Lecture 12- Cancer immunotherapy

Question 1

Mechanism by which tumours evade the immune system - see diagram

Answer 1

• Low immunogenicity
• Tumour treated as self antigen
• Antigenic modulation
• Tumour induce immune suppression – secret factors to suppress immune cells
• Tumour induced privileged site – secrete factors to form a physical barrier

Question 2

Innate immunity

Answer 2

Short term

defence is inborn or innate in that its action does not depend on prior exposure to a particular pathogen

Question 3

Adaptive immunity

Answer 3

Long term -

- immunity is acquired during the lifetime of the individual as an adaptive response to a particular pathogen

Question 4

Innate immunity - cell s

Answer 4

• Neutrophils
• Macrophages
• NKCs

Question 5

Adaptive – cells

Answer 5

• -APC
• Lymphocytes
  B or T cells
  Anti tumour ability – ability to attack the c=tumour cells
• Response to cytokines

Question 6

Hallmarks of Cancer

Answer 6

Growth self-sufficiency
•  Evade apoptosis
•  Ignore anti-proliferative signals 
•  Limitless replication potential 
•  Sustained angiogenesis
•  Invade tissues
•  Escape immune surveillance

Question 7

What dictates the type of response ?

Answer 7

Cell type

Question 8

Recognition mechanisms of innate immunity

Answer 8

Rapid response
Invariant
limited number of specificities
constant during response

Question 9

Recognition mechanisms of adaptive/acquired immunity

Answer 9

slow response
variable
numerous highly selective specificities
improve during response

Question 10

Steady State

Answer 10

• Embryonic progenitor derived macrophage
• Monocyte derived Macrophage
  >Tissue homeostasis
  > Tissue specific functions

Question 11

Infection

Answer 11

-Effector Monocyte/macrophage/DCC
>Recruitment
- Tissue resident macrophage
> Expansion

Question 12

Tumour

Answer 12

trTAM
tiTAM
- immune modulation
- dysregulated maintenance of tissue homeostasis

Question 13

Tumour associated Macrophages

Answer 13

M2 and M1

Question 14

TAM- M1

Answer 14

Scarce 
Immunostimulatory 
Pro-inflammatory 
Tumoricidal 
Perform ADCC

Question 15

TAM- M2

Answer 15

Pro -tumour 
Predominant 
Immunosupressive 
Pro-angiogenic 
Maintain T-regs 
Do not perform ADCC

Question 16

Majority of tumours contain

Answer 16

macrophages

Question 17

Immunotherapy

Answer 17

– harness immune system to kill tumours

Induce immune response against tumours

Question 18

Timeline

Answer 18

1850 – patients with cancer tumours – tumour would shrink in response to another infection

1985- T cells taken from patient expanded and put them back in
1990 – discovery of checkpoint inhibitors
2015- oncolytic HSV virus used to treat melanoma

Question 19

5 types of immunotherapy

Answer 19

1. Monoclonal antibodies
2. Immune check point inhibitors
3. Cancer vaccines
4. Adoptive cell transfer
5. Cytokines

Question 20

Immunotherapy-Active

Answer 20

vaccination, augmentation of host immunity to tumours

Question 21

Immunotherapy - Passive

Answer 21

1. Adoptive Cellular Therapy (T cells) 2. Anti-tumour Antibodies (Her-2/Neu,
   CD20, CD10, CEA, CA-125, GD3 ganglioside)

Question 22

Cell based therapy

Answer 22

Can be used to active a patients own immune system to attack cancer
Can be used for delivery of therapeutic agent
Dendritc cells popular choice of cell

Question 23

Dendritic cell-

See diagram

Answer 23

• Found throughout the body (0.1-0.5%)
• Interstitial cells (Liver, heart, liver), Langerhans cells of the epidermis.
• Detect and chew up foreign “invader” proteins and then “present” piece of the invaders on their surface.
• To make a DC vaccine, the blood of the cancer patient is collected and enriched to increase the population of DC.

Question 24

Active Immunotherapy - Vaccines

Answer 24

1. Killed tumour vaccine
2. Purified tumour antigens
3. Professional APC-based vaccines
4. Cytokine- and costimulator-enhanced vaccines 5. DNA vaccines
5. Viral vectors

Question 25

T cells- Killer Cells

Answer 25

Tumour biopsy 1. Tumour Fragments (Isolation) and TIL separated 2. TILs propagated on tumour fragments - (Cultivation) 3. Melanom Reactive TILS (Expansion) 4. T cell fusion

Question 26

Trojan Horse- Treatment

Answer 26

City of troy – tumour need to access Horse – macrophages Macrophages go in – produce a virus which replicate and infect more cells and attach the tumour - TAMs accumulate in hypoxic areas Extract blood > monocytes > macrophage > therapeutic macrophage (with virus) > tumour Hypoxic tumour cells grow

Question 27

Hypoxia

Answer 27

Hypoxia (low oxygen) is a prominent feature of malignant tumours Inability of the blood supply to keep up with growing tumour cells Hypoxic tumour cells adapt to low oxygen- increase there survival

Question 28

Tumour hypoxia

Answer 28

Poor patient prognosis 1. Stimulates new vessel growth 2. Suppresses immune system 3. Resistant to radio- and chemotherapy (repopulate the tumour) 4. Increased tumour hypoxia after therapy

Question 29

macrophages in tumours

Answer 29

can get deep into tumours | - in most cells

Question 30

macrophages

Answer 30

Great receptors - big eaters - add anything they take it up

Question 31

Evidence of hypoxia increase with therapy use

Answer 31

prostate cancer mice models - treat with Doxacetl - increase in hypoxia - leads to more macrophages been taken to the tumour

Question 32

Combo approach- use classic therapy followed by macrophage therapy

Answer 32

used- Naked mice with no adaptive immune system- grow human cells inside the mice - implant tumour - inject macrophage therapy - 48 hours later removed tumour to see if therapy has reached it - within the hypoxic area of the 3 million macrophage added only small number get there but widespread production of the virus - only need a small number to spread a lot of virus

Question 33

Trojan horse therapy combined with Docetaxel

Answer 33

When you give docetaxel and macrophage therapy you can shrink and keep tumours small - stops metastasis from developing

Question 34

Trial

Answer 34

- Funded then dropped - virus made for a study injecting directly into prostate - Idea could get to all tumours in the body - 1.4 million to make the virus - enough for the trial nut not enough to be stability tested

Question 35

Magnetic macrophage therapy –

Answer 35

- MRI to steer magnetic macrophages to deep tumour lesion s - Monocytes removed from patients insert therapeutic virus load with MNPs - Macrophages circulate in bloodstream- steered to target by magnets

Question 36

in vivo targeting of magnetic macrophages in mouse models -

Answer 36

Day 0 - inject prostate tumour cells Day 28- prepare macrophages and transfect with pmaxgfp Day29- load macrophages with MNP and administer to mice by tail vein injection -Anaesthetise mice and apply magnetic field to surface of tumour for 5 hr -Kill mice divide tissue into two, snap freeze half and run remainder through FACs

Question 37

Magnetic macrophages traffic to the prostate tumours

Answer 37

5 % of macrophages getting to tumour with no magnet 15% of macrophages getting to tumour with magnet - improving drug delivery -less drug needed> less toxicity

Question 38

Issue with the current research with magnetic macrophages

Answer 38

- currently tested on surface tumour which can be surgically removed anyway

Question 39

MRI

Answer 39

target deep into the tumour - locate tumour with MRI - program Magnetic field to the tumour - pulsed on and off Removed tumours – and looked to see had more therapy got to more of the tumour – 4% to 7% nearly half had got to tumour - improved the therapy - image the tumour before and after > dark patches at the end