Anti Tumour Immunity And Immunotherapy For Cancer Flashcards
How are cancer cells different from normal cells?
Rapid uncontrolled growth
Increase mobility
Invade tissue
Evade immune system
Metastasize
How does the immune system play a integral role in cancer?
Immunodeficiency lead to tumour formation
Inflammatory conditions lead to cancers too
Tumours infiltrated with lymphocytes have better prognosis
Can the body defend against cancer?
Antibody responses can kill the tumour cells
Production of immune memory cells
Describe the experiment using mice to demonstrate the immune response t tumour cells
Mice were induced with sarcoma and methylholanthrene
The tumour cells were then surgically removed and cultured
They were then transplanted Into three different mice
Syngeneic (genetically similar mouse) - tumour growth
Tumour bearing mouse - no tumour growth
Syngeneic + CD8 cells from original mouse - no tumour growth
What is meant by tumour immunosurveilance?
A process where the immune system continually recognise cancerous and pre-cancerous cells leading to their elimination before they can cause damage
What are the 3 E’s of immunoediting?
Elimination
Equilibrium
Escape
What is tumouigenesis?
Normal cells that develop abnormal tumour antigens
Danger signals such as extra-cellular matrix products
- inflammation
- radiation
- viral infection
Start to become cancer
What occurs during ELIMINATION?
NKs NKTs, MCs and DCs - innate immunity takes place to destroy tumour cells
INFy and chemokine lead to tumour death
Tumour specific DCs activate adaptive immunity in draining lymph nodes
Tumour specific CD4 and CD8 T cells join response to tumour cells.
What occurs during EQUILIBRIUM?
Elimination phase incomplete
Tumour cells lie dormant and may modulate tumour antigen expression and stress signals
Immune syste eliminated susceptible tumour clones when possible, preventing tumour expansion
Tumour heterogeneity resulting in “Darwinian” selection
What occurs during ESCAPE?
The immune system is unable to suppress the tumour cell growth, easing to tumour progression
How can cytokines (INTERFERON) be used as a immunotherapy for cancer?
Interferon type 1 (A and B)
Produced by virally infected cells
Most cells have a a viral detection pathways - upregulation of MHC 1, tumour antigen expression and adhesion molecules
Activated T cells, B cells and DC.
Used successful in metastatic melanoma
Nasty side effects (flu like symptoms)
How can cytokines (INTERLEUKIN-2) be used as a immunotherapy for cancer?
T cell growth factor
Success in RCC and melanoma
Toxicity
LAK cells treated with IL-2 and re infused into patients reduces toxicity
How can cytokines (GM-CSF) be used as a immunotherapy for cancer?
GM-CSF stimulates APC
Trilled in melanoma, evidence of some success
May be of benefit if used with IL-2
What are 3 ways antibodies can prevent tumour growth?
- Direct tumour cell killing - antibodies can block receptors ,or can be conjugated to toxins, or act as a cell agonist to lead to apoptosis
- Immune educated tumour cell killing
- antibodies binding will expose the macrophage Fc receptors allowing macrophages to destroy the cell
- antibody binding allows T cell to recognise tumour cell without MHC restriction
- antibody binding to CTLA4 prevents T cell from switching off
- antibodies bind to tumour material, and tumour material is taken up and presented by dendritic cells - Vascular and stromal cell abiation — antibodies binds attract T cell, ultimately destroying the blood vessel supply tumours need to grow
Give two examples of drugs used to block growth factors on tumour cells
Tastuzumab targets ERBB2 on breast cancer cells
Bevacizymab targets VEGF and blocks signalling, used on colon cancer and kidney cancer
What drugs can be used to induce apoptosis?
Rituximab: anti-CD20, used for CD20 positive B cell non-Hodgkin’s lymphoma and chronic lymphocytic lymphoma
Alemtusuma: anti CD52, used for B-CLL
What drugs are used in immunomodulation?
Ipilimumab (anti-CTLA-4) blocks the inhibition due to CTLA-4 signalling
Used in metastatic melanoma
How can checkpoint inhibition be used?
Ipilimumab (anti-CTLA-4) combined with Nivolumab and pembrolizumab
Blocked of effector cell death
Antibody against Programmed cell death protein 1 (PDL-1)
Expressed on T cells and can induce apoptosis when bound by PDL-1
PDL-1 can be found on tumour cells
What are the cell based therapies for cancer?
LAK
NK-T cells
Gd T cells
DC
TIL
CAR
How can LAK cells be used to treat cancer?
Lymphokine activated killers - mad by PBMC taken from patients and cultured with IL-2 in vitro
NK, NKT and CD25 T cells (Predominantly NK cells)
Higher then normal anti-tumour activity
Can target NK resistant tumour cells
How can natural killer cells be used to treat cancer?
Recognise lack of MHC1
About 5-10% of human peripheral blood lymphocytes
Majority are CD3 - CD56+
Primarily found in blood, BM, spleen and liver
Main type in LAK populations
How can NK-T immunotherapy be used in cancer treatment?
A galactosyl ceramide
Used for in vitro expanded NKT based vaccines
Used a-gal cer pulsed DCs
Well tolerated
Induce expansions of NKTs in vivo
some stable disease in a variety of cancers
How can the gd T cell be used in cancer treatment?
TCR tructurally similar to alpha-beta
May not need normal antigen presentation mechanisms
May not recognise peptides and therefore no need for protein processing
May detect stress or small organic molecules which signify infection
Can respond to MICA and MICB expressed on stressed cells
Can recognise small organic molecules secreted by bacteria
What Is a therapeutic vaccination?
Induces a long lasting response against tumour
Stimulate the adaptive arm of the immune response
Use professional APC such as Dendritic
What are the principles of DC vaccination?
- Isolation of monocytes from peripheral blood of patients
- Generation of immature dendritic cells
- Isolation of patient tumour cells
- Lysate preparation from tumour cells
- Loading of dendritic cells with whole cell tumour-Lysate
- Mature antigen presenting dendritic cells are vaccinated into the patient
Why do we think TILs are important?
Presence of lymphocytes has prognostic significance
Large numbers of TILs in many tumours
High number of CD8 cells also has prognostic significance
High CD8/Treg ratio
Pre-existing antigen specificity of TILs has been correlated with outcome in immunotherapy of melanoma
Describe what occurs in adoptive therapy with TILS
- Tumour biopsy
- In vitro polyclonal stimulation (IL-2 and nit CD3 antibody)
- Lymphodepletion of patient (enhances persistence of transferred T cells)
- Stimulated T cells reintroduced into the patient
What are the results expected to be seen after adoptive cellular therapy with TILS?
Cytotoxicity against tumour cells in culture
> 50% response rate
Best results when patients are pre-treated with peripheral lymphodepletion regimen of total body irradiation
What are the disadvantages of adoptive cell therapy with TILs?
Need enough tumour to generate sufficient CTLs
TILs may be refractory to stimulation
Time consuming and labour intensive
Culture time may be too long
Culture time MAY influence quality of T cells
High failure rate of culture
What is the use of peripheral blood derived T cells in local expansion?
- Isolate peripheral blood PBMCs/PBLs
- Simulate in vitro with autologous DC + antigen
- Grow out tumour reactive clones
When is clonal expansion against a known antigen used?
Used extensively for treatment of pos-transplant lymphoproliferative diseases
Used in haemolytic malignancies with some success
What is a advantage of clonal expansion against a known antigen to treat cancer?
Easy availability of large numbers of T cells
What is a disadvantage of clonal expansion against a known antigen to treat cancer?
Cloning and culture takes a long time
What occurs during high finite TCR transduction?
TCRs reactive to TAAs characterised and cloned
- Alpha and beta chains oof TCR are engineered into a retroviral vector
2 Patients CD8 T cells from peripheral blood are removed and transducer with TCR virus
- Adoptive transfer back into patients
What are the limitations of high finite TCR transduction?
2/15 patients with. Clinical response
T cells remain in peripheral blood for up to one year
Epitopes need to be characterised and matched to HLA
Must be present in tumour
Becomes a patient specific therapy
Autoimmunity? Off-target hits, have lead to death
What are chimeric antigen receptors (CARs)?
Similar in nature to TCR transgenics
Composed of
- antibody recognition domains
- cytoplasmic til with multiple signalling domains that activate T cells
Advantages of specificity and high affinity
Not yet extensively studied
Does immunotherapy work?
CPI now in regular use for some cancers
Much improved survival
We keep improving
