Lecture 11 - cancer immunotherapy I Flashcards
how do immune cells recognise cancer cells?
immune cells recognise cancer cells by cancer associated antigens
examples of cancer associated antigens are;
neoantigens - result fromgene mutationsin cancer cells and have not been seen previously by the immune system
Overexpressed self antigen
Self antigens that are expressed during embryonic development but are not expressed or are expressed at very low levels after birth
Cancer-associated antigens mark cancer cells as abnormal or foreign and can causekiller T cells to mount an attack against them
what are cancer cell strategies to evade detection by the immune system?
Many cancer-associated antigens are only slightly altered versions of self antigens and difficult for the immune system to recognize
Cancer cells may undergo genetic changes that may lead to the loss of the processing or presentation of cancer-associated antigens
Overexpression of proteins (PDL1) which suppress immune response
Some cancer cells produce and secrete immunosuppressive cytokines (e.g. IL-10, TGF-β).
what are tumour associated macrophages?
Tumours release a range of chemokines, cytokines and growth factors to attract monocyte into the tumour stroma where they differentiate into tumour associated macrophages (TAM)
TAMs stimulate tumour growth, invasion, migration and metastatic spread
what does antibodies in cancer immunotherapy do?
Exploits the expression of a specific antigen expressed by cancer cells but absent or expressed at low levels by normal cells.
To stimulate the host immune response to kill cancer cell
To inhibit tumour growth signals
To carry drug or a radioactive molecules to the cancer cell
what is rituximab
Chimeric (mouse and human) monoclonal antibody against CD20 expressed on B lymphocytes
Non Hodgkin lymphomas, chronic lymphocytic leukaemia (CLL), cancers which develops in B lymphocytes
Side effects, which can cause death and disability include:
Immune toxicity (depletion of B cells in 70% to 80% of lymphoma patients)
CD20 expressed is also expressed on normal B cells
Any healthy B cells destroyed by CD20-targeted therapy can be readily replenished
Pulmonary toxicity
what is the mechanism of action of rituximab?
The function of CD20 is unclear
Cell death induced by:
-Apoptosis
-ADCC antibody-dependent cellular cytotoxicity
Fc arm of the antibody engages Fc receptor (FcR)-positive inflammatory cells, such as natural killer cells and macrophages.
-CMC complement mediated cytotoxicity
describe the mechanisms of action of Herceptin
Herceptin binds to HER2 receptors which can be over expressed in breast cancer cells. Binding prevents signals that triggers cell growth and division of cancer cells.
cell cycle arrest, stimulation of proapoptotic pathways etc
what is the mechanism of Herceptin administration?
HER2-overexpressing metastatic breast cancer
- In combination with paclitaxel for first- line treatment
- Single agent in patients who have received one or more chemoregime
Breast cancer Adjuvant treatment of HER2 overexpressing node positive or node negative (ER/PR negative)
Metastatic gastric cancer
administration
Intra venous infusion
Subcutaneous injection –early breast cancer only
Breast cancer every 1 or 3 weeks up to 1 year
Gastric cancer every 3 weeks.
describe Herceptin
HER2 receptor expression is upregulated in 25% of breast cancer cells
HER2 activates MAPK and PI3K pathways which increases cell growth, survival, adhesion, migration, and differentiation
Herceptin binds to HER2 receptor
Main side-effect is Cardiac dysfunction (2-7% of patients)
Approximately 10% of patients are unable to tolerate this drug because of pre-existing heart problems
what are checkpoint proteins?
T cell response might be suppressed by inhibitory check point proteins
Inhibitory check point proteins are crucial for modulating the duration and amplitude of physiologicalimmuneresponses in peripheral tissues
Minimise collateral tissue damage
describe ipilimumba and its mechanism of action
CTLA-4 is an inhibitory checkpoint receptor protein expressed on T cells
Antibody against CTLA-4 (cytotoxic T-lymphocyte-associated protein 4-receptor) expressed on T-cells
Antigen presenting cell (DC or macrophages) presents a processed antigen in the context of MHCII
Recognised by TCR on T-cell
For T-cell activation co-stimulatory signals from APC is needed (CD28 binds B7)
CTLA4 binds B7 no T-cell to terminate activation
Ipilimumab block CTLA-4
Common side effects related to inflammatory responses
Fatigue, diarrhea, skin rash, vomiting. Intravenous infusion 3 mg/kg every 3 weeks for 4 doses
what are cancer approved treatment for ipilimumab?
Ipilimumab is approved for use in combination with the PD-1 inhibitor nivolumab to treat unresectable melanoma
Advanced treatment-naive renal cell carcinoma (RCC)
Metastatic microsatellite instability high (MSI-h) or mismatch repair deficient (dMMR) colorectal cancer that has progressed on previous treatment
Describe PD-1/PD-L1
PD-1 is a checkpoint receptor protein expressed on T cells and B cells
PD-L1 and PD-L2 are ligands to PD1 and is expressed by dendritic cells, macrophage (APC).
PD-L1 is expressed in various types of cancers, especially in NSCLC, melanoma, renal cell carcinoma, gastric cancer, hepatocellular as well as cutaneous and various leukemias, multiple myeloma etc.
It is present in the cytoplasm and plasma membrane of cancer cells, but not all cancers or all cells within a cancer express PD-L1
describe PD-1/PD-L1 inhibitors.
- Tumour cells produce mutated antigens that are captured by dendritic cells
- The dendritic cells prime T cell with tumour antigen and stimulate the activation of cytotoxic T cells
- Activated T cells then travel to the tumour and infiltrate the tumour environment
- The activated T cells recognize and bind to the
cancer cells - The bound effector T cells release cytotoxins, which induce apoptosis in their target cancer cells
- The cancer cell can block the T-cell attack through PDL1 (cancer cells) binding to PD1 on T-cell
describe the regulation of PDL1 expression on cancer cells
PD-L1 expression is induced by multiple proinflammatory molecules including types I and II IFN-γ, TNF-α, LPS, GM-CSF and VEGF, as well as the cytokines IL-10 and IL-4
The most potent inducer of PDL1 expression is IFN-γ
IFN-γ and TNF-α are produced by activated type 1 T cells
GM-CSF and VEGF are produced by a variety of cancer stromal cells, the tumour microenvironment upregulates PD-L1 expression, thereby, promotes immune suppression allowing tumour cells to escape immunosurveillance
