Cancer immunotherapy

Question 1

How does the immune system target cancer cells?

Answer 1

Cancer down-regulates MHC1 to avoid recognition

Innate cells attack cells with this problem

• during process factors released that kill tumour cells
• innate cells also release cytokines to trigger a response
• APCs alerted
• more innate cells are recruited
• more factors produces
• APCs take cell debris to lymph nodes to trigger adaptive response
• Second wave of immune attack through T cells and B cells/plasma cells

Question 2

Describe the concept of immunoediting

Answer 2

• Elimination: default setting. Immune system will cut back the tumour
• Equilibrium: immune system is not eradicating the cancer. The cancer is not growing. stage can last decades.
• Escape: The tumour produces a cell that is able to avoid or suppress the immune system. Generates an escape clone that is able to grow unchecked. The tumour will reach a certain size when the immune system will contribute to the cancer rather than just removing it

Question 3

What are the four approaches to immunotherapy?

Answer 3

• vaccination strategies
• Non-specific therapies
• Antibody therapies
• Cell-based therapies

Question 4

Describe the vaccination strategy of immunotherapy

Answer 4

You take tumour antigens,
re-vaccinate the patient with it and generate a
stronger immune response and therefore get the
immune system working again.

Question 5

What are the disadvantages of vaccination immunotherapy

Answer 5

• Requires an intact immune system to work

- They’re generally not very effective

Question 6

How do non-specific immunotherapies work?

Answer 6

Generate an immune or inflammatory reaction which try to target the cancer non-specifically

Question 7

What are antibody immunotherapies?

Answer 7

• e.g. monoclonal antibodies

Question 8

What are cell therapies in immunotherapy?

Answer 8

Taking one or more immune cell components from a patient or donor and using these as the driving
mechanisms for killing the tumour.

Question 9

What is the idea behind bacterial non-specific immunotherapy?

Answer 9

found that if you injected a mixture of killed bacteria into a tumour, you could stimulate a non-specific inflammatory response that would help to resolve the tumour in many cases.

Question 10

Name a non-specific immunotherapy and describe how it works

Answer 10

Aldara - a toll-like receptor 8 antagonist

This triggers a non-specific immune response in
humans that drives inflammatory cells to the site.

Question 11

What are the drawbacks of bacterial-based non-specific immunotherapies

Answer 11

people’s immune systems react in different ways, can
be difficult to gauge the response and dose
accordingly.

Question 12

What are the non-bacterial non-specific immunotherapies

Answer 12

IL-2 (a T-cell growth factor) for therapy.

Premise: making more T-cells is beneficial

Question 13

What are the disadvantages of IL-2 therapy?

Answer 13

• Have to be a licensed IL-2 physician, as the
  therapeutic window is so narrow
• quite a toxic cytokine - as the response can be so
  severe
• patients kept on a high dependency unit whilst the
  medication is administered

Question 14

How can IL-2 be used to kill target cells?

Answer 14

by tagging a toxin to the end of it and administer it.
This is for cases where the cancer is predominantly
driven by T regulatory cells.

Question 15

What are T regulatory cells and their role in cancer?

Answer 15

T regulatory cells are an effective method of
suppressing the immune system.

Certain cancers such as renal cell carcinomas actively
recruit T regs into the tumour to protect the tumour
from the immune response.

Question 16

How is IL-2 used to target T reg cells?

Answer 16

One of the ways this is treated is by targeting the T
regs rather than the tumour.

T regs love IL-2 and suck up huge amounts of it, meaning they will preferentially eat the poisoned IL-2, which
will kill them.

Question 17

What are conjugate monoclonal antibodies and how are they used in cancer?

Answer 17

Conjugates are also used in cancer. These have a
radioactive tag (radioactive isotope or some sort of
toxin) attached that attack the tumours specifically
with radiation or chemotherapy.

Question 18

What are the advantages of monoclonal antibody immunotherapies?

Answer 18

These are highly effective in many cases and are used
often. Also are synthetic so can be made very
effectively.

Question 19

What properties make a cell an appropriate target for monoclonal antibody immunotherapies?

Answer 19

If you have a target that is specific to that cell and nothing else, this has the best outcome as treatment wont
have any knock on effect on other cells.

cancers of the blood, which are disseminated so they are easy to
target with monoclonal antibodies through the peripheral blood or lymph nodes are easier to treat than solid tumours

Question 20

How can the immune system be targeted with immunotherapies?

Answer 20

Targeting immune system checkpoints to ensure T cells are switched off

Question 21

What are the T cell checkpoints?

Answer 21

• CTLA-4

- PD-1

Question 22

What is CTLA-4?

Answer 22

When a T cell is activated, it is a two step process. The T cell receptor and the antigen presenting cell stick
together with the T cell receptor and the antigen. However, this is insufficient to drive a T cell to respond. You
need, whats called a co-stimulatory factor. In most cases, this is CD28, which activates the T cell and causes
them to grow and attack.
You have to be able to switch a T cell off. The innate mechanism for that is by CTLA-4. This binds to the same
molecule that CD28 binds to, B7, and turns T cells back off again.

Question 23

What is CTLA-4s role in cancer?

Answer 23

CTLA-4 is up-regulated very heavily on T cells by the tumour. It has subverted the immune response,
by turning T cells of when they should be activated.

Question 24

Why are checkpoint inhibitors used?

Answer 24

If the T cells are switched off, you can’t switch them back on again, unless you have a way of turning off the off switch

Question 25

Name a CTLA-4 inhibitor

Answer 25

Ipilimumab blocks CTLA-4. By switching off the off switch, the T cells will become activated again and are able to work much more effectively.

Question 26

What are the disadvantages of CTLA-4 inhibitors

Answer 26

Initially, the fear of side effects from overstimulated T cells was a big concern. This was potentially a big problem in the gut, which constantly has new antigens exposed due to the foods we eat. If these T cells couldn’t be switched off. This does happen. About 15-20% patients will have ulcerative colitis.

Question 27

How are side effects of CTLA-4 inhibitors overcome?

Answer 27

by balancing the dose of ipilimumab with steroids to counter the off-target effects, while still achieving the anti-cancer effects.

Question 28

What is PD-1 and its function?

Answer 28

PD-1 (programmed death 1) is expressed on T cells. Surveillance for cells missing the ligand.

Question 29

What is PDL-1 and its function?

Answer 29

PDL-1 (programmed death ligand 1) is expressed on every cell. This allows the cell to let T cells know ‘i’m ok’

Question 30

What is PDL-1s role in cancer?

Answer 30

Tumour cells massively up-regulate PDL-1, which allows them to protect themselves from the immune system. By blocking this, the activated T cells should be able to work much more effectively.

Question 31

Name a PDL-1 inhibitor

Answer 31

Nivolumab blocks PDL-1

Question 32

What are the advantages of PDL-1 inhibitors

Answer 32

The effect of the drug was so good that the trial was stopped early as it was no longer ethical to treat the control group with the inferior treatment.

Question 33

What are the disadvantages of PDL-1

Answer 33

- need to find the best way of use - effective in certain types of cancers - first reports of resistance

Question 34

What is the main disadvantage of chemotherapy and radiotherapy

Answer 34

One of the main problems of chemotherapy and radiotherapy is that they kill fast growing cells. Apart from the tumour, the skin, mucosa, hair follicles and immune cells are all fast growing. Using a chemotherapy, you are killing the immune system that is needed to fight it.

Question 35

List different cell therapies for cancer

Answer 35

- haematopoietic stem cells - tumour-inflitrating T cells - Dendritic cell vaccines - NK cells - gamma-delta T cells - Virus-specific T cells - genetically engineered T cells

Question 36

How are stem cells harvested?

Answer 36

can be drawn directly from the hip bone, but this procedure can be very painful A new method, called plerixifor, which blocks CXCR4 (one of the chemokine receptors that is intrinsicly important in keeping stem cells where they are) and has been extremely effective in emptying out the bone marrow.

Question 37

How are autologous stem cells used in immunotherapies?

Answer 37

Using the patient’s own stem cells, you take them all out and harvest them. Then you would give radiation or chemotherapy (or both) to kill back all of the tumour, and as a result wipe out the remaining stem cell population in the body. The harvested stem cells are then returned back into the body.

Question 38

What are the pros and cons of autologous stem cells

Answer 38

Pros: This is method is the best tolerated in terms of graft vs host. Cons: If you haven’t eliminated all of the leukaemic cells from the stem cells that you have returned to the patient, then you could return the leukaemia back into the body.

Question 39

How are allogeneic stem cells used in immunotherapies?

Answer 39

Have been more popular in terms of a curative response, as you are returning a different stem cell population component, and as a result a different immune system that can attack the leukaemia that remains.

Question 40

What are the pros and cons of allogeneic immunotherapies?

Answer 40

Pros: Highly effective against leukaemias Cons: Much more harsh on the patient Can be very difficult to stabilise a patient who has received an allogeneic stem cell transplant Graft vs host response

Question 41

What is provenge?

Answer 41

The only dendritic cell licensed for use combines vaccination therapy and cell therapy

Question 42

How does dendritic cell therapy work?

Answer 42

You take out monocytes and turn them into dendritic cells, feed them with a combination fusion protein of the tumour antigen, with GM-CSF growth factor. They will make dendritic cells, which will be grown and put back into the patient. This makes a preformed immune response that will go into the lymph node and drive a new immune response.

Question 43

What are the pros and cons of dendritic cell therapy?

Answer 43

Pros: In the right patient, this can generate a good immune response and an anti-cancer response, which is durable. Cons: In many patients, this does not work

Question 44

What is PTLD?

Answer 44

PTLD = post-transplantion lympho-proliferative disease | This is a rare cancer that is currently emerging.

Question 45

How does PTLD occur?

Answer 45

found in patients that have epstein barr virus, which is commonly carried by the population. the virus stays dormant in B cells and is not eliminated. When the immune system becomes perturbed, such as in post-transplantation, where you have immune supression, those virus-infected B-cells can become reactivated again. This reactivation creates an immortal cell line that is essentially a B-cell cancer.

Question 46

What were the treatment options for PTLD?

Answer 46

Chemotherapy is ok, but these patients have just received a transplant and will not be in the best of health to tolerate chemotherapy. other option is to remove the patient’s immune suppression. This allows their adaptive immune response to kick off and attack the virus cells.

Question 47

What are the new treatment options for PTLD?

Answer 47

white cells are harvested, the T cells are isolated from this pool and are given to a patient who has the right HLA type. They are given a series of 4 doses. This causes the viral load to peak slightly and drop dramatically. By the fourth dose ~8 months in these patients are viral negative and their immune system has accepted their graft and they will be taken off immune suppression.

Question 48

What are the future hopes for CAR-T cell therapies?

Answer 48

is trying to avoid having to use the HLA system. Recently tried to design a receptor that works without having any HLA involvement. This was done by designing a construct, that are the two binding portions of an antibody against a tumour with a linking bit, a hinge, a bit of transmembrane, and then the intracellular signalling motif from the T cell receptor (which drives the activation of the T cell).