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BIOL3043 - Cellular and molecular pathology > Lectures 9&10 - Cancer immunology > Flashcards

Lectures 9&10 - Cancer immunology Flashcards

1
Q

What are the different subsets of the immune system

A

Natural killer - early responder

Specialised responders t cells and B cells – create lasting memory against particular antigens

Negative regulatory systems – need control – suppressor cells

Cancer – immune system becomes suppressed

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2
Q

Explain antigen presentation

A

Innate immune cells sat in tissue, on infection they sense the antigens and molecules expressed by bacteria

They become activated and migrate to the lymph nodes and they then present the antigen which interacts with naive T cells

Activated T cells then go back to the tissue that is infected and release chemicals to help break down infected cells

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3
Q

Out of chemotherapy and and immunotherapy, which is long lasting?

A

immunotherapy

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4
Q

What are the different T cells that can be created from nieve CD4+T cells and whats interlukins cause them to develop into them?

A

Treg- IL-2, TGFb

Th1 - Il-12

Th2 - Il-4

Th17 - TGFb, IL-6, IL-21

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5
Q

What percentage of a tumour can be immune cells

A

50%

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6
Q

What different things are regulatory t cells involved with

A

dominant consumption of IL-2
Inhibitory cytokines
Induction of apoptosis
Immune checkpoint molecules mediated immunosupression and Treg activation
Treg reinvigoration by immune cgeckpoint blockade
Inhibition via DCs
Promote IDO expression on APC
ATP-Adenosine metabolism

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7
Q

Explain simply how tumours turn t-reg cells from anti to pro-tumour

A

tumour gives them false signals,

tumour cells promote the Treg cells to proliferate and differentiate

And so Treg cells end up supporting the growth of the tumour

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8
Q

What is a TAM?

A

Tumour associated macrophage

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9
Q

Explain features of TAMS

A

Macrophages within the tumour

very immunosuppressed and are pro-tumour

can secrete factors that support the tumour growth and promote metastasis of the tumour, can also help help the generation if new blood vessels (angiogenesis) which helps with growth and spread

TAMS can also suppress the growth and production of other immune cells

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10
Q

How do Myeloid-derived supressor cells (MDSCs) work?

A

Myeloid cells also become immunosuppressed in the tumour microenvironment by mechanisms such as cell surface receptors which are expressed, secretion of enzymes, anti-inflammatory cytokine release

One of these factors IDO: Idoleamine 2,3-dioxygenase

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11
Q

Explain the normal function if IDO and what happens to it during cancer

A

Intracellular enzyme that initiates the breakdown of tryptophan in the tumour microenvironment. Tryptophan is required to build proteins for cellular growth as well as immune function

Can also promote Treg cells

So IDO is used normally to control immune function and cellular growth

In cancer:

Tumors take advantage of this and excessively release IDO into the environment supressi9ng the T cells that effect tumour cells and increases Treg cells

Companies are developing IDO inhibitors which they hope will be able to reverse some of these immunosupressions

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12
Q

Explain William coley’s work on cancer immunology

A

1891 William coley – surgeon, noticed some of the cancer patients that were infected by bacteria were getting cured of their cancer

Over a number of years he realised that sometimes the infection can potentially somhow supress the growth of the tumour cells

he put this to test : Started injecting patients with bacteria and worked in some patients

Bacteria themselves did not prevent tumour, but they create much needed inflammation which reverses immunosuppression

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13
Q

Explain cancer immunology discoveries on the mid 1900’s

A

1953 - using experimental animals- injected mice with tumour and after a while remove tumour surgically

Once mice cured – re-injecting tumour into mice and they would reject the tumour

This suggests the existence of tumour-specific antigens

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14
Q

What non-specific cancer immunotherapy was discovered in 1957

A

interferon - an immune stimulating cytokine

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15
Q

What year was the first humanized antibodies approved by FDA in the US for transpatation use

A

1986

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16
Q

what cancer immunotherapy was approved by the FDA in 1997?

A

rituximab - for treating non-Hodgkins lymphoma

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17
Q

When did the first theraputic cancer vacine win approval in russia for treating kidney cancer? what was it called?

A

2008 - called Oncophage

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18
Q

When did the FDA approve the first antibody for cancer treatment?

A

2010 - called provenge, for the treatment of prostate cancer

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19
Q

Explain an experiment that helped show how immunodeficiency increases risk of tumour development

A

Mice are RAG2-/- hosts
either immunodeficient or immunocompetent
inject with carcinogen
Immunodeficient mice got many more tumours

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20
Q

What phases happen when normal cells turn into transformed cells

A

Divided into three different phases:

Elimination – normal cell then starts getting cancer and changing its molecular pattern and immune cells notice and remove cancer from body

If elimination fails through evading the immune system:

Equilibrium – tumour cell is in dormancy/giving suppressing signals

Escape – tumour cells become more apparent, they have escaped the immune system, a point of no return

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21
Q

Explain a cold and hot tumour

A

Cold tumor – tumor which is actively excluding immune cells from tumor

Hot tumour – still have ability for immune cells to get into tumor, most often these become suppressed but there is the chance for immune cells to work again and makes giving treatments easier/work better

22
Q

The presence of TIL (tumour infiltrating lymphocytes) often correlates with what in cancer?

A

survival (especially in melanoma and breast cancer)

23
Q

what are (T) cells seeing in a tumour?

A

Mostly new antigens that are created as a result of the mutations that the tumours have

24
Q

Which cancers tend to have a lot more mutations? and what do many mutations mean in terms of immunotherapy?

A

Lung and melanoma, patients with many mutations tend to respond better to immunotherapy

25
Q

what are the steps of the Cancer immunity cycle?

A
  1. Release of cancer cell antigens
  2. Cancer antigen presentation
  3. Priming and activatiob
  4. Trafficking of T cells to tumours
  5. Infiltration of T cells into tumours
  6. Recognition of cancer cells by T cells
  7. Killing of cancer cells
    back to 1
26
Q

What are the passive immunotherapy stratagies?

A

You can activates the immune system but don’t do anything to specifically determine the antigen

Can also have direct targeting antibodies

Macrophage can directly engulf cells

NK cells release chemicals that make pores in the tumours

27
Q

What are the active immunotherapy stratagies?

A

Determine what antigens are in the tumour and cans see mutations

Artificially generate mutated DNAs and inject in the form of a vaccine to create an immune response

Dendritic vaccines Take dendritic cells in culture, feed them with new antigens, they start expressing antigens on surface (APC) and then inject back into tumour sites

Bispecific antibodies – artificially change the antibody so it can recognise two different epitopes one recognises a T cell receptor, other recognises a tumor cell, helping to bring the T cell closer to tumour cells

MORE

28
Q

Explain antibody based immunotherapies

A

ADCs (antibody drug conjugates) label them so can have a radioactive particle, a chemotherapy targeting a tumour

Can have engineered cells called CAR cells: CAR-T, CAR-NK, CAR-MA etc. - artificially loaded with antibody and then that way when we inject the cells back into the patient they can go and specifically find the tumors and point to them so you bypass unessecary steps

29
Q

What are the three immunotherapy stratagies?

A

Non-specific immunotherapes
monoclonal antibodies
vaccines

30
Q

Explain non-specific immunotherapies to treat cancer

A

Cytokines or other chemicals that stimulate the general immune response, usually used alongside other therapies

example: IL-2

31
Q

Explain the monoclonal antibody treatments for cancer

A

Proteins stick to specific antigens, tagging them for destruction or directly affecting them, uses include:
- carrying drugs to target cells
-tagging cell for destruction by immune cell
- blocking signalling pathway to halt growth or proliferation

32
Q

Explain how vaccines work for cancer treatment

A

Vaccines are made from cancer cells, parts of cells, or antigens designed to stimulate the immune system to attack a tumour. Multiple approaches are being tested, including DC vaccines:

  1. A patients DCs are removed, stimulated and re-infused with a cancer specific antigen
  2. Treated DCs present the antigen to other immune cells
  3. Activated immune cells, primed to recognise the cancer, mature and proliferate
33
Q

Explain how oncolytic virus immunotherapy works

A

Virus is injected inti the tumour mass, transfected cells then take over the machinery and proliferate and grow, causing the cell to rupture, killing it

this not only releases antigens but also creates inflammation leading to a stronger immune response

clinical trailas for this therapy for melanoma are ongoing

34
Q

Give two examples of antibodies that block checkpoint inhibitors

A

Anti-PD-1 and anti-CTLA-4 antibodies

35
Q

Explain how PD-1 blocking antibodies work

A

Tumour cell expresses a ligand called PDL-1

PD-L1 interacts with PD-1 on the T cell and that sends a negative signal to the T cells and the T cell shuts down and stops attacking the tumour

Blocker (antibody (anti-PD-1)) can come along and stop that happening

36
Q

Explain how CTLA-4 blocking antibodies work

A

CTLA-4 is a ligand present on tumour-specific T cells but this when activated by B7 (receptor on tumour cell or APC) it shuts down t cell activation

But this competes with the ligand CD28 (also on T cell) which identofies antibodies and trys to stop tumour cells,

so anti-CTLA4 antibody used to block ligand and allow immune response to tumour cells

37
Q

Explain how normal antibodies are used to target cancer

A

Antibody coats tumour cell

Two cells can recognise this coating:

NK cells – release perforin and granzymes which causes cells to lyse

Macrophages: on macrophage can easily engulf up to 20 cells at a time

38
Q

Explain a second effect that treatment of cancer by anti-CTLA-4 antibodies have to help treat cancer

A

depleting Treg cells
Deleting Tregs removes the immunosuppression quite a lot

39
Q

What are some of the most successful checkpoint inhibitor antibodies

A

Opdivo (nivolumab)= PD-1

Keytruda (pembrolizumab)= PD-1

Yervoy (ipilimumab)= CTLA-4 inhibitor

40
Q

Explain the potentiation of immunotherapy by FMT

A

FMT = Fecal microbiota transplantation
Correlations between microbiome and effectivness of immunotherapy

Can now transplant good microbiota e.g. FMT into patients that are going to receive therapy

Provides a much more effective immune stimulation

41
Q

Where does the future lie in terms of immunotherapy treatments for cancer

A

Large area of other receptors, other inhibitors we can block or other stimulating receptors we can activate (agonistic antibodies)

Combination therapy and choices of combinations will also increase

42
Q

Explain adoptive cell transfer (ACT) as an immunotherapy treatment in cancer

A

Using neoantigens to expand T cells

Taking tumor from body and taking T cells out of tumor, sequence to find out what the mutations are or can expand the TILs (tumour infiltrating lymphocytes) in culture e.g. using IL-2 then reinfuse them back into the patient

This has been donme in trials for breast cancer and melanoma

43
Q

Describe the design of a TCR vs CAR

A

Chimeric antigen receptor (CAR)

A T cell itslef has a TCR which recognises the antigen

CAR takes away this opportunity and only allows expression of the antibodies

e.g. anti CD20 or anti-CD19 or any other antigen that the tumours expressed, this way we bypass all the T cell activations required

44
Q

Explain CAR T cell therapy

A

What they’ve done with new generations is the chimeric receptor, downstream of that you can put immunostimulant molecules to generate a powerful positive signal to activate the T cells

1) T Cell
Collection

2) T Cell
Transfection
1 . Binding
2. Fusion
3. Integration
4. Transcription and
protein expression
5. CAR cell
membrane
insertion

3) T Cell Adoptive
Transfer
+1—Lymphodepleting
conditioning

4) Patient
Monitoring

a) Disease response
—CT scans
—Bone marrow biopsies
—Peripheral blood
flow cytometry
b) CAR-T Cell persistence
—Immunohistochemistry
of bone marrow biopsy
-RT-PCR and flow
cytometry of blood
and bone marrow
aspirate

Although adoptive cell transfer has been restricted to small clinical trials so far, treatments using these engineered immune cells have generated some remarkable responses in patients with advanced cancer.

45
Q

Explain results of CAR T cell therapy of refectory patients

A

Recently pubished 10 year data from patients that started treatment 10 years ago, most still had some CAR T cells in their bodies

This means it can sit quietly and if the tumour comes back it can be activated again

Side effects of CAR T cell therapy:

There are side effects but they are not as bad as the cancer itself

Immune activation – can potentially lead to damage of other tissues

46
Q

Explain features of the anti-hCD20 mAb - Rituximab

A

First monoclonal antibody (mAb) approved for the treatment of cancer

Has since treated millions of people

Being used to treat an expanding number of autoimmune disorders

Despite success some diseases/patients are resistant

47
Q

Explain the mechanisms of action for resistance to the anti-hCD20 mAb - Rituximab

A

Antibody – opsonises CD20 on tumour cell surface

Macrophages and tumour cells come and cause tumour cell disruption

One of the things that the tumour cells do is remove this antibody from the surface – internalisation of the antibody receptor complex

Tumors are actively removing the antibody from surface and evading destruction

48
Q

Explain the drug that the university of southampton created to try and block the interaction that creates resistance to Rituximab immunotherpy

A

Antibody CD32B has a homologue which is almost 94% identical to Antibody CD32A, so difficult to generate a specific antibody, manages to create one that can recognise the 6% difference

Treated with either rituximab (purple) or hCD32B mAb (blue) and both together (green) and together the depletion of the B cells is much longer

CD32B mAb is also called 6G11

49
Q

explain how Patient derived xenograft (PDX) models showed that rituximab and 6G11 (CD32B mAb) when used in combination gave better outcomes in patients

A

Made PDXs – using mice which are lacking an immune system and Engraph them with the patient cells

Got blood cells from patients

Showed that the patient cells can populate the mice

Then started treating them

When you combine rituximab with new drug 6G11 (the CD32B mAb) we can significantly reduce tumour burden

Even some patients who didn’t respond at all to rituximab, when used in combination started to respond more

50
Q

What phase of clinical trials is the CD32B monoclonal antibody in in the UK/USA

A

Phase I/II

51
Q

Summarise the points of intervention in the cancer immunity cycle

A
  1. Release of cancer cell antigens

Chemotherapy

Radiation therapy

Targeted therapy

C2. ancer antigen presentation

Vaccines

GM-CSF

IFN-a

Anti-CD40 (agonist)

TLR agonists

  1. Priming and activation

Anti-CTLA4

Anti-CD137 (agonist)

Anti-OX40 (agonist)

Anti-C027 (agonist)

IL.12

IL-2

  1. Trafficking of T cells to tumors
  2. Infiltration of T cells into tumors

Anti-VEGF

  1. Recognition of cancer cells by T cells

CARs

  1. Killing of cancer cells

Anti-PD-L1

Anti-PD1

IDO inhibitors

BIOL3043 - Cellular and molecular pathology (11 decks)

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