Immunotherapy

Transcription

Immunotherapy

Assistentencurriculum
Adrian Ochsenbein
Universitätsklinik für Medinische Onkologie, Bern
1
Universitätsklinik für Medizinische Onkologie, Inselspital Bern
Overview
 Milestones in Immuno-Oncology
 Immunosurveillance of Cancer
 Immunotherapy
 Antigen-specific Immunotherapy
 Active Immunotherapy
 Passive Immunotherapy
 Immune Checkpoint Blockade
 Blocking B7/CTLA-4 Interaction
 Blocking PD1/PD-L1 Interaction
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Milestones of Immuno-Oncology
First Tumor-Immunotherapy
using bacteria (Wilhelm
Busch)
Tumor Immunosurveillance
Hypothesis (F. Burnet Thomas)
„Magic bulltes“ recognize tumor
cells (Paul Ehrlich)
Vaccination with
bacteria extracts;
William Coley
(Coley-Toxin)
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First allogeneic stem
cell transplantation
in leukemia in
Seattle
(Edward D. Thomas)
Milestones of Immuno-Oncology
Approval of BCG
(Bacillus
Calmette-Guérin) for
bladder cancer
Discovery of
Dendritic cells
First tumorspecific
monoclonal
antibody
First adoptive
T-cell
Immunotherapy
Immune system induces
spontaneous regression of
melanoma
Cloning of first
Tumor-antigen
(MAGE-1)
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Approval of IFN-α as
adjuvant therapy of
melanoma
Approval of
Immunotherapy for
prostate cancer
(Sipuleucel-T)
Discovery of Checkpoint
Inhibitory Molecules
Approval of Rituximab for the
therapy of B-Zell-lymphoma
Approval of IL-2 therapy for
metastatic RCC and
melanoma (US)
Approval of the first
Checkpoint
Inhibitory molecule
Ipilimumab for the
treatment of
metastatic
melanoma
Hanahan D, Cell 2011
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Overview
 Immunotherapy
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Immunosurveillance Hypothesis
- 1909 „… the immune system recognizes and eliminates developing tumors…“
Paul Ehrlich
- 1957
„… the primary function of cellular immunity is in fact not to promote allograft
rejection but rather to protect from neoplastic disease, thereby mainatining
tissue homeostatis in complex multicellular organisms.“
Lewis Thomas
„It is by no means inconceivable that small accumulations of tumour cells may
develop and because of their possession of new antigenic potentialities
provoke an effective immunological reaction with regression of the tumour
and no clinical hint of its existence.“
Sir Macfarlane Burnet
- 1964
„In large, long-lived animals, like most of the warm-blooded vertebrates,
inheritable genetic changes must be common in somatic cells and a
proportion of these changes will represent a step towards malignancy. It is
an evolutionary necessity that there should be some mechanism for
eliminating or inactivating such potentially dangerous mutant cells and it is
postulated that this mechanism is of immunological character.“
Sir Macfarlane Burnet
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Immunosurveillance of
lymphohematopoietic tumors
Higher incidence of lymphomas in patients with congenital or acquired immunodeficiency
→ Immunodeficiency-associated lymphoproliferative disorders (IALD)
extranodal sites
rapid progression
diffuse large cell histology
association with EBV
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congenital :
X - linked agamaglobulinemia
a taxia telangiectasia
0.7%
12 - 15%
acquired:
bone marrow transplantation
heart - lung transplantation
0.5%
10%
Tumors in immunodeficient mice
Shankaran V, Nature 2001
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Spontaneous tumors in immunodeficient mice
RAG2-/-: no B and no T cells
STAT1-/-: defect in IFNg signaling
Shankaran V, Nature 2001
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Successful immunosurveillance in humans?
Ovarian cancer St. III,IV
Zhang et al. NEJM 2003
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Immune responses against cancer

Innate immunity
 Natural killer cells
(NK-Zellen)
 complement
 macrophages
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
Aquired immunity
 antibodies
 helper cells
(CD4+ T-cells)
 Cytotoxic T-cells
(CD8+ T-cells)
Induction of a tumor-specific CTL response
ICAM-1
LFA-1
LFA-3
CD40-CD40L
CD27-CD70
IL-2
Signal 1
+ Signal 2
T
B7
CD28
activation
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Signal 1
T
anergy
deletion
Anti-tumoral immune response
CD8
immature
DC
tumor
CD8
mature
DC
CD8
CD8
CD4
CD4
CD8
B
CD8
DC
lymph node
Ochsenbein AF et al. Cancer Gene Ther 2003
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Escape
TAA
MHC-I
Ferrone S
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Cancer Immunoediting
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Ignorance
Ochsenbein AF et al. Nature 2001
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Tolerance
Crespo J. Current Opinion in Immunology 2013
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Exhaustion
T
T
T
T
T
T
T
T
Exhausted T cell express PD-1!!
Mumprecht S et al. Blood 2009
Riether C et al. Leukemia 2015
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Recruitment of regulatory T cells in
ovarian cancer fosters immune privilege
and predicts reduced survival
Curiel, Nature Medicine 2004
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Overview
 Immunotherapy
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Cancer Immunotherapy
CD8
immature
DC
tumor
CD8
mature
DC
CD8
CD8
CD4
CD4
CD8
B
CD8
DC
Lymph node

Active Immunization





Inactivated tumor cells
Tumor antigens, peptides
Dendritic cells
DNA vaccination
Viral vectors
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
Passive Immunization



Infusion of autologous T
cells
DLI of allogenic T cells after
bone marrow
transplantation
Infusion of monoclonal
antibodies
Cancer Immunotherapy
“It would be as difficult to reject
the right ear and leave the left
ear intact, as it is to immunize
against cancer.”
W.H.Woglom, Cancer Research (1929)
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Shrinkage of melanoma metastasis after
peptide immunisation
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Peptide-based Immunizations
Adjuvants!
The immunologists dirty little secret
Janeway CA, 1989, Cold Spring Harbor Symp. 54,1-13
• enhance immunogenicity
• depot effect
 Aluminium salts
 Tensoactive compouds (Saponin)
 Microorganism-derived adjuvants (LPS, CpG)
 Emulsions (Freund‘s, Montanide)
 Cytokines (GM-CSF)
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Immunotherapy: Peptide Immunization
tumor
antigen
adjuvant
immune
response
clinical
response
(CR+PR)
reference
melanoma
gp100 (g209)-2M
IFA+IL2
28/31
13/31
Rosenberg et al. Nat. Med. 1998
melanoma
MART-127-35
IFA
7/8
1/18
Cormier et al. Cancer J Sci Am
1997
melanoma
gp 100
IFA+IL-12
or GMCSF
16/27
0/27
Rosenberg et al. J. Imm. 1999
melanoma
MART-127-35
IFA
13/25
0/25
Wang et al. Clin Cancer Res. 1999
melanoma adjuvant
(III,IV)
gp100 (210M)+
tyrosinase
IFA+IL-12
37/48
t.t. relaps: 20
month
Lee et al. J Clin Oncology 2001
melanoma
MAGE-3.A1
None
3/25
7/25
Marchand et al. Int J Cancer 1999
melanoma
tyrosinase
GM-CSF
3/18
0/18
Schiebenbogen et al. J
Immunotherapy 1999
melanoma and others
NY-ESO-1
+GM-CSF
12/12
0/12
(7 SD)
Jager et al. PNAS 2001
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Dendritic-cell based vaccines
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Immunotherapy: Dendritic cell Immunization
Tumor
(Stage IV)
antigen
DC
immune
Response
clinical
response
reference
CR+PR
melanoma
tumor lysates
/MAGE-peptides
Mo-DC
11/16
5/16
Nestle et al. Nat. Med. 1998
melanoma
MAGE-3 peptide
Mo-DC
8/8
0/8
Schuler et al. J Immun 2000
melanoma
5 peptides
Mo-Dc
16/16
1 (CR)/16
(8 SD)
Schuler et al. J Exp Med.
2002
melanoma
4 peptides
CD34 derived
16/18
7/17
Banchereau et al. Cancer
Res. 2001
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Negative Phase III trials
(significantly negative!)
EORTC 18961 (Melanoma Stage II)
MMAIT-III (Melanoma Stage III)
- Ganglioside / Carrier / Adjuvants
- allogeneic irradiated melanoma cells
observation
GMK Vaccine
HR 1.57 p=0.03
BCG+Canvaxin
HR 1.26 p=0.04
years
Eggermont AM, ASCO 2010
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% overall survival
% overall survival
BCG+Placebo
month
Morton DL, ASCO 2007
Dendritic cell - based Immunizations
metastatic
castration-refractory
prostate cancer
(n=512)
sipuleucel-T
(3 infusions every 2 wks)
placebo
primary endpoint: OS
2:1 randomisation
HR: 0.78, p=0.03
Median survival:
- sipuleucel T 25.8 mts
- control 21.7 mts
Kantoff PW, NEJM 2010
Kantoff PW, NEJM 2010
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Sipuleucel-T immunization
in prostate cancer
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Sipuleucel-T immunization
in prostate cancer
Immune responses Sipuleucel-T
Immune responses:
A) antibodies
PA2024:
66.2% in sipuleucel-T treated patients
2.9% in controls
PAP:
1.4% in controls
→ correlation with survival
B)
T cell responses
PA2024:
12.1% in controls
PAP:
8.0% in controls
→ no correlation with survival
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Adoptive T cell therapy
Walter EA, NEJM 1995
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Clinical Response
Stable disease
Mixed response
Minor response
Progressive disease
5
1
2
2
(2-21month)
Yee C et al. JEM 2000
Yee C et al. PNAS 2002
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Autologous T cell therapy
after lymphodepletion
1. lymphodepletion: Fludarabin + Endoxan d1-7
2. adoptive transfer of lymphocytes
3. IL-2 i.v.
Dudley et al. Science 2002
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Autologous T cell therapy
after lymphodepletion
Dudley et al. Science 2002
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with chimeric antigen receptors (CAR)
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hinge 4-1BB
CD3z
VH,VL CD19
Porter DL. NEJM. 2010
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Monoclonal Antibodies
immune-mediated
effects
effector cell
target cell
soluble ligands
receptors
Complement component C1q
Fc-g receptors
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bioregulatory effects
tumor size
Role of Fc-Receptors in mAb
treatment with Mabthera and Herceptin
weeks
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Clynes et al. Nat. Med. 2000
Role of Fc-Receptors in mAb
treatment with Erbitux
H histidine
R arginine
F phenylalanine
V valine
39 pts, Cetuximab monotherapy
Zhang W. JCO. 2007
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Novel antibody formats: bispecific antibodies
•
•
•
Phase II trial in refractory B precursor ALL
189 patients
41% compete remissions
Topp MS. Lancet Oncology. 2015
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Overview
 Immunotherapy
 Other pathways
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Immunecheckpoint Modulation
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CTLA-4 blockade
• CD8+ T cell activation
• CD4+ T cell activation
• Inactivation of regulatory T cells (Treg constitutively express CTLA4)
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MDX010-20 trial: Ipilimumab 2. line
Ipilimumab + gp100
Melanoma, St. IV,
inoperable St. IIIc
(n=676)
Ipilimumab
3:1:1 randomisation
gp100
Main Inclusion Criteria
Main Exclusion Criteria
Only adults > 18 years
Previous history of cancer in the last 5 years
Advanced (unresectable or metastatic)
melanoma
Primary ocular melanoma
One or more of the following: IL-2,
dacarbazine, temozolomide, fotemustine, or
carboplatin
Autoimmune disease
All patients were HLA-A2*0201 type; this HLA
type supports the immune presentation of
gp100†
Active, untreated metastases in the central
nervous system
Long-term use of systemic corticosteroids
Hodi FS, NEJM 2010
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MDX010-20 trial: Survival
First radiological assessment 12 wk
Hodi FS, NEJM 2010
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CA184-24: First-line Ipilimumab
Main Inclusion Criteria
Main Exclusion Criteria
Previous history of cancer in the last 5 years
Only adults > 18 years
Primary ocular melanoma
Advanced (unresectable or metastatic)
melanoma
Autoimmune disease
Nor prior chemo- or immune therapy
metastases in the central nervous system
independent of HLA status
Long-term use of systemic corticosteroids
Robert C, N Engl J Med 2011
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CA184-024: survival
First radiological assessment 12 wk
HR (95% CI): 0.72 (0.59–0.87)
Median OS, months: 11.2 vs 9.1
P value: 0.0009
-
36.6% in Ipilimumab arm recieved all 4 doses (chemo+immunotherapy)
65.5% in placebo arm recieved all 4 doses (chemo)
-
≥ 1 maintenance cycle of Ipilimumab was only given to 17% of all pts
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Long term survial after ipilimumab treatment
Wahrscheinlichkeit Gesamtüberleben
• Data summarized of 1.861 melanoma patients
(8 Ph. II-, 2 Ph. III-, 2 Ph. IV-Studien)
1.0
0.9
0.8
0.7
Median OS, month (95% KI): 11,4 (10,7–12,1)
3-year OS, % (95% KI): 22 (20–24)
0.6
0.5
0.4
0.3
0.2
0.1
Ipilimumab
Zensiert
0.0
0
12
24
36
48
60
72
84
96
108
120
120
26
15
5
0
Monate
Patients at risk
Ipilimumab 1.861
839
370
254
192
170
Schadendorf, ESMO 2013
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Ipilimumab: Pattern of Response
first radiological tumor assessment after 12 weeks !
Wolchok JD, Clin Cancer Res 2009
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anti-CTLA-4 blockade:
anti-tumor immunity, autoimmunity
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Ipilimumab adverse events
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33%
40%
5%
4%
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Microenvironment in tumor
Lymph node
effector
T cells
MHC
TCR
TCR
Dendritic B7 CD28
cell
B7 CTLA-4
+++
+++
+++ T-cell
---
Anti-CTLA-4
MHC
T-cell
PD-1
PD-L1
--Anti-PD-1/PD-L1
PD-1
PD-L2
--Anti-PD-1
CTLA-4 signaling
PD-1 signaling
activation phase
effector phase
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tumor cell
Blocking PD-1 / PD-L1 interaction
Topalian SL, N Engl J Med 2012
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Brahmer JR, N Engl J Med 2012
Phase I multidose study anti-PD1 antibody
BMS-936558

296 patients initiated treatment 10/2008 – 02/2012:
NSCLC (122), MEL(104), RCC (34), CRC (19), CRPC (17)
• Median age = 63 years
• ECOG PS=0 (43%) or 1 (53%)
• 47% had received ≥3 prior systemic therapies
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BMS-936558 related Adverse Events
5% of pts (15 of 296) discontinued treatment due to related AEs
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BMS-936558 Clinical activity
Tumor
Type
MEL
NSCLC
RCC
Dose
(mg/kg)
No. pts
ORR (CR/PR)
No. pts (%)
SD 24 wk
No. pts (%)
0.1-10
94
26 (28)
6 (6)
1-10
76
14 (18)
5 (7)
1 or 10
33
9 (27)
9 (27)
 20/31 responses lasted ≥1 year in patients with ≥1 year follow-up
 No ORs were observed in 19 CRC or 13 CRPC patients
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100
NSCLC
Median OS:
9,9 month
80
Overall survial (%)
Overall survival (%)
Clinical activity in different tumor entities
60
40
42%
24%
20
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57
Overall survival (%)
month after treatment start
100
80
70%
100
Melanoma
Median OS:
16,8 month
80
60
62%
43%
40
20
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
Renal cell carcinoma
median OS:
>22 month
60
50%
40
20
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
Topalian ASCO 2013: J Clin Oncol 2013; Hodi F.ECC 2013. Brahmer, WCLC 2013, 2013
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Phase III CA209-066: Nivolumab first line
Eligible patients with
unresectable stage III or IV
melanoma (N=418)
•
•
BRAF wild-type
Treatment-naïve
Stratified by:
•
PD-L1 status†
•
M-stage
Nivolumab
3 mg/kg IV Q2W
+
Placebo
IV Q3W
Double-blind
R
1:1
N=210
(206 treated)
Placebo
IV Q2W
+
Dacarbazine
1000 mg/m2 IV Q3W
Treat until progression*
or unacceptable toxicity
Primary endpoint:
•
OS
Secondary endpoints:
•
PFS
•
ORR
•
PD-L1 correlates
N=208
(205 treated)
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Phase III CA209-066: Nivolumab first line
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Phase III Keynote 6: Pembrolizumab versus Ipilimumab
Ipilimumab
3 mg/kg IV Q3W
X4
Eligible patients with
unresectable stage III or IV
melanoma (N=834)
Stratified by:
•
PD-L1 status†
•
ECOG
•
Line of therapy
R
1:1:1
Pembrolizumab
10mg/kg Q3W
max 24 month
Pembrolizumab
10mg/kg Q2W
max 24 month
treatment-related AE grade 3 to 5:
- pembrolizumab 13.3% and 10.1%
- ipilimumab 19.9%.
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Nivolumab in combination with ipilimumab in
advanced melanoma
Wolchok JD, N Engl J Med 2013
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Nivolumab in refractory Hodgkin’s disease
Ansell SN, N Engl J Med 2015
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Nivolumab in refractory Hodgkin’s disease
Ansell SN, N Engl J Med 2015
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Proportion of patients
Correlation of PD-L1
expression in pretreatment
tumor biopsies with clinical
outcomes ?
Melanoma
17/17
*
16*/25
RCC
9/25
p=0.006
0/17
42 pts include 18 MEL, 10 NSCLC, 7 CRC,
5 RCC, and 2 CRPC.
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NSCLC
Correlation of PD-L1 expression in pretreatment tumor
biopsies with clinical outcomes ?
NSCLC
Melanom
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Classification of tumor antigens
specificity
tolerance
avidity
patient, tumor
-
+++
tumor
-
+++
Cancer-testis antigens
various tumors
-
+++
Differentiation antigens
tissue of origin
+
++
most tumors
++
+
Mutational antigens
Viral antigens
Overexpressed gene
products (oncogens)
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Genetic Basis for Clinical Response
to CTLA-4 Blockade
Alexandrov LB, Nature 2013
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Genetic Basis for Clinical Response
to CTLA-4 Blockade
Snyder A, N Engl J Med 2014
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Synergy with other treatment strategies
Radiotherapy
Adhäsion Moleküle
(CAM-1) und Todesrezeptoren (FAS)
Peptide
Pool
CD8 T-Zelle
Up-Regulierung von MHCI
Uploading of
Antigen
processing
machinery
Chemotherapy
Targeted Therapy
Vaskuläre Normalisierung
T-Zell-Initiation
Effector immune infiltrate
Tumor-AntigenFreisetzung (cascade)
ZytokinFreisetzung
Translokation von
Calreticulin
CD8 T-Zellen
TAA crosspresentation
Dendritische
Zelle
MDSC
Tregs
M2 Makrophagen
TAA
up-reguliert MHCI
Adhäsion Moleküle/
Todesrezeptoren
Antigen processing
machinery
CD8 T-Zellen
(homeostatisch
peripheral expansion)
MDSC
CD8 T-Zellen
T-Zell-Funktion
Tregs
Aktivierung der apoptotischen
Blockade des Zell-Zyklus
APM = antigen processing machinery; TAA = tumor-associated antigen.
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Targeting the «don’t eat me signal» CD47
Majeti R, Cell 2009
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Cancer Immunotherapy 2015
Operation
Immunonkologie
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Strahlentherapie
?
Chemo- &
zielgerichtete
Therapien
77

Immunotherapy

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