Lecture 12- Cancer immunotherapy Flashcards
Mechanism by which tumours evade the immune system - see diagram
- 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
Innate immunity
Short term
defence is inborn or innate in that its action does not depend on prior exposure to a particular pathogen
Adaptive immunity
Long term -
- immunity is acquired during the lifetime of the individual as an adaptive response to a particular pathogen
Innate immunity - cell s
- Neutrophils
- Macrophages
- NKCs
Adaptive – cells
- -APC
- Lymphocytes
B or T cells
Anti tumour ability – ability to attack the c=tumour cells - Response to cytokines
Hallmarks of Cancer
Growth self-sufficiency • Evade apoptosis • Ignore anti-proliferative signals • Limitless replication potential • Sustained angiogenesis • Invade tissues • Escape immune surveillance
What dictates the type of response ?
Cell type
Recognition mechanisms of innate immunity
Rapid response
Invariant
limited number of specificities
constant during response
Recognition mechanisms of adaptive/acquired immunity
slow response
variable
numerous highly selective specificities
improve during response
Steady State
- Embryonic progenitor derived macrophage
- Monocyte derived Macrophage
>Tissue homeostasis
> Tissue specific functions
Infection
-Effector Monocyte/macrophage/DCC
>Recruitment
- Tissue resident macrophage
> Expansion
Tumour
trTAM
tiTAM
- immune modulation
- dysregulated maintenance of tissue homeostasis
Tumour associated Macrophages
M2 and M1
TAM- M1
Scarce Immunostimulatory Pro-inflammatory Tumoricidal Perform ADCC
TAM- M2
Pro -tumour Predominant Immunosupressive Pro-angiogenic Maintain T-regs Do not perform ADCC
Majority of tumours contain
macrophages
Immunotherapy
– harness immune system to kill tumours
Induce immune response against tumours
Timeline
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
5 types of immunotherapy
- Monoclonal antibodies
- Immune check point inhibitors
- Cancer vaccines
- Adoptive cell transfer
- Cytokines
Immunotherapy-Active
vaccination, augmentation of host immunity to tumours
Immunotherapy - Passive
- Adoptive Cellular Therapy (T cells) 2. Anti-tumour Antibodies (Her-2/Neu,
CD20, CD10, CEA, CA-125, GD3 ganglioside)
Cell based therapy
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
Dendritic cell-
See diagram
- 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.
Active Immunotherapy - Vaccines
- Killed tumour vaccine
- Purified tumour antigens
- Professional APC-based vaccines
- Cytokine- and costimulator-enhanced vaccines 5. DNA vaccines
- Viral vectors
T cells- Killer Cells
Tumour biopsy
- Tumour Fragments (Isolation) and TIL separated
- TILs propagated on tumour fragments - (Cultivation)
- Melanom Reactive TILS (Expansion)
- T cell fusion
Trojan Horse- Treatment
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
Hypoxia
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
Tumour hypoxia
Poor patient prognosis
- Stimulates new vessel growth
- Suppresses immune system
- Resistant to radio- and chemotherapy (repopulate the tumour)
- Increased tumour hypoxia after therapy
macrophages in tumours
can get deep into tumours
- in most cells
macrophages
Great receptors
- big eaters
- add anything they take it up
Evidence of hypoxia increase with therapy use
prostate cancer mice models
- treat with Doxacetl
- increase in hypoxia
- leads to more macrophages been taken to the tumour
Combo approach- use classic therapy followed by macrophage therapy
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
Trojan horse therapy combined with Docetaxel
When you give docetaxel and macrophage therapy you can shrink and keep tumours small
- stops metastasis from developing
Trial
- 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
Magnetic macrophage therapy –
- 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
in vivo targeting of magnetic macrophages in mouse models -
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
Magnetic macrophages traffic to the prostate tumours
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
Issue with the current research with magnetic macrophages
- currently tested on surface tumour which can be surgically removed anyway
MRI
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
