PED1003/L26 Cancer Therapeutics

Question 1

Describe the two methods of ATP synthesis in healthy cells.

Answer 1

Some by glycolysis in cytoplasm
More by oxidative phosphorylation in mithchondria

Question 2

What is the Warburg effect?

Answer 2

Shift towards glycolysis associated with immune cell activation, cancer and age-related diseases

Question 3

Why do cancer cells switch to favour glycolysis? (3)

Answer 3

Scarcity of oxygen
Faster ATP production (100x)
Intermediates used for DNA synthesis, proteins and lipids

Question 4

How do cancer cells speed up their energy production?

Answer 4

Uptake more glucose through GLUT1-4
Elevate expression of glycolytic enzymes

Question 5

Name 2 glycolysis enzymes.

Answer 5

HK2
PFK1
PK-M2
LDHA

Question 6

Give 2 roles of lactate inside cancer cells.

Answer 6

Regeneration of NADH
Reduction of ROS production

Question 7

Give a role of lactate outside cancer cells.

Answer 7

Lactate lower pH of microenvironment (pro-invasive)

Question 8

What is the role of lactate in metabolic symbiosis? (3)

Answer 8

Lactate converted to pyruvate in normoxic cells
Enters TCA cycle
Energetic source for these cells

Question 9

What is the role of lactate in immunosuppression? (3)

Answer 9

Promotes TME acidification
Lower pH within immune cells affecting signalling pathways
Inhibit CD4, CD8 T cells NK cells dendritic cells by lowering pH
Apoptosis of CD8 T cells and NK cells

Question 10

Explain how immune destruction is avoided. (4)

Answer 10

When tumours arise, immune cells recognise and eliminate them
Variant tumour cells arise that are more resistant to being killed
Over time a variety of different cancer cells develop
One variant may escape killing mechanism or recruit regulatory cells to protect it so can spread unchallenged

Question 11

Give the 5 main mechanisms by which immune destruction is avoided.

Answer 11

Low immunogenicity
Tumour treated as self antigen
Antigenic modulation
Tumour-induced immune suppression
Tumour-induced privileged site

Question 12

Describe low immunogenicity. (3)

Answer 12

No peptide:MHC ligand
No adhesion molecules
No co-stimulatory molecules

Question 13

Describe tumour treated as self antigen.

Answer 13

Tumour antigens taken up and presented by APCs in absence of co-stimulation tolerize T cells

Question 14

Describe antigenic modulation.

Answer 14

T cells may eliminate tumours expressing immunogenic antigens but not tumours that have lost such antigens

Question 15

Describe tumour-induced immune suppression. (2)

Answer 15

Factors secreted by tumour cells inhibit T cells directly
Expression of PD-L1 tumours

Question 16

Describe tumour-induced privileged site.

Answer 16

Factors secreted by tumour cells create a physical barrier to the immune system

Question 17

How are monoclonal antibodies used in cancer immunotherapy? (2)

Answer 17

Tumour-specific antigen must be expressed on tumour cell surface
Trastuzumab targets HER2 receptor overexpressed in 25% breast cancers
Rituximab - anti-CD20 antibody trigger apoptosis of B cells used in non-Hodgkin B-cell lymphoma

Question 18

Give 2 problems with using monoclonal antibodies in cancer.

Answer 18

Inefficient killing of cancer cells
Inefficient penetration of antibody into tumour mass
Soluble target antigens mopping up antibody

Question 19

Give 2 solutions with using monoclonal antibodies in cancer.

Answer 19

Linking antibody to toxin
Coupling it to radiation or a drug
Use of small body fragments

Question 20

Give an example of a small body fragment.

Answer 20

Blinatumomab
ScFv targeting CD19/CD3 approved for Acute Lymphoblastic Leukemia

Question 21

Describe how Blinstumomab works. (3)

Answer 21

Enables patient’s T cells to recognise malignant B cells
Combines 2 binding sites for CD3 T cells and CD19 site for target B cells
Links 2 cell types and activates T cell to exert cytotoxic activity on target cell

Question 22

How are T cells used to express CARs in cancer? (4)

Answer 22

T cells harvested from blood of patient with B-cell tumour
Retrovirus encoding an anti-CD19 CAR infects T cells that are activated with antibodies to CD3 and CD28
Infected T cells express an anti-CD19 CAR
T cells infused into patient to mediate antitumour activity

Question 23

What is a Chimeric Antigen Receptor (CAR)?

Answer 23

A fusion receptor that contains extracellular antigen-specific domains fused to intracellular domains that provide signals for activation and stimulation
Allow target specificity to be almost any molecule recognisable by antibody rather than just peptide:MHC complexes

Question 24

Give 2 ways in which a vaccine can be prepared.

Answer 24

Mixing cell tumour extracts with killed bacteria
Antigen-loaded dendritic cells (or other APC cells) to stimulate cytotoxic T cells against tumours

Question 25

Describe Sipulelucel and how it works in prostate cancer treatment.

Answer 25

Monocytes extracted from patieents treated with prostatic antigen and GM-CSF to stimulate monocyte differentiation in dendritic cells

Question 26

Give a positive and negative checkpoint in the immune response.

Answer 26

T-cell response is modulated by B7 co-stimulatory receptors on APC Inhibitory receptors such as CTLA-4 and PD-1 block activation of potentially autoreactive T cells

Question 27

Describe how iplimumab and pembrolizumab work. (3)

Answer 27

Monoclonal antibody-mediated blockade of CTLA-4 or PD-1 expressed by CD8 cytotoxic or CD4 helper cells Blocks inhibitory signals and allows for untreated T-cell effector function and attack on cancer cells CTLA-4 blockade affects Tregs which express CTLA-4