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MB4030 > L9: Cancer & Immunotherapy > Flashcards

L9: Cancer & Immunotherapy Flashcards

1
Q

What percentage of cancers are caused by environmental factors and lifestyle?

A

~80%
(20% caused by genetic predisposition)

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2
Q

What is lymphoma?

A

tumour in lymphoid tissue, bone marrow, lymph nodes

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3
Q

What is leukaemia?

A

cancer of the blood or bone marrow (abnormal increase in immature WBCs called blasts)

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4
Q

Immune response to tumours

A
  • antibodies to tumour antigens can promote ADCC
  • CTLs recognise TAAs, trigger apoptosis
  • NK cells detect lack of MHC Class I, trigger apoptosis
  • macrophages cluster around tumour, producing TNFα & lytic enzymes (associated with tumour regression)
  • many tumours contain lymphoid cell infiltrates (favourable sign)
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5
Q

2 main types of tumour antigens

A

Tumour-specific antigens (TSAs)
Tumour-associated antigens (TAAs)

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6
Q

What are TSAs?

A
  • antigens expressed on tumour cells but NOT normal cells
  • encoded by oncogenic viruses
  • oncofoetal proteins (e.g. CEA) that are normally expressed in foetal development, not in adult tissue, can be re-expressed in some cancers
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7
Q

What are TAAs?

A
  • antigens that are expressed on normal cells but aberrant, mutated, dysregulated or overexpressed in tumours
  • appear before immune system develops B cell and T cell tolerance to self-antigens, so they are recognised as non-self and should trigger an immune response
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8
Q

TAAs are products of…

A

mutated genes e.g. mutated oncogene (K-ras in colon cancer, leading to ‘gain of function’) and mutated TSG (p53, leading to ‘loss of function’)

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9
Q

Chromosomal translocations are seen in some __.

A

leukaemias

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10
Q

What are non-synonymous mutations?

A

Random point mutations in protein-encoding genes that can give rise to changes in the amino acid sequence of the protein

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11
Q

Immune cells are driven to the tumour __ via a __ gradient.

A

tumour microenvironment (TME)
chemokine gradient

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12
Q

In the TME, DCs take up and process tumour antigens and present them on MHC Class I or II molecules through __.

A

cross-presentation

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13
Q

Cross-presentation may occur through the __ pathway or the __ pathway.

A

cytosolic or vacuolar

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14
Q

CD8+ T cell responses are amplified by __ secreted by __.

A

amplified by IL-2 secreted by CD4+ T cells

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15
Q

What is CTLA-4?

A

An immune checkpoint protein that can inhibit the development of an active immune response by acting primarily at the level of T cell development & proliferation

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16
Q

How do most cancers establish an immunosuppressive environment?

A
  1. Promotion of anergy: an immunologic tolerance characterised by the failure to mount a full immune response against the tumour
  2. Failure to present cancer antigens due to down-regulation of MHC I
  3. Failure of APCs (DCs & macrophages) to efficiently present antigen to CD4+ & CD8+ T cells
  4. Failure of CTLs to engage & kill the cancer cell by apoptosis
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17
Q

Understanding the __ is crucial in coming up with treatments against solid tumours.

A

TME

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18
Q

What do tumours release under hypoxic conditions?

A

adenosine and the metabolite D-2HG, which both suppress T cell activation

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19
Q

Which immunosuppressive cytokines are secreted by tumour cells?

A

IL-10 and TGFβ

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20
Q

3 sites for therapeutic intervention against tumours

A
  1. Promoting the antigen-presentation functions of DCs
  2. Promoting production of protective T cell responses
  3. Overcoming immunosuppression in the tumour bed
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21
Q

Tumour __ is made up of neoplastic cells.

A

parenchyma

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22
Q

What does the tumour stroma mainly consist of?

A

basement membrane, fibroblasts, ECM, immune cells & vasculature

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23
Q

What can the tumour stroma promote?

A

Growth, invasion and metastasis

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24
Q

What part of the tumour determines the biological behaviour of the tumour (and gives the tumour its name)?

A

Tumour parenchyma

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25
Q

Distinguish the 3 distinct immune profiles that help correlate with immunotherapy response

A
  1. Immune-inflamed phenotype
  2. Immune-excluded phenotype
  3. Immune-desert phenotype
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26
Q

What is the immune-inflamed phenotype characterised by?

A
  • presence in tumour parenchyma of both CD4 & CD8 T cells, myeloid cells and monocytes in the tumour proximity
  • contains inflammatory cytokines to aid T cell activation: IL-2, IL-12, IL-23 and TNFα
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27
Q

What is the immune-excluded phenotype characterised by?

A
  • presence of immune cells but they do NOT penetrate the tumour parenchyma, mainly in the stroma
  • immunosuppressive cytokine expression: IL-10 & TGFβ
  • Tregs promote tolerance
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27
Q

Immune-__ phenotype & immune-__ phenotype are considered non-inflamed tumours.

A

excluded and desert

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28
Q

What is the immune-desert phenotype characterised by?

A
  • a shortage of T cells in either parenchyma or stroma of tumour
  • some myeloid cells can be present but few or no CTLs
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29
Q

Different types of immunotherapy (both immunostimulatory and immunoinhibitory)

A
  • Antivirals (e.g. anti-HCV)
  • CART-T cell therapy
  • Monoclonal antibodies (to TSAs)
  • Cancer vaccines (with or without DCs)
  • Interferons and cytokines (and their antagonists)
  • Vaccine adjuvants
  • Immune checkpoint inhibitors (‘wake up’ immune system)
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30
Q

Use of monoclonal antibodies to which molecules are commonly used in immunotherapy?

A

PD-1 (Pembrolizumab), PD-L1 (Atezolizumab) and CTLA4 (Ipilimumab)

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31
Q

What is expressed on many solid tumours?

A

PDL1

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32
Q

CTLA-4 is expressed on?

A

activated T cells

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33
Q

CTLA4 ligands

A

B7-1 (CD80) and B7-2 (CD86)

34
Q

What cells express the PD1 receptor?

A

activated T cells, Tregs, B cells & NK cells

35
Q

PD1 receptor interacts with __, leading to __.

A

PDL1, leading to T cell exhaustion

36
Q

CAR-T cell therapy combines

A

the specificity of an antibody with the cytotoxic ability of a T cell

37
Q

What are chimeric antigen-receptors?

A

molecules genetically engineered into a polyclonal T cell population, giving the T cells the ability to recognise TAAs

38
Q

The CAR on the T cell surface is comprised of

A

a single-chain variable fragment (scFv), derived from a mAb, connected to various intracellular signalling domains to ensure the T cell can be activated

39
Q

Types of cancer that CAR-T cell therapy could be used for

A

refractory B cell non-Hodgkin lymphoma (NHL)
ALL (acute lymphoblastic leukaemia)
AML (acute myeloid leukaemia)
CLL (chronic lymphoblastic leukaemia)

40
Q

Problems with autologous T cells collected from cancer patient in CAR-T cell therapy

A

Low T cell count, poor T cell quality and/or high tumour burden, takes weeks to months

41
Q

Greatest barrier to developing ‘off-the-shelf’ CAR-T cells from allogenic donor T cells

A

GVHD

42
Q

What is Kadcyla?

A

an antibody-drug conjugate consisting of Herceptin mAb linked to cytotoxic agent mertansine (DM1), a Tubulin inhibitor
- approved for metastatic breast cancer treatment

43
Q

2 examples of prophylactic vaccines

A

HBV vaccine against HCC (liver cancer)
HPV vaccine against cervical and head & neck cancer

44
Q

Effective anti-tumour immunity is associated with

A

the presence of T cells against cancer neoantigens (MHC-bound peptides that arise from tumour-specific mutations)

45
Q

What are vaccine adjuvants?

A

molecules or compounds that have intrinsic immunomodulatory properties and, when administered in conjugation with an antigen, effectively potentiate the host antigen-specific immune responses compared to responses when antigen is given alone

46
Q

What is the most common vaccine adjuvant?

A

Alum, an aluminium salt

47
Q

What is Squalene (C30H50)?

A

a component of some adjuvants that are added to vaccines to enhance the immune response
- is not an adjuvant itself
- an intermediate in the biosynthesis of sterols

48
Q

What is an adjuvant that is added to the FLUAD flu vaccine?

A

MF59

49
Q

__ CpG DNA is found in bacterial DNA.

A

unmethylated

50
Q

What is the PRR for unmethylated CpG DNA?

A

TLR9 (highly expressed on B cells and pDCs in humans)

51
Q

What does stimulation of TLR9 lead to?

A

Proinflammatory cytokine response
B cells: IL-6, IL-10, IL-12
pDCs: IFNα, IFNβ, TNFα, IL-12, IP-10

52
Q

What have been developed to induce immune responses through TLR9?

A

CpG oligodeoxynucleotides (ODNs)

53
Q

Example of CpG as a vaccine adjuvant

A

Heplisav-B vaccine targeting Hepatitis B

54
Q

ODNs must be able to survive attack by __ in body fluids.

A

DNases

55
Q

Chemical modification of CpG ODN

A

Replace natural phosphodiester backbone with phosphorothioate

56
Q

What cytokine therapy was approved in 1995 for treatment of malignant melanoma?

A

Recombinant IFN-α2 (Intron A)

57
Q

Immunostimulatory cytokines with anti-cancer activities

A

IL-2 (Proleikin)
TNF-α (Beromun)

58
Q

Stimulators of haemopoiesis

A

GM-CSF (Leucomax)
EPO (Amgen)

59
Q

Immunosuppressive cytokines for treatment of RA, psoriasis, IBD

A

IL-4
IL-10

60
Q

What is the name of the anti-TNFα mAb used to treat rheumatoid arthritis?

A

Infliximab

61
Q

Following first exposure to allergen, B cells __ to __.

A

class-switch to IgE

62
Q

Elevated IgE binds to __ on mast cells, triggering __.

A

IgE Fc receptors
degranulation

63
Q

New treatment for Hypersensitivity Type I

A

SIT: allergen-specific immunotherapy
- gradual change from IgE production to IgG

64
Q

Example of a mAb to IgE

A

Omalizumab
- approved to treat moderate to severe persistent allergic asthma in patients 6 yrs or older whose asthma symptoms are not controlled by inhaled corticosteroids

65
Q

Example of anti-IL4 mAb

A

Dupixent (Dupilumab)
- binds IL-4 to prevents it binding to its receptor on B & T cells, reducing IgE levels
- approved for treatment of adults with severe atopic dermatitis, and >12 yrs as an add-on maintenance treatment for severe asthma

66
Q

What are the two macrophage phenotypes? Briefly explain the role of each

A

M1 and M2 phenotypes
M1: mainly involved in proinflammatory responses (produce IL-6 & IL-12), LPS & TNF drive macrophage polarisation to M1
M2: mainly involved in anti-inflammatory responses (produce IL-10, TGFβ, CCL17 & CCL22), IL-4 drives polarisation to M2

67
Q

How do activated T cells, B cells and anti-tumour antibodies facilitate tumour cell death?

A

by direct tumour cell lysis, ADCC and/or complement-dependent cytotoxicity

68
Q

Immunosuppression is triggered by…

A
  • tumour
  • Tregs
  • M2 macrophages
69
Q

Solid tumours preferentially use __ __, metabolising glucose to __.

A

aerobic glycolysis, metabolising glucose to lactate

70
Q

The majority of cancers have tissue-infiltrating __ effector cells present.

A

FoxP3

71
Q

Tregs are often associated with a poor prognosis because they can create an __ __.

A

immunosuppressive environment

72
Q

Examples of cell surface molecules selectively enriched on tumour-infiltrating Tregs that can be good targets for antibody-mediated Treg depletion

A

CD25 and CTLA-4

73
Q

Which cells constitutively express CTLA-4?

A

Tregs in the PERIPHERY

74
Q

An example of a monoclonal antibody to CTLA-4

A

Ipilimumab

75
Q

Which cytokine attracts Tregs, allowing for some cancers to evade an immune response?

A

CCL17

76
Q

In tumours, macrophage polarisation is driven by…

A
  • low pH
  • hypoxia
  • ECM
77
Q

What is an example of an alkaline agent that can be trapped in the lysosome to increase the pH?

A

Chloroquine

78
Q

Example of a serine protease inhibitor that is over-expressed in many cancers

A

SerpinE2
- inhibition can help promote M1 polarisation and inhibit tumour spread

79
Q

What’s given post-chemo to increase the number of WBCs?

A

G-CSF & GM-CSF
(Erythropoietin also given to increase RBCs)

80
Q

What are the 3 HPV vaccines?

A
  • bivalent vaccine Cervarix (against HPV types 16 & 18)
  • quadrivalent vaccine (Gardasil-4)
  • nonavalent vaccine (Gardasil-9)
81
Q

How are neoantigens recognised?

A

by whole exome sequencing of tumour genome and comparing it to the sequences from normal tissue

82
Q

__ encodes 40 neoantigens for treatment of HCC.

A

GNOS-PV02

83
Q

Advantages of nucleic acid vaccines

A
  • induce a strong MHC I mediated CD8+ T cell response
  • can simultaneously deliver multiple antigens
  • can encode full-length tumour antigens allowing APCs to cross-present various epitopes
  • simple and fast

MB4030 (10 decks)

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