L26 - Anti-tumour Immunity & Immunotherapy for Cancer Flashcards
How are cancer cells different to normal cells?
Rapid uncontrolled growth Increase mobility Invade tissue Evade immune system Metastasize
What is Tumour Immunosurveillance?
A process where the immune system, namely lymphocytes continually recognise cancerous and pre-cancerous cells leading to their elimination before they can cause damage
Describe Interferon as a cytokine used in cancer immunotherapy?
Type I interferon (a and b)
Produced by virally infected cells
Viral detection pathways within most cells
Upregulates MHC Class 1, tumour antigens and adhesion molecules.
Activates T cells, B cells and DC
Used successfully in metastatic melanoma
Nasty side-effects (‘flu-like symptoms)
Why is BC used in cancer immunotherapy?
Bacillus Calmette-Guerin
Vaccine for TB
Good immunological adjuvant
Stimulates the innate immune system TLRs
Used in bladder cancer- intravessicular injection
MOA? DC activation, direct NK activation, bystander T cell activation.
Describe Interleukin 2 as a cytokine used in cancer immunotherapy?
T cell growth factor
Success in RCC and melanoma
Toxicity
LAK cells, PBMC treated with IL-2 and re-infused into patients
Describe GM-CSF as a cytokine used in cancer immunotherapy?
GM-CSF stimulates APC
Trialled in melanoma, evidence of some success
May be of benefit if used in conjunction with IL-2
How do Antibodies cause direct cell killing?
Antibodies can block receptors asa directr antagonist, they can block enzymes, they can be conjugated to toxins which destroy the cell.
In some cases they can be receptor agonist which can lead to apoptosis of the cell
How do Antibodies cause immune-mediated tumour cell killing?
Antibodies from phagocytes bind to molecules on the surface of tumour cell will expose the FC potyion to the FC receptor on macrophages allowing the macrophage to destory the cells
Fc portion of antobody will also bind complement and attack the membrane.
Antibodies of tumour cell may activate NK cells, causing the release of perforin and granzymes
How do Antibodies cause vascular and stromal cell ablation?
Antobosies can create ablation of the vasculature and the stroma that the tumours need to set up a lesion
What are some antibodies that can cause the blockade of growth factors and what cancers can they be used in?
Trastuzumab (Herceptin) targets ERBB2 (human epidermal growth factor) on breast cancer cells. Blocks ERBB2 signalling and allows targetting of ADCC
Bevacizumab (Avastin) targets VEGF and blocks signalling. Used against colon cancer, NSCLC, glioblastoma and kidney cancer.
What are some antibodies that can cause the induction of apoptosis?
Rituximab: anti-CD20, used for CD20 positive B cell Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Lymphoma.
Alemtuzumab (Campath): anti CD52, used for B-CLL
What are some antibodies that can cause immunomodulation?
Ipilimumab (anti CTLA-4), blocks the inhibition due to CTLA-4 signalling. Used in metastatic melanoma.
Activates a stronger and longer T-cell response
What are LAK cells and how can they be used in cellular therapy to kill tumour cells?
LAK cells: Lymphokine Activated Killers
PBMC (Peripheral blood mono-nuclear cells) taken from patients and cultured with IL-2 in vitro.
Activates Heterogeneous population
NK, NKT and T cells (CD25+)
Predominantly NK cells
Higher than normal anti-tumour activity
Can target NK resistant tumour cells
How can NK- T cells be used in cellular therapy to kill tumour cells?
Recognises a-galactosyl ceramide
can be Used for in vitro expanded NKT based vaccines
Used a-gal cer pulsed DCs which activates NK-T cells
Well tolerated
Induce expansions of NKTs in vivo
Some stable disease in a variety of cancers
Describe the principle of DC vaccination?
- isolate monocytes from patients
- monocytes can be driven into DCs by GM-CSF and Interleukin 4
- Immature DCs need to be loaded with tumour antigen (can be isolated from patient and prepared with lysate
- Marure the DCs and then put back into patient
- Polulation of classical APCs which present tumour antigens to the T-cells
