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Prof. Lana E. Kandalaft
Director| Centre of Experimental Therapeutics, Deparment of Oncology, UNIL CHUV
Assisant Professor, Ludwig Cancer Reaserch Branch Adjunct Assistant Professor, University of Pennsylvania
Vaccines
2
Immunotherapy Cycle
The Two major Players
3
Immunotherapy Cycle
Reality
Dendritic Cells at the Center
of the Immunological
Universe
Sampling the environment
Sensing pathogens
Trafficking from the periphery
to Lymph Nodes
Presenting antigen
and Shaping the immune response
Inhibiting unwanted responses ( tolerance)
And activating needed responses
The Journal of Experimental Medicine 1973;137:1142-1162.
Nobel Prize winner 2011
Ralph Steinman
What are they doing???
How are they doing it??
Dendritic Cells: Shaping the immune response by the
environmental signal
TLR2:
• bacterial
lipoproteins
• LPS
• peptidoglycans
• …
TLR3:
• double
stranded
RNA
TLR5:
• flagellin
TLR7:
• viral small
molecules
TLR9:
• bacterial DNA
• synthetic DNA
• CpG
TLR4:
• LPS
• Lipid A
• Taxol
• …
• � INFα,β,γ
• � TNFα
• � IL-12
• � MHC II, B7
• …
Dendritic cell activation: Toll-like receptorsDendritic cell activation: Toll-like receptors
Dendritic CellDendritic Cell
• TLR recognize Pathogen-Associated Molecular Patterns (PAMPs)
• TLRs are members of the Pathogen Recognition Receptors (PRR)
Th1 Response Th1 Response O. Michielin
Immature DC Mature DC
Dendritic Cell Maturation :
The control point of cellular immunity
Microbial Products/AdjuvantsTLR, NOD and lectin ligands
LPS, DNA,RNA
Tissue Damage
Uric acid, HSPs
Cells of adaptive Immunity
T and B cells, CD40L
RANK
Cells of Innate Immunity
pDC, NK, NK T, Neutrophils,
IFN, TNF, GM-CSF
Steinman & Mellman
Immature DC
Immature Dendritic Cells allow peripheral tolerance
Steinman & Mellman
Sentinels
Phagocytic
Sampling normal tissue environment
Traffic to LN with self antigens
Instructs Immune system to be tolerant
Mature DC
Mature Dendritic Cells allow immunity
Steinman & Mellman
Trigger maturation
Reduce phagocytosis
Present antigen
Traffic to LN
Interact with T cells
Type I signal
The Different Types of DCs
Immunological Goals of Vaccination
Prophylactic Vaccines
Priming - Generation a new Immune response
Boosting of immune memory
Therapeutic Vaccines
Priming
Generate CD8 T cells able to kill cancer
Reprogram pathogenic ( defective immune responses to protective
ones )
CD4+CD4+
CD8+CD8+
TCRTumor CellTumor Cell
Tumor AgTumor Ag
MHC-I
IL-2 IL-2 +
+
MHC-IMHC-I
MHC-IIMHC-IIMHC-II
B7
CD28
CpGCpG
Vaccination: Activation of DCs
Dendritic CellDendritic Cell
Activated
✓
Tumor CellTumor Cell
Tumor AgTumor Ag
O. Michielin
Peptides and adjuvants
Viral vectors
DNA vaccines
Transduced tumor cells
Random In vivo DC TargetingEx vivo antigen loaded DCs
Anti DC Antibody fused to a certain
antigens and DC activators
Specific In vivo DC Targeting
Dendritic Cells as Targets for vaccination
William B. Coley
Surgical Resident in New York
1890
Retrospective review in hospital records ….
Patient with an inoperable neck sarcoma who had
developed erysipelas and experienced a spontaneous remission
found out that the patient was alive 7 years
Performed a clinical study - He identified a patient with sarcoma- Streptococcal
culture broth – Erythema – regression- another injection – complete tumor
regression – free of tumor for 5 years
When it all began
Chiang CL, Balint K, Coukos G, Kandalaft LE.
Expert Opin Biol Ther. 2015 Jan 2:1-14
Cancer VaccinesDifferent Types
Personalized approaches to active immunotherapy in cancerEran Ophir, Sara Bobisse, George Coukos, Alexandre Harari, Lana E. Kandalaft Biochimica et Biophysica Acta (BBA)- August 2015
Type of Tumor Antigens
?????????
Single Antigen vaccination
Multiple Antigen vaccination
Personalized vaccine
Alexandrov et al., Nature (2013)
The prevalence of somatic mutations across human cancer types
Neoantigen based vaccines are feasible in tumors with high mutational load
Personalized vaccines are warranted
A Personalized NeoAntigen Specific Vaccine
Personalized approaches to active immunotherapy in cancerEran Ophir, Sara Bobisse, George Coukos, Alexandre Harari, Lana E. Kandalaft Biochimica et Biophysica Acta (BBA)- August 2015
Cheryl Chiang
Kandalaft et al, JTM 2013
A Pilot Clinical Trial of Dendritic Cell Vaccine Loaded with
Autologous Tumor for Recurrent Ovarian, Primary Peritoneal OR
Fallopian Tube cancer
VEGF
ANTI-VEGF THERAPY
T CELL HOMING
CYCLOPHOSPHAMIDE
xx xx
xx
Rationale of combining antiangiogenesis therapy and metronomic chemotherapy on
the tumor microenvironment
TREGS
Kandalaft et al, JTM 2013
Antiangiogenic effect
Vaccine induced T cell response responding to TAAs
Tanyi & Kandalaft, under review
PBMC
Pre Post0.0
0.5
1.0
1.5
% R
espo
nder
T c
ells
Pre Post0.00
0.05
0.10
0.15
% R
espo
nder
T c
ells
CTE008
CTE023
CTE025
CTE024
CTE017
0 20 40 60 80 100 120 300 400 500
No Antigen
Mesothelin
NY-ESO1
WT-1
PHA
IFNγ producing cells/105 PBL
Pre Post
100
1000
10000
spot
s/10
5 ce
lls
CTE-0002
CTE-0008
CTE-0010
CTE-0013
CTE-0015
CTE-0016
CTE-0023
CTE-0024
CTE-0017
CTE-0019
CTE-0009
CTE-0010
CD8 T cells
(P=0.13)
CD4 T cells
(P=0.013)
Alex Harari
Sara Bobisse
Vaccine induced T cell response specific to autologous tumor
antigen and achieved Tumor killing
Eran Ophir
% ly
sis
Effector/Target Ratio
R:T cellsR:T cells + MHC-I AbNR:T cells
***
60
40
20
01 3 10 30 90
Tum
or V
olum
e (m
m3)
Days
No T cellsPre-treatment T cellsPost-treatment T cells
***
600
400
200
00 20 40 60
CTE-0001
PBMC
Tanyi & Kandalaft, under review
Vaccine induced T cell response specific correlates with clinical
benefitc
Tanyi&Kandalaft, under review
PF
S (
%)
Vax Non-RespondersVax Responders
p=0.03
100
80
60
40
20
00 5 25201510
Months
Tumor Non-RespondersTumor Responders
p=0.0001
0 5 25201510
Months
100
80
60
40
20
0
Response to vaccine is associated with improved PFS
Eran Ophir
Janos Tanyi
Tanyi & Kandalaft et al, Submitted
Increased Immune response and survival in patientstreated with cyclophosphamide
0 5 10 15 20 250
20
40
60
80
100
Months
Per
cent
Aliv
e
Cy/Bev/OCDC
Bev/OCDC
P=0.012
1
0
1
2
3
4
5
6
Fo
ld e
xpan
sio
n o
f vx-
spec
ific
T c
ells
P=0.002
No Cy Cy
Vaccines must be combined with other drugs
Vaccine In combination with Standard of Care has Benefit
Tanyi, Coukos & Kandalaft, Submitted
WHY ??????
SUCCESSES ~ 10% clinical response rate in late stage patients
Are we still studying them???>?
Summary of required considerations to implement a successful vaccination strategy
Martin Lluesma S, Wolfer A, Harari A, Kandalaft LE.
Biomedicines. 2016 May 3;4(2). pii: E10. doi: 10.3390/biomedicines4020010. Review.
George Coukos
Janos Tanyi
Dan Powell
Cheryl Chiang
Rosemarie Mick
Drew Torigian
Harvey Nisenbaum
Carl June
Bruce Levine
Alex Harari
Sara Bobisse
Eran Ophir
Raphael Genolet
Annalisa Roberti
Brian Stevenson
Christian Iseli
Anita Wolfer
Silvia Martin Lluesma
Our Patients
