsule: 130471690
(dreamstime.com)
Lio, C. W., & Hsieh, C. S. (2011). Becoming self-aware: the thymic education of
regulatory T cells. Current opinion in immunology, 23(2), 213–
219. https://doi.org/10.1016/j.coi.2010.11.010
Wikipedia. (2020) Thymocyte. Retrieved from: Thymocyte - Wikipedia

17. CTLA‐4
(cytotoxic T-lymphocyte-associated protein 4)

18. • The immune system’s main property is the ability to
discriminate between “non‐self” and “self” so that
invading pathogens can be attacked and then
eliminated.
• The immune system has accelerators and brakes
within it. Accelerators are immune checkpoints which
spur on the immune response to take down the
pathogens. Brakes are immune checkpoints which act
to slow down or stop the immune response.
• The intricate balance between these accelerators and
brakes is fundamental for tight control of the immune
system. The immune system needs to be sufficiently
engaged in attack against invading pathogens as
excessive activation of the immune system may lead
to autoimmune problems resulting in healthy cells and
tissues being destroyed.
CTLA‐4 acting as a brake,
binding to the APC and
inhibiting the T cell from
producing an immune response
Figure 1:

19. During the 1990s, James P. Allison studied CTLA‐4 in his
laboratory at the University of California. He, along with
several other scientists, discovered that CTLA‐4 functions as a
brake on T cells.
Allison had developed an antibody that could bind to CTLA‐4
in order to block its function. Allison’s aim was to use the
CTLA‐4 blockade to disengage the T cell brake so that the T
cells and the immune system could attack cancer cells.
Allison and his team managed to produce positive results
during their first experiment which involved curing mice with
cancer by treating them with the antibodies that blocked the
CTLA‐4.
Alisson continued with his attempts to carry forward this
treatment and in 2010 an important clinical study was carried
out on patients with advanced melanoma. This clinical study
produced very successful results. In multiple patients, signs of
any remaining cancer had completely disappeared. These
results had not been seen before in this group.
Figure 2 shows Alisson hard at work in his laboratory in the late
1980s
Figure 2:

20. The nobel prize in physiology or medicine was awarded to James P. Allison and Tasuku Hanjo for their pioneering work in
cancer therapy by inhibition of negative immune regulations. The immune system can distinguish self from non self this
enables the immune system to eradicate pathogens or tumour cells. For tumour cells to grow, they need to avoid detection by
the immune system by producing molecules. Cancer is a disease of uncontrolled proliferation of cell division. When changes
occur in cell cycle regulators for instance, when they are overactive, or underactive such changes are known to have direct
correlation to the development of tumour cells. These alterations in activity are due to mutations in genes that are known to
encode cell cycle regulator proteins.
Cancer cells have replicative immortality. They can proliferate indefinitely unlike the proliferation of normal somatic cells, which
have a set number of cell divisions. Normal functioning cells enter a state of replicative senescence in which they can no longer
proliferate however remain metabolically active. one of the triggers of senescence state is exposed telomerase. Telomeres are
nucleoproteins structures that cap the end of chromosomes and maintain genome stability. They protect the genome from
nucleolytic degradation , unrequired repair , recombination and intrachromosomal fusion.
Telomeres play a pivotal role in preserving the integrity of the information in our genome. They are known to shorten with
each round of cell division once they reach a critical length , they lead to the senescence state by regulatory pathways that
respond to deoxyribonucleic acid (DNA) damage. Cancer cells express an enzyme known as ‘’ telomerase’’ which reverses the
wearing down of chromosome ends that normally occurs during cell divisions. The replicative immortality in cancer cells
involves the usage of enzymatic pathways that enhance the length of telomere length or inactivation the DNA damage
response.

21. 1. Here is the CTLA‐4 blockade in
action. It binds to the CTLA‐4 brake
which stops the CTLA‐4 brake from
binding to the APC and in turn
inhibiting an immune response from
the T cell.
2. The T cell accelerator can
now bind to the APC and spur
on the T cell to produce an
immune response.
3. The T cell will now be
able to recognise the
cancer cell as “non‐self”
and attack it.
Figure 3:

22. 

Figure 4:
Nobel laureate James P. Alisson still hard at work attempting to
develop immune checkpoint therapy.

23. References
Parham, P. (2012). Chapter 1 [E-book]. In The immune system (Fourth ed., pp. 1–2). Garland
Science.
https://books.google.co.uk/books?id=Ph7ABAAAQBAJ&dq=immune+system&lr=&source=gbs_n
avlinks_s
Sompayrac, L. (2019). How the Immune system works (6th ed.) [E-book]. John Wiley & Sons
Incorporated. https://ebookcentral.proquest.com/lib/shu/detail.action?docID=5660373

24. Alberola-Ila, J. Hogquiest, K. A. Swan, K. A. Bevan M. J. Perlmutter,
R. M. (1996). Positive and negative selection invoke distinct signaling
pathways. Retrieved from: https://doi.org/10.1084/jem.184.1.9
Kasyanyuk, V. (n.d.) Anatomy of the thymusgland. Retrieved from: Anatomy Of The
Thymus Gland. Stock Vector - Illustration of immunity, capsule: 130471690
(dreamstime.com)
Lio, C. W., & Hsieh, C. S. (2011). Becoming self-aware: the thymic education of
regulatory T cells. Current opinion in immunology, 23(2), 213–
219. https://doi.org/10.1016/j.coi.2010.11.010
Wikipedia. (2020) Thymocyte. Retrieved from: Thymocyte - Wikipedia