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Biotherapeutics > Cancer Vaccines > Flashcards

Cancer Vaccines Flashcards

1
Q

What are 4 tumour antigens?

A

HPV
HBV
Epstein Barr
CEA

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2
Q

What are 4 aims of cancer vaccines?

A

harness specificity of immune system to: recognize tumours, amplify tumour specific responses & destroy tumour

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3
Q

Which tumour antigen was approved?

A

Sipuleucel-T (Provenge)

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4
Q

When was antitumour immunity in mice discovered?

A

1950s

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5
Q

What are 2 vaccines preventing HPV?

A

Gardasil
Cervarix

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6
Q

What are prophylactic vaccines?

A

Prevent cancer by targeting viruses & given to healthy individuals
eg Hepatitis B & HPV

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7
Q

What are therapeutic vaccines?

A

For Pts who already have cancer
eg. metastatic prostrate cancer (Provenge)
& Ebstein Barr virus-associated cancers (WGc-043)

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8
Q

What are 3 treatments for prostrate cancer?

A

Hormone deprivation therapy
Chemotherapeutic agents
Vaccine therapies

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9
Q

What % of men have recurrence of PC after surgery?

A

20

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10
Q

What T cells are MHC class I communicating with?

A

CD8

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11
Q

What T cells are MHC class II communicating with?

A

CD4 T helper cells

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12
Q

What are 3 APCs?

A

Dendritic cells
macrophages
B cells

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13
Q

When is MHC class 1 activated?

A

If antigen that is presented is produced in the cytosol

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14
Q

When is MHC class 2 activated?

A

If antigen enters from outside via endosomes

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15
Q

What do dendritic cells activate?

A

naive & memory T cells

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16
Q

How is the Provenge vaccine made?

A

Harvest APC from blood samples -> incubate with tumour associated antigens called prostatic phosphatase in cytokine presence (GMSF) -> APC shipped back to Pt -> infused with APC -> go to lymph nodes -> initiate cytotoxic T cell response

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17
Q

What are 3 downfalls of Provenge?

A

Takes 4 days and costs 90,000 & only available in 50 centres in USA

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18
Q

What did the 3 clinical trails for Provenge see?

A

No sig. change in time to disease progression

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19
Q

What did the study DP9901 see?

A

Difference of median survival of 4.5 mths
8 fold increase in T cell proliferation
Provenge compared to placebo

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20
Q

What did the study DP9902A see?

A

Sig. reduction in risk of death of 33% compared to placebo 15%
Less adverse events
no sig change in risk of disease progression

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21
Q

What are 4 cancer vaccine challenges?

A

Anti-tumour immunity
Failure to produce tumour antigen
Mutation of MHC genes or genes needed for antigen processing
Secretion of immunosuppressive proteins or expression of inhibitory cell surface proteins

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22
Q

What % of cancer Pts do not respond to checkpoint inhibitors?

A

50

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23
Q

What are 3 suppressive immune cells?

A

MDSCs
TAMs
T reg

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24
Q

What are 3 benefits of combining tumour vaccine & checkpoint inhibition?

A

De novo tumour specific T cell response
Amplification of existing tumour specific T cell response
Increased breadth & diversity of tumour-specific T cell response

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25
Q

What are 4 new approaches to improve cancer vaccines?

A

Better tumour antigens (neoadjuvants)
Better delivery methods
Better adjuvants
Better formulations

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26
Q

What are 4 components of the tumour vaccine?

A

Tumour antigens eg. TAA
Formulation eg. protein or peptide based
Immune adjuvants eg. TLR agonist
Delivery vehcicle eg. liposomes

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27
Q

What are examples of TAAs?

A

MART-1
HER-2
if present in normal tissues - can initiate tolerance

28
Q

What are neoantigens?

A

random somatic mutations in tumour cells whoch are Pt specific eg. CDK4, catenine & caspase-8

29
Q

How are neoantigens identified?

A

whole exosome sequencing

30
Q

What are 4characteristics of neoantigens?

A

Potent T cell response
rare
Difficult to predict
recognised as non-self

31
Q

What is high neoantigen load associated with?

A

Better survival (65%)

32
Q

Which TLRs are stimulated with adjuvants?

A

TLR3/7/8/9

33
Q

What are 4 TLR agonists?

A

TLR4 - MPL
TLR3 - poly ICLC
TLR7 - imiquimod
TLR9 - CpG

34
Q

What are saponins?

A

Saponin adjuvant with cholesterol & phospholipid to stimulate ER strfess for immune response

35
Q

What are liposomes?

A

Delivery to endosome & cytosol to stimulate immune response

36
Q

What is NY-ESO-1?

A

Cancer testis antigen (180aa) expressed in a range of tumours & normal cells

37
Q

What type of response is seen with NY-ESO-1 tumours?

A

Spontaneous T cell & Ab response

38
Q

How was the NY-ESO-1 vaccine delivered?

A

Peptide, whole, fusion protein (HSP70)
range of adjuvants (CpG, Poly-ICLC, resiquimod, lipid matrices)

39
Q

What is glioblastoma?

A

Most common form of primary brain tumour in adults - poor survival

40
Q

What is the standard care for Glioblastoma?

A

Surgery, radiotherapy & chemo (temozolmide) since 2003

41
Q

What vaccine has been made for Glioblastomas?

42
Q

How is GlioVac made?

A

Surgical resected tumour (only get 80%) -> mixes it with other tumours -> immunised into Pt -> targets immune response at nonresected remnants -> cycles of autologous & allogenic antigens
6 vials from donor
4 vials from Pt

43
Q

What is added to Glio-Vac?

A

GM-CSF to stimulate immune response

44
Q

Was survival extended in GlioVac?

45
Q

What phase is GlioVac in?

46
Q

How are neoantigens being identified?

A

Comparing tumours to healthy matched control
Look at NS, MHC binding screen

47
Q

What are 3 parts of the typical workflow for neoadjuvant idenfication?

A

Single suspension of tumor cells & matched normal cell
HLA typing on normal cells
Antigenicity of NeoAg - predicted by affinity of binding to HLAtype for patient

48
Q

What is NeoVax?

A

Phase 1 trial for melanoma Pts

49
Q

What ere given to Pts in NeoVax?

A

20-mer Neopeptides specific to Pt tumour with Poly-ICLC

50
Q

What was the result of NeoVax?

A

No recurrence for up to 32 mths in stage III
Complete tumor regression after PD-1 therapy for 2 pts in staged 4

51
Q

What is the aim of mRNA use for delivery strategy?

A

Potent T cell responses

52
Q

What is needed for mRNA vaccine?

A

CD8+ T cells with CD4+
Requires cytolsic delivery for MHC class I

53
Q

Is an adjuvant added to mRNA?

A

No mRNA is selfadjuvanting

54
Q

What is a challenge in mRNA vaccines?

A

APC targeting

55
Q

What did Sahin et al 2017 do?

A

Melanoma vaccine admistered via percutaneous intranasal injection -> mRNA stability & good translation efficiency -> Dc maturation via TLR7
MHC class II restricted

56
Q

What was the result of Sahin 2017?

A

2/5 vaccine related responses
1/5 PD-1 + vaccine = complete response

57
Q

How is mRNA delivered to tumour?

A

Taken up by DC (adaptive)
Play with charge -> can enter lymphatic system themselves -> activate DC in spleen (innate)

58
Q

How are neoantigen RNA lipoplex formulations made?

A

neoepitope discovery
mRNA in vitro transcription
RNA lipoplex formulation
IV injection
APC targeting in spleen

59
Q

What is IVAC MUTABOME?

A

13 Pts
combinations of RNA for TAAS with intranodal bossters containing 10 NeoAg RNAs

60
Q

What was the result of IVAC MUTABOME?

A

5 pts with metastic disease - 2 had objective response & 1 with complete response

61
Q

What was the Keynote trial?

A

mRNA 4157 neoantigen with Pembro reduced death & metastasis by 65%

62
Q

What is mRNA 4157?

A

Personalised mRNA encoding 34 different Pt specific neoantigens

63
Q

What are the 4 stages of the Keynote process?

A

Sequencing of each Pt tumour & healthy tissues
Identify tumour specific mutations
6 week process
9 mRNA 4157 im doses (every 3 weeks) & 9 IV of Pembro

64
Q

What afre advances of Keynote trial?

A

Merck & Moderna - phase III
1089 Pts II - IV
mRNA 4157 + pembrolizumab

65
Q

What are 3 conclusions of using NeoAg?

A

CD4+ & CD8+ in all vaccinated Pts
60 -70 % immunising NeoAg recognized
Complete responses with PD-1 blockers

66
Q

What arfe 3 trials NeoAg used in?

A

Peptide based eg glioblastoma
Poly-epitope RNA based eg. pancreatic
Peptide loaded DC vaccine eg . colorectal

67
Q

What 4 things are needed to improve NeoAg?

A

More CD4+ epitopes than CD8+ atm
Detection of presented antigens on tumour cells
Prediction of class I & II bindng epitopes
Understanding Ag process
better preclinical models for optimization, scheduling & formulation

Biotherapeutics (10 decks)

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