L32 Receptor Blockades (T cell co-signalling and immunotherapy in lymphoma/cancer) Flashcards
How are T cells activated?
Signal 1: CD3 or T cell receptor engangement
Signal 2: co-stim molecules (can be co-inhibitory from immune checkpoints though)
Cancer-immunity cycle
- cancer grows unchecked but some of the cells do die
- when they die they release antigens/proteins
- we want APC to detect and pick up the tumour antigen
- the APC can then become activated
- it presents the antigen to a T cell in a lymph node
(this is signal 1) - then T cells clonally expand
- they then travel aroudn the blood to attack the tumor
tumor antigen types
tumor specific (tumor antigen types)
antigens encoded by genes specifically expressed by tuors
mutational antigens (tumor antigen types)
antigens encoded by variant forms of normal genes that have been altered by mutation
differentiation antigens (tumor antigen types)
antigens normally epxressed only at certain stages of cell differentiation or only by certain cell lineages (cancer/testis antigennormally expressed in Germ cells)
abnormal gene expression (tumor antigen types)
antigens that are overexpressed in particular tumors
viral antigens (tumor antigen types)
viruses that lead to cancer e.g. HPV
immune responses to tumors
- T cell killing
- NK cell activity
- macrophage-mediated tumor destruction
Why does the cancer-immunity fail in cancer?
- they secrete immuno-supressive factors (like TGF-B)
- they also ‘co-opt’ and take advantage of immune checkpoint pathways
- upregulate coinhibitory receptors (T cells, but also the ligands) which supresses the T cell attack
example of what tumors secrete in order to increase immunosupression
TGF-Beta
example of tumors taking advantage of immune checkpoint pathways
- upregulating inhibitory ligands, e.g. PDL-1
- the T cells will also upregulate the receptors like PD-1 or PD-4
immune checkpoint blockcade cancer immunotherapy
- drugs that target and block immune checkpoint molecules and unleash anti-tumor immune responses
classical signal 2 of T cell activation
CD28
common co-inhibitory molecules that allow down-regulation of T cell signalling/responses
PD-1 and CTLA- 4
CDLA-4 mechanism
has a central role in maintaining immune tolerence in lymph node tissue
- a type of immune checkpoint
- its exoression on activated T cells dampens CD28 co-stimulation by outcompeting CD-28 for binding
PD-1 is activated when ______ it also inhibits ______ through _____
- when signal 1 occurs
- T cells from becoming over-active
- phosphatase PP2A
cancer cells upregulate both the ligand ____ and the receptor ______ in order to dampen T cell response
PDL-1 ligand
PD-1 receptor
- cancer increases it because it is inhibitory
mechanisms by which cancer upregulates the PD-1 ligand (PD-L1)
- intrinsic reistence (tumor cells express oncogenic pathways that drive cancer proliferation and transcriptionally active the ligand)
- adaptive reistence (T cells that have been activated express IFN-y, and when cancer encounters IFN-y it absorbs it and causes it to activate STATs signalling which upregulates PD-L1)
cancer upregulates PD-L1 through adaptive resistance because
the IFN-y that active T cell express is absorbed by the cancer and causes activation of STATs signalling (which upreg. PD-L1)
PDL1 pathway induced immunosupressionin the microenvironment causes…..
T cell exhaustion and apoptosis
and Treg induction
Anti-PDL-1
inhibits the immuno-suppressive nature of the cancer so that the T cells can attack the tumor
anti-PD-1 therapies works very well for
-hodgkins lymphoma
- melanoma
challenges of anti-PD-1 immunotherapies
they don’t work very well
- anti CTLA-4 hasnt worked very well
- cancer cells vastely outnumer the T cells
compo therapy to optimise
- using both CTLA4 blockade and PD-1 in blockade
‘co-stim’ drugs
- activates the co-stim receptors of T cells to drive their proliferation
- e.g. CD28, 4-1BB
bispecific antibodies
immunotherapy that redirects T cells toward haematological tumor cells
benefit of bispecific antibody drugs
- don’t need to genetically modify them so cheaper and easier
type of bispecific antibodies (BsAbs)
BiTEs (bispecific T cell engagers)
- have 2 single-chain variable fragments specific for CD3 (expressed on almost all T cells) and a tumor antigen
- the CD19-specific BiTE blinatumobab has shown impressive clinical results
How does BiTE work?
- double binding mechanism to force the T cell and tumor cell to interact
1. it binds to an antigen on the T cell (CD3) to provide an agonist stimulation that strongly activates the CD3 receptor
2. also binds to a tumour antigen
building blocks of BsAbs
- antigen binding domains
- multimerization core
- link connecting other blocks
have to maintain stability and structure for when they ultimately reach a patient
By bridging T cells and target cells with a bispecific antibody (BsAb)…..
T cell activation is major histocompatibility complex (MHC) UNRESTREICTED or independed
and therefore no longer depends ont he native T cell receptor specificity of the activated T cell
This is because the drug forces the reaction that the MHC would have done
Similarities and Differences of CAR vs BiTES or bispecific antibodies
Differences:
- CAR is genetically modified to person, Bites can be off the shelf becuase they are just recombinant antibodies
-
Similarities:
- activate T cells
- independent of MHC (don’t need the signal 1 activation)
- serial killers, can kill many
- secrete cytotoxic enzymes (perforin and granzyme B)
- toxic (b/c activating a lot of T cells/giving a lot), so can cause symptoms
BsAb Design
- divided into 2 large groups based on if they have an FC DOMAIN
what does the Fc domain do in BsAb design?
- facilitates purification, adds stability and increases the half life of the molecule in vivo
- also induce activation -dependent cell mediated cytotoxicity by recruiting NK and macrophages
Potential downfalls of Fc domain do in BsAb design
- might also induce ADCC (cytotoxicity) of T cells once they have bound to T cell surface
