L9: Cancer & Immunotherapy Flashcards
1
Q
What percentage of cancers are caused by environmental factors and lifestyle?
A
~80%
(20% caused by genetic predisposition)
2
Q
What is lymphoma?
A
tumour in lymphoid tissue, bone marrow, lymph nodes
3
Q
What is leukaemia?
A
cancer of the blood or bone marrow (abnormal increase in immature WBCs called blasts)
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)
5
Q
2 main types of tumour antigens
A
Tumour-specific antigens (TSAs)
Tumour-associated antigens (TAAs)
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
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
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’)
9
Q
Chromosomal translocations are seen in some __.
A
leukaemias
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
11
Q
Immune cells are driven to the tumour __ via a __ gradient.
A
tumour microenvironment (TME)
chemokine gradient
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
13
Q
Cross-presentation may occur through the __ pathway or the __ pathway.
A
cytosolic or vacuolar
14
Q
CD8+ T cell responses are amplified by __ secreted by __.
A
amplified by IL-2 secreted by CD4+ T cells
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
16
Q
How do most cancers establish an immunosuppressive environment?
A
- Promotion of anergy: an immunologic tolerance characterised by the failure to mount a full immune response against the tumour
- Failure to present cancer antigens due to down-regulation of MHC I
- Failure of APCs (DCs & macrophages) to efficiently present antigen to CD4+ & CD8+ T cells
- Failure of CTLs to engage & kill the cancer cell by apoptosis
17
Q
Understanding the __ is crucial in coming up with treatments against solid tumours.
A
TME
18
Q
What do tumours release under hypoxic conditions?
A
adenosine and the metabolite D-2HG, which both suppress T cell activation
19
Q
Which immunosuppressive cytokines are secreted by tumour cells?
A
IL-10 and TGFβ
20
Q
3 sites for therapeutic intervention against tumours
A
- Promoting the antigen-presentation functions of DCs
- Promoting production of protective T cell responses
- Overcoming immunosuppression in the tumour bed
21
Q
Tumour __ is made up of neoplastic cells.
A
parenchyma
22
Q
What does the tumour stroma mainly consist of?
A
basement membrane, fibroblasts, ECM, immune cells & vasculature
23
Q
What can the tumour stroma promote?
A
Growth, invasion and metastasis
24
Q
What part of the tumour determines the biological behaviour of the tumour (and gives the tumour its name)?
A
Tumour parenchyma
25
Distinguish the 3 distinct immune profiles that help correlate with immunotherapy response
1. Immune-inflamed phenotype
2. Immune-excluded phenotype
3. Immune-desert phenotype
26
What is the immune-inflamed phenotype characterised by?
- 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
27
What is the immune-excluded phenotype characterised by?
- 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
27
Immune-__ phenotype & immune-__ phenotype are considered non-inflamed tumours.
excluded and desert
28
What is the immune-desert phenotype characterised by?
- a shortage of T cells in either parenchyma or stroma of tumour
- some myeloid cells can be present but few or no CTLs
29
Different types of immunotherapy (both immunostimulatory and immunoinhibitory)
- 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)
30
Use of monoclonal antibodies to which molecules are commonly used in immunotherapy?
PD-1 (Pembrolizumab), PD-L1 (Atezolizumab) and CTLA4 (Ipilimumab)
31
What is expressed on many solid tumours?
PDL1
32
CTLA-4 is expressed on?
activated T cells
33
CTLA4 ligands
B7-1 (CD80) and B7-2 (CD86)
34
What cells express the PD1 receptor?
activated T cells, Tregs, B cells & NK cells
35
PD1 receptor interacts with __, leading to __.
PDL1, leading to T cell exhaustion
36
CAR-T cell therapy combines
the specificity of an antibody with the cytotoxic ability of a T cell
37
What are chimeric antigen-receptors?
molecules genetically engineered into a polyclonal T cell population, giving the T cells the ability to recognise TAAs
38
The CAR on the T cell surface is comprised of
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
Types of cancer that CAR-T cell therapy could be used for
refractory B cell non-Hodgkin lymphoma (NHL)
ALL (acute lymphoblastic leukaemia)
AML (acute myeloid leukaemia)
CLL (chronic lymphoblastic leukaemia)
40
Problems with autologous T cells collected from cancer patient in CAR-T cell therapy
Low T cell count, poor T cell quality and/or high tumour burden, takes weeks to months
41
Greatest barrier to developing 'off-the-shelf' CAR-T cells from allogenic donor T cells
GVHD
42
What is Kadcyla?
an antibody-drug conjugate consisting of Herceptin mAb linked to cytotoxic agent mertansine (DM1), a Tubulin inhibitor
- approved for metastatic breast cancer treatment
43
2 examples of prophylactic vaccines
HBV vaccine against HCC (liver cancer)
HPV vaccine against cervical and head & neck cancer
44
Effective anti-tumour immunity is associated with
the presence of T cells against cancer neoantigens (MHC-bound peptides that arise from tumour-specific mutations)
45
What are vaccine adjuvants?
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
What is the most common vaccine adjuvant?
Alum, an aluminium salt
47
What is Squalene (C30H50)?
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
What is an adjuvant that is added to the FLUAD flu vaccine?
MF59
49
__ CpG DNA is found in bacterial DNA.
unmethylated
50
What is the PRR for unmethylated CpG DNA?
TLR9 (highly expressed on B cells and pDCs in humans)
51
What does stimulation of TLR9 lead to?
Proinflammatory cytokine response
B cells: IL-6, IL-10, IL-12
pDCs: IFNα, IFNβ, TNFα, IL-12, IP-10
52
What have been developed to induce immune responses through TLR9?
CpG oligodeoxynucleotides (ODNs)
53
Example of CpG as a vaccine adjuvant
Heplisav-B vaccine targeting Hepatitis B
54
ODNs must be able to survive attack by __ in body fluids.
DNases
55
Chemical modification of CpG ODN
Replace natural phosphodiester backbone with phosphorothioate
56
What cytokine therapy was approved in 1995 for treatment of malignant melanoma?
Recombinant IFN-α2 (Intron A)
57
Immunostimulatory cytokines with anti-cancer activities
IL-2 (Proleikin)
TNF-α (Beromun)
58
Stimulators of haemopoiesis
GM-CSF (Leucomax)
EPO (Amgen)
59
Immunosuppressive cytokines for treatment of RA, psoriasis, IBD
IL-4
IL-10
60
What is the name of the anti-TNFα mAb used to treat rheumatoid arthritis?
Infliximab
61
Following first exposure to allergen, B cells __ to __.
class-switch to IgE
62
Elevated IgE binds to __ on mast cells, triggering __.
IgE Fc receptors
degranulation
63
New treatment for Hypersensitivity Type I
SIT: allergen-specific immunotherapy
- gradual change from IgE production to IgG
64
Example of a mAb to IgE
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
Example of anti-IL4 mAb
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
What are the two macrophage phenotypes? Briefly explain the role of each
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
How do activated T cells, B cells and anti-tumour antibodies facilitate tumour cell death?
by direct tumour cell lysis, ADCC and/or complement-dependent cytotoxicity
68
Immunosuppression is triggered by...
- tumour
- Tregs
- M2 macrophages
69
Solid tumours preferentially use __ __, metabolising glucose to __.
aerobic glycolysis, metabolising glucose to lactate
70
The majority of cancers have tissue-infiltrating __ effector cells present.
FoxP3
71
Tregs are often associated with a poor prognosis because they can create an __ __.
immunosuppressive environment
72
Examples of cell surface molecules selectively enriched on tumour-infiltrating Tregs that can be good targets for antibody-mediated Treg depletion
CD25 and CTLA-4
73
Which cells constitutively express CTLA-4?
Tregs in the PERIPHERY
74
An example of a monoclonal antibody to CTLA-4
Ipilimumab
75
Which cytokine attracts Tregs, allowing for some cancers to evade an immune response?
CCL17
76
In tumours, macrophage polarisation is driven by...
- low pH
- hypoxia
- ECM
77
What is an example of an alkaline agent that can be trapped in the lysosome to increase the pH?
Chloroquine
78
Example of a serine protease inhibitor that is over-expressed in many cancers
SerpinE2
- inhibition can help promote M1 polarisation and inhibit tumour spread
79
What's given post-chemo to increase the number of WBCs?
G-CSF & GM-CSF
(Erythropoietin also given to increase RBCs)
80
What are the 3 HPV vaccines?
- bivalent vaccine Cervarix (against HPV types 16 & 18)
- quadrivalent vaccine (Gardasil-4)
- nonavalent vaccine (Gardasil-9)
81
How are neoantigens recognised?
by whole exome sequencing of tumour genome and comparing it to the sequences from normal tissue
82
__ encodes 40 neoantigens for treatment of HCC.
GNOS-PV02
83
Advantages of nucleic acid vaccines
- 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
