Flashcards in Cancer immunotherapy Deck (48):
How does the immune system target cancer cells?
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
Describe the concept of immunoediting
- 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
What are the four approaches to immunotherapy?
- vaccination strategies
- Non-specific therapies
- Antibody therapies
- Cell-based therapies
Describe the vaccination strategy of immunotherapy
You take tumour antigens,
re-vaccinate the patient with it and generate a
stronger immune response and therefore get the
immune system working again.
What are the disadvantages of vaccination immunotherapy
- Requires an intact immune system to work
- They’re generally not very effective
How do non-specific immunotherapies work?
Generate an immune or inflammatory reaction which try to target the cancer non-specifically
What are antibody immunotherapies?
- e.g. monoclonal antibodies
What are cell therapies in immunotherapy?
Taking one or more immune cell components from a patient or donor and using these as the driving
mechanisms for killing the tumour.
What is the idea behind bacterial non-specific immunotherapy?
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.
Name a non-specific immunotherapy and describe how it works
Aldara - a toll-like receptor 8 antagonist
This triggers a non-specific immune response in
humans that drives inflammatory cells to the site.
What are the drawbacks of bacterial-based non-specific immunotherapies
people’s immune systems react in different ways, can
be difficult to gauge the response and dose
What are the non-bacterial non-specific immunotherapies
IL-2 (a T-cell growth factor) for therapy.
Premise: making more T-cells is beneficial
What are the disadvantages of IL-2 therapy?
- 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
- patients kept on a high dependency unit whilst the
medication is administered
How can IL-2 be used to kill target cells?
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.
What are T regulatory cells and their role in cancer?
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.
How is IL-2 used to target T reg cells?
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.
What are conjugate monoclonal antibodies and how are they used in cancer?
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.
What are the advantages of monoclonal antibody immunotherapies?
These are highly effective in many cases and are used
often. Also are synthetic so can be made very
What properties make a cell an appropriate target for monoclonal antibody immunotherapies?
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
How can the immune system be targeted with immunotherapies?
Targeting immune system checkpoints to ensure T cells are switched off
What are the T cell checkpoints?
What is CTLA-4?
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.
What is CTLA-4s role in cancer?
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.
Why are checkpoint inhibitors used?
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
Name a CTLA-4 inhibitor
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.
What are the disadvantages of CTLA-4 inhibitors
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.
How are side effects of CTLA-4 inhibitors overcome?
by balancing the dose of ipilimumab with steroids to counter the off-target effects,
while still achieving the anti-cancer effects.
What is PD-1 and its function?
PD-1 (programmed death 1) is expressed on T cells. Surveillance for cells missing the ligand.
What is PDL-1 and its function?
PDL-1 (programmed death ligand 1) is expressed on every cell. This allows the cell to let T cells know ‘i’m ok’
What is PDL-1s role in cancer?
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.
Name a PDL-1 inhibitor
Nivolumab blocks PDL-1
What are the advantages of PDL-1 inhibitors
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.
What are the disadvantages of PDL-1
- need to find the best way of use
- effective in certain types of cancers
- first reports of resistance
What is the main disadvantage of chemotherapy and radiotherapy
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.
List different cell therapies for cancer
- haematopoietic stem cells
- tumour-inflitrating T cells
- Dendritic cell vaccines
- NK cells
- gamma-delta T cells
- Virus-specific T cells
- genetically engineered T cells
How are stem cells harvested?
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
How are autologous stem cells used in immunotherapies?
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.
What are the pros and cons of autologous stem cells
This is method is the best tolerated in terms of graft vs host.
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.
How are allogeneic stem cells used in immunotherapies?
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.
What are the pros and cons of allogeneic immunotherapies?
Highly effective against leukaemias
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
What is provenge?
The only dendritic cell licensed for use
combines vaccination therapy and cell therapy
How does dendritic cell therapy work?
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.
What are the pros and cons of dendritic cell therapy?
In the right patient, this can generate a good immune
response and an anti-cancer response, which is durable.
In many patients, this does not work
What is PTLD?
PTLD = post-transplantion lympho-proliferative disease
This is a rare cancer that is currently emerging.
How does PTLD occur?
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.
What were the treatment options for PTLD?
Chemotherapy is ok, but these patients have just received a transplant and will not be in the best of health to
other option is to remove the patient’s immune suppression. This allows their adaptive immune response
to kick off and attack the virus cells.
What are the new treatment options for PTLD?
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.