L32 Receptor Blockades (T cell co-signalling and immunotherapy in lymphoma/cancer)

Question 1

How are T cells activated?

Answer 1

Signal 1: CD3 or T cell receptor engangement
Signal 2: co-stim molecules (can be co-inhibitory from immune checkpoints though)

Question 2

Cancer-immunity cycle

Answer 2

1. cancer grows unchecked but some of the cells do die
2. when they die they release antigens/proteins
3. we want APC to detect and pick up the tumour antigen
4. the APC can then become activated
5. it presents the antigen to a T cell in a lymph node
   (this is signal 1)
6. then T cells clonally expand
7. they then travel aroudn the blood to attack the tumor

Question 3

tumor antigen types

Answer 3

Question 4

tumor specific (tumor antigen types)

Answer 4

antigens encoded by genes specifically expressed by tuors

Question 5

mutational antigens (tumor antigen types)

Answer 5

antigens encoded by variant forms of normal genes that have been altered by mutation

Question 6

differentiation antigens (tumor antigen types)

Answer 6

antigens normally epxressed only at certain stages of cell differentiation or only by certain cell lineages (cancer/testis antigennormally expressed in Germ cells)

Question 7

abnormal gene expression (tumor antigen types)

Answer 7

antigens that are overexpressed in particular tumors

Question 8

viral antigens (tumor antigen types)

Answer 8

viruses that lead to cancer e.g. HPV

Question 9

immune responses to tumors

Answer 9

• T cell killing
• NK cell activity
• macrophage-mediated tumor destruction

Question 10

Why does the cancer-immunity fail in cancer?

Answer 10

• 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

Question 11

example of what tumors secrete in order to increase immunosupression

Answer 11

TGF-Beta

Question 12

example of tumors taking advantage of immune checkpoint pathways

Answer 12

• upregulating inhibitory ligands, e.g. PDL-1
• the T cells will also upregulate the receptors like PD-1 or PD-4

Question 13

immune checkpoint blockcade cancer immunotherapy

Answer 13

• drugs that target and block immune checkpoint molecules and unleash anti-tumor immune responses

Question 14

classical signal 2 of T cell activation

Answer 14

CD28

Question 15

common co-inhibitory molecules that allow down-regulation of T cell signalling/responses

Answer 15

PD-1 and CTLA- 4

Question 16

CDLA-4 mechanism

Answer 16

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

Question 17

PD-1 is activated when ______ it also inhibits ______ through _____

Answer 17

• when signal 1 occurs
• T cells from becoming over-active
• phosphatase PP2A

Question 18

cancer cells upregulate both the ligand ____ and the receptor ______ in order to dampen T cell response

Answer 18

PDL-1 ligand
PD-1 receptor
- cancer increases it because it is inhibitory

Question 19

mechanisms by which cancer upregulates the PD-1 ligand (PD-L1)

Answer 19

• 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)

Question 20

cancer upregulates PD-L1 through adaptive resistance because

Answer 20

the IFN-y that active T cell express is absorbed by the cancer and causes activation of STATs signalling (which upreg. PD-L1)

Question 21

PDL1 pathway induced immunosupressionin the microenvironment causes…..

Answer 21

T cell exhaustion and apoptosis
and Treg induction

Question 22

Anti-PDL-1

Answer 22

inhibits the immuno-suppressive nature of the cancer so that the T cells can attack the tumor

Question 23

anti-PD-1 therapies works very well for

Answer 23

-hodgkins lymphoma
- melanoma

Question 24

challenges of anti-PD-1 immunotherapies

Answer 24

they don’t work very well
- anti CTLA-4 hasnt worked very well
- cancer cells vastely outnumer the T cells

Question 25

compo therapy to optimise

Answer 25

• using both CTLA4 blockade and PD-1 in blockade

Question 26

‘co-stim’ drugs

Answer 26

• activates the co-stim receptors of T cells to drive their proliferation
• e.g. CD28, 4-1BB

Question 27

bispecific antibodies

Answer 27

immunotherapy that redirects T cells toward haematological tumor cells

Question 28

benefit of bispecific antibody drugs

Answer 28

• don’t need to genetically modify them so cheaper and easier

Question 29

type of bispecific antibodies (BsAbs)

Answer 29

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

Question 30

How does BiTE work?

Answer 30

• 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

Question 31

building blocks of BsAbs

Answer 31

1. antigen binding domains
2. multimerization core
3. link connecting other blocks

have to maintain stability and structure for when they ultimately reach a patient

Question 32

By bridging T cells and target cells with a bispecific antibody (BsAb)…..

Answer 32

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

Question 33

Similarities and Differences of CAR vs BiTES or bispecific antibodies

Answer 33

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

Question 34

BsAb Design

Answer 34

• divided into 2 large groups based on if they have an FC DOMAIN

Question 35

what does the Fc domain do in BsAb design?

Answer 35

• 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

Question 36

Potential downfalls of Fc domain do in BsAb design

Answer 36

• might also induce ADCC (cytotoxicity) of T cells once they have bound to T cell surface