Receptor Blockade Flashcards
Give one example of each of the following. Tumour specific mutated oncogene or TS. Germ cell. Differentiation. Abnormal PTM. Oncoviral.
CDK / B-catenin (melanoma) MAGE-1 (melanoma) Tyrosinase (melanoma) MUC-1 (breast, pancreas) HPV type 16, E6 and E7 (cervical).
What are the functions of CTLA-4?
Activates SHP2 and PP2A
Active in lymph nodes and maintains immune tolerance.
Constitutively expressed on Tregs.
What are the functions of PD-1.
Limits T cell immunosurveillance within tissues
Increases proliferation, survival and maintenance of Tregs.
Activates SHP2 and PP2A
Active in tumour microenvironment.
What are the two ligands for PD-1 and how do they differ?
PD-L1 and PD-L2
1 = activated on haematopoietoc cells by cytokine IFN-Y
L2 expressed on DCs and some macrophages.
What is particularly exciting about blocking immune checkpoints?
With the antibodies, after cessation, some patients continued to respond suggesting the immune system had fundamentally been changed.
How effective have trials with anti-PD-1 and ant PD-L1 been?
Have shown unprecedented 30-35% durable response rates in patients with advanced melanoma.
Currently being studied in relation to lung, breast, bladder and RCCs.
How can tumours evade immune recognition?
Lose expression of MHC
T and taken up and presented by APCs in absence of co-stimulation –> tolerised and treated as self antigen.
TGF-b secreted by tumour cells inhibit T cells directly, Treg induction.
How can we measure efficacy of immune cell checkpoint blockade drugs?
Look at F actin immune synapse formation.
Or % granzyme B production.
Ramsay et al showed T cells (previously inactive in cancer cells ) - activated after first cycle and activation increased with dose.
What drugs are currently approved?
Ipilumimab - anti-CTLA-4
Nivolumab - anti-PD-1
LAG-3-Ig (in trials).
