Anti-tumour Immunity And Immunotherapy For Cancer Flashcards
Which tumours does immunodeficiency lead to?
Kaposi sarcoma and lymphoma
What does tumour immunosurveillance describe?
A process where the immune system continually recognises cancerous and pre-cancerous cells leading to their elimination
What are the three phases of immunoediting?
Elimination
Equilibrium
Escape
What cells are involved in the elimination phase of immunoediting?
NK, NKTs, macrophages and dendritic cells
What chemicals lead to tumour death?
INFgamma and chemokines
What happens in the elimination phase of immunoediting?
Tumour specific dendritic cells activate adaptive immunity to drain lymph nodes
Tumour specific CD4+ and CD8+ T cells join to clear the tumour
When does the equilibrium phase happen?
If the elimination phase is incomplete
What happens in the equilibrium phase of immunoediting?
Tumour cells lie dormant and may modulate tumour antigen expression and stress signals
What is tumourigenesis?
Normal cells undergoing change develops tumour antigens
Danger signals such as extracellular matrix products can be detected by the immune system
How does the BCG vaccine help with bladder cancer?
Involves DC activation
Direct NK activation
Bystander T cell activation
What are type 1 interferons produced by?
Virally infected cell
What do type 1 interferons do?
Upregulates MHC class1, tumour antigens and adhesion molecules
Activates T cells, B cells and dendritic cells
What is type 1 interferon used in the treatment of?
Metastatic melanoma
What is a T cell growth factor?
Interleukin-1
What is interleukin-1 used for?
Renal cell carcinoma and melanoma
What are LAK cells?
PBMC treated with IL-2 and re-infused into patients
What does GM-CSF do?
Stimulates APCs
What can GM-CSF be used to treat?
Melanoma
What ways can antibodies affect tumour growth?
Direct tumour cell killing
Immune-mediated tumour cell killing
Vascular and stromal cell ablation
How does antibody direct tumour cell killing work?
Antibodies block receptors and enzymes so they’re conjugated to toxins
How does immuno mediated direct tumour cell killing work?
Antibodies binding to cell surface of tumour cell exposes fc portion of the fc receptors on macrophages which then destroy the cell
What is vascular and stromal cell ablation?
Removal/destruction of vascular and stromal cells to prevent growth of tumour
What blocks ERBB2 signalling?
Herceptin
What does avastin target?
VEGF and blocks signalling
What is avastin used against?
Colon cancer
NSCLC
Gliblastoma
Kidney cancer
What is rituximab used for?
Anti-CD20 used for CD20 positive B cell non-Hodgkin lymphoma and chronic lymphocytic lymphoma
What is alemtuzumab?
AntiCD52
What is alemtuzumab used for?
B-CLL
How does ipilimumab work?
Blocks the inhibition of CTLA-4 signalling
What is ipilimumab used in?
Metastatic melanoma
What are the ways in which immunotherapy drugs can be delivered?
90-yttrium labelled ibritumomab tiuxetan
Brentuximab vedotin
Ontak
How does 90-yttrium labelled ibritumomab tiuxetan work?
Antibody to CD20 delivering radiotherapy to follicular B cell non-Hodgkin lymphoma
How does brentuximab vedotin work?
Antibody to CD30 delivering MMAE
How does Ontak work?
IL-2 delivering diphtheria toxin in T cell lymphoma
How does checkpoint inhibition work?
Antibody against PD-1
What are the cell based therapies for cancer?
LAK, NK-T, gamma delta T cells
Dendritic cells
What does LAK stand for?
Lymphokine activated killers
How does LAK cell therapy work?
PMBCs taken from patients and cultured with IL-2 in vitro
Causes formation of NK cells which then have higher than normal anti-tumour activity
What do NK cells recognise?
Lack of MHC-1
What are NK-T cells used for?
In vitro expanded NKT based vaccines
What is the main cell type of NK cells?
LAK populations
What are the gamma delta T cells structurally similar to?
Alpha beta cells
What may the gamma delta T cells not need?
Normal antigen presentation mechanisms
Recognise peptides and therefore no need for protein processing
What do gamma delta T cells recognise/respond to?
Respond to MICA and MICB expressed on stressed cells and recognise small organic molecules secreted by bacteria
How do you derive dendritic cells for cell based cancer therapy?
Isolate monocytes from a patient Derive them into immature dendritic cells using GM-CSF and IL-4 Load DCs with a tumour antigen Mature DCs into APCDCs Put back into patient
What is the prognosis if lymphocytes are seen in a tumour?
Good
What is the prognosis if there is a high CD8+/Treg ratio?
Higher
What has pre-existing antigen specificity of TILs been correlated with?
Outcome in immunotherapy on melanoma
What is the method for adoptive cell therapies with TILs?
Tumour biopsy
In vitro polyclonal stimulation
Lymphodeletion of patient
Stimulated T cells reintroduces into the patient
What are the results of adoptive cellular therapy with TILs?
Cytotoxicity against tumour cells culture
Homing of transferred T cells to tumour in vivo
When do you get the best results for adoptive cellular therapy with TILs?
Patients are pre-treated with peripheral lymphodeletion regimen of total body irradiation
What are the disadvantages of adoptive cellular therapy with TILs?
Need enough tumour to generate sufficient CTLs
TILs may be refractory to stimulation
Time consuming and labour intensive (requires infrastructure)
Culture time may be too long or influence the quality of T cells
High failure rate of culture
What does CAR stand for?
Chimeric antigen receptors
What is CAR composed of?
Antibody recognition domains
Cytoplasmic tail with multiple signalling domains that activate T cells
What are the advantages of CAR?
Specificity and high affinity
What is the point of theraputic vaccination?
To induce a long lasting response against tumour
Stimulate the adaptive arm of the immune response
Use professional APC such as dendritic cells
What happens in high affinity TCR transduction?
TCRs reactive to TAAs are characterised and cloned
Alpha and beta chains of TCR are engineered into retro viral vector
Patients CD8+ T cells from peripheral blood are removed and transducers with TCR virus
Adoptive transfer back into patients
What are the issues with high affinity TCR transduction?
Initial results -> 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 the tumour
Becomes a patient specific therapy
