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Cancer Vaccines Flashcards

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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
What are 4 new approaches to improve cancer vaccines?
Better tumour antigens (neoadjuvants) Better delivery methods Better adjuvants Better formulations
26
What are 4 components of the tumour vaccine?
Tumour antigens eg. TAA Formulation eg. protein or peptide based Immune adjuvants eg. TLR agonist Delivery vehcicle eg. liposomes
27
What are examples of TAAs?
MART-1 HER-2 if present in normal tissues - can initiate tolerance
28
What are neoantigens?
random somatic mutations in tumour cells whoch are Pt specific eg. CDK4, catenine & caspase-8
29
How are neoantigens identified?
whole exosome sequencing
30
What are 4characteristics of neoantigens?
Potent T cell response rare Difficult to predict recognised as non-self
31
What is high neoantigen load associated with?
Better survival (65%)
32
Which TLRs are stimulated with adjuvants?
TLR3/7/8/9
33
What are 4 TLR agonists?
TLR4 - MPL TLR3 - poly ICLC TLR7 - imiquimod TLR9 - CpG
34
What are saponins?
Saponin adjuvant with cholesterol & phospholipid to stimulate ER strfess for immune response
35
What are liposomes?
Delivery to endosome & cytosol to stimulate immune response
36
What is NY-ESO-1?
Cancer testis antigen (180aa) expressed in a range of tumours & normal cells
37
What type of response is seen with NY-ESO-1 tumours?
Spontaneous T cell & Ab response
38
How was the NY-ESO-1 vaccine delivered?
Peptide, whole, fusion protein (HSP70) range of adjuvants (CpG, Poly-ICLC, resiquimod, lipid matrices)
39
What is glioblastoma?
Most common form of primary brain tumour in adults - poor survival
40
What is the standard care for Glioblastoma?
Surgery, radiotherapy & chemo (temozolmide) since 2003
41
What vaccine has been made for Glioblastomas?
GlioVac
42
How is GlioVac made?
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
What is added to Glio-Vac?
GM-CSF to stimulate immune response
44
Was survival extended in GlioVac?
Yes
45
What phase is GlioVac in?
Phase 3
46
How are neoantigens being identified?
Comparing tumours to healthy matched control Look at NS, MHC binding screen
47
What are 3 parts of the typical workflow for neoadjuvant idenfication?
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
What is NeoVax?
Phase 1 trial for melanoma Pts
49
What ere given to Pts in NeoVax?
20-mer Neopeptides specific to Pt tumour with Poly-ICLC
50
What was the result of NeoVax?
No recurrence for up to 32 mths in stage III Complete tumor regression after PD-1 therapy for 2 pts in staged 4
51
What is the aim of mRNA use for delivery strategy?
Potent T cell responses
52
What is needed for mRNA vaccine?
CD8+ T cells with CD4+ Requires cytolsic delivery for MHC class I
53
Is an adjuvant added to mRNA?
No mRNA is selfadjuvanting
54
What is a challenge in mRNA vaccines?
APC targeting
55
What did Sahin et al 2017 do?
Melanoma vaccine admistered via percutaneous intranasal injection -> mRNA stability & good translation efficiency -> Dc maturation via TLR7 MHC class II restricted
56
What was the result of Sahin 2017?
2/5 vaccine related responses 1/5 PD-1 + vaccine = complete response
57
How is mRNA delivered to tumour?
Taken up by DC (adaptive) Play with charge -> can enter lymphatic system themselves -> activate DC in spleen (innate)
58
How are neoantigen RNA lipoplex formulations made?
neoepitope discovery mRNA in vitro transcription RNA lipoplex formulation IV injection APC targeting in spleen
59
What is IVAC MUTABOME?
13 Pts combinations of RNA for TAAS with intranodal bossters containing 10 NeoAg RNAs
60
What was the result of IVAC MUTABOME?
5 pts with metastic disease - 2 had objective response & 1 with complete response
61
What was the Keynote trial?
mRNA 4157 neoantigen with Pembro reduced death & metastasis by 65%
62
What is mRNA 4157?
Personalised mRNA encoding 34 different Pt specific neoantigens
63
What are the 4 stages of the Keynote process?
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
What afre advances of Keynote trial?
Merck & Moderna - phase III 1089 Pts II - IV mRNA 4157 + pembrolizumab
65
What are 3 conclusions of using NeoAg?
CD4+ & CD8+ in all vaccinated Pts 60 -70 % immunising NeoAg recognized Complete responses with PD-1 blockers
66
What arfe 3 trials NeoAg used in?
Peptide based eg glioblastoma Poly-epitope RNA based eg. pancreatic Peptide loaded DC vaccine eg . colorectal
67
What 4 things are needed to improve NeoAg?
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

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