Michael WellerDepartment of Neurology
& Brain Tumor CenterUniversity Hospital Zurich
Frauenklinikstrasse 26CH-8091 Zurich
ESMO Preceptorship Programme
Immuno -Oncology From the essentials of tumour immunology to clinica l application
Glioblastoma3 February 2017 – Madrid, Spain
Disclosures
� Research grants: Acceleron , Actelion , Bayer, Isarna, MSD, Merck & Co, Novocure, OGD2, Piqur, Roche
� Honoraria for lectures or advisory board participation or consulting: BMS, Celldex, Immunocellular Therapeutics, Isarna, Magforce, MSD, Merck & Co, Northwest Biotherapeutics, Novocure, Pfizer, Roche, Teva
• 60 years old male patient
• Diagnosis of glioblastoma in the left temporal lobe 3/2 014
• IDH1 wild-type; MGMT promoter unmethylated
• 3/2014 biopsy
• 4-5/2014 TMZ-based radiochemotherapy
• 6-11/2014 6 cycles of maintenance TMZ
• 11/2014 tumor progression � enrolment CA209-143
Case Report
11/2014Tumor progression
Start Nivolumab
3/2015(Pseudo-)progression?
Decision to continuenivolumab treatment
9/2014During maintenance TMZ
2/20168/20156/2015
Nivolumab
7/2016
• Patient on nivolumab for 27 months (ongoing)
• Clinically stable
• Nivolumab is well tolerated
• SAE: pulmonary embolism 11/2015
(rather unrelated to study drug)
Case Report
Immunosuppression in glioblastoma:challenging a popular assumption
• The brain is an immunoprivileged site: is there nee d for additional immunosuppression?
• Glioblastoma cells (may) lack tumor-specific antige ns: why additional suppression of a „blinded“ immune system ?
• Is there evidence that immune surveillance accounts for the low incidence of systemic metastasis in glioblastom a?
• The increased incidence of glioblastoma in the elde rly may relate to immune senescence, but why is there no in creased risk with immunodeficiency states including AIDS?
Current approaches of immunotherapy for glioblastoma
• Ipilimumab (anti-CTLA-4) (Yervoy , BMS)
• Pembrolizumab (anti-PD-1) (Keytruda , MSD)
• Nivolumab (anti-PD-1) (Opdivo , BMS)
• Atezolizumab (anti-PD-L1) (Roche)
• TGF-β antisense oligonucleotide (Trabedersen®, Antisense P harma/Isarna)
• TGF-β receptor antagonists (LY2157299, Galunisertib®, Lill y)
• Vaccination against EGFRvIII (Rindopepimut, Rintega®, Celldex)
• DC/peptide-based immunotherapy (ICT-107, Immunocellul ar)
• DC/lysate-based immunotherapy (DCVax, NW Biotherapeutics)• Personalized multipeptide vaccination (IMA950, Immatic s→GAPVAC)
• DC/CMV-targeted immunotherapy (Duke)
• IDH-targeted immunotherapy (Heidelberg, and others)
• Chimeric antigen receptor (CAR) therapy (e.g., EGFR vIII)
Expression and prognostic role of PD-L1 in glioblastoma
Current status of the PD-1/PD-L-1 axis in glioblastoma
• PD-L1 is expressed in human glioblastoma in vivo
• TCGA and other public data bases do not define a majorprognostic role for PD-L1 expression in glioblastoma
• The significance as a biomarker of tumoral versus non-tumoral PD-L1 expression remains to be determined in glioblastoma, like in many other cancers
• Preclinical studies demonstrate activity of PD-1 inhibition in rodent glioma models
Current approaches of immunotherapy for glioblastoma
CheckMate 143
CheckMate 143Transition from phase II to III
Trial name / ClinicalTrials.gov Identifier
Target population Treatment arms Phase Primary endpoin t Status (as per March 2016)
CheckMate 143NCT0201771
First recurrence of glioblastoma
Experimental: nivolumabComparator: bevacizumab
III OS Accrual completed
CheckMate 498NCT02617589
Newly diagnosed glioblastomaUnmethylated MGMT promoter
Experimental: RT + nivolumabComparator: TMZ/RT�TMZ
III OS Not yet recruiting
CheckMate 548NCT02667587
Newly diagnosed glioblastomaMethylated MGMT promoter
Experimental: TMZ/RT�TMZ + nivolumabComparator: TMZ/RT�TMZ + placebo
II OS Not yet recruiting
NCT02550249 Newly diagnosed or recurrent glioblastoma requiring surgery
Nivolumab (neoadjuvant, before surgery)
II PD-L1 expression (lymphocytes, tumor)
Recruiting
NCT02311920 Newly diagnosed glioblastoma Arm 1: TMZ + ipilimumabArm 2: TMZ + nivolumabArm 3: TMZ + ipilimumab + nivolumab
I MTD (ipilimumab, nivolumab, combination)
Recruiting
NCT02313272 Recurrent high grade glioma Hypofractionated stereotactic re-RT + bevacizumab + pembrolizumab
I MTD (pembrolizumab) Recruiting
NCT02337491 Recurrent glioblastoma Cohort A: pembrolizumab + bevacizumabCohort B: pembrolizumab
II Cohort A: PFS-6Cohort B: MTD (pembrolizumab)
Not recruiting
NCT02337686 Recurrent glioblastoma Pembrolizumab II PFS-6 Recruiting
NCT02658279 Recurrent glioblastoma, hypermutator phenotype
Pembrolizumab n/a Response rate Recruiting
NCT02336165 Newly diagnosed or recurrent glioblastoma
MEDI4736, Bevacizumab + MEDI4736, RT + MEDI4736
II OS-12, PFS-6, OS-6 (depending on treatment)
Recruiting
Nduom et al. Neuro-Oncology 2015:17:vii9-vii14
Immunosuppression in the glioblastomamicroenvironment
Current approaches of immunotherapy for glioblastoma
• Ipilimumab (anti-CTLA-4) (Yervoy , BMS)
• Pembrolizumab (anti-PD-1) (Keytruda , MSD)
• Nivolumab (anti-PD-1) (Opdivo , BMS)
• Atezolizumab (anti-PD-L1) (Roche)
• TGF-β antisense oligonucleotide (Trabedersen®, Antisense P harma/Isarna)
• TGF-β receptor antagonists (LY2157299, Galunisertib®, Lill y)
• Vaccination against EGFRvIII (Rindopepimut, Rintega®, Celldex)
• DC/peptide-based immunotherapy (ICT-107, Immunocellul ar)
• DC/lysate-based immunotherapy (DCVax, NW Biotherapeutics)• Personalized multipeptide vaccination (IMA950, Immatic s→GAPVAC)
• DC/CMV-targeted immunotherapy (Duke)
• IDH-targeted immunotherapy (Heidelberg, and others)
• Chimeric antigen receptor (CAR) therapy (e.g., EGFR vIII)
TGF-β and immunosuppression in glioblastoma: clinical studies
Current approaches of immunotherapy for glioblastoma
• Ipilimumab (anti-CTLA-4) (Yervoy , BMS)
• Pembrolizumab (anti-PD-1) (Keytruda , MSD)
• Nivolumab (anti-PD-1) (Opdivo , BMS)
• Atezolizumab (anti-PD-L1) (Roche)
• TGF-β antisense oligonucleotide (Trabedersen®, Antisense P harma/Isarna)
• TGF-β receptor antagonists (LY2157299, Galunisertib®, Lill y)
• Vaccination against EGFRvIII (Rindopepimut, Rintega®, Celldex)
• DC/peptide-based immunotherapy (ICT-107, Immunocellul ar)
• DC/lysate-based immunotherapy (DCVax, NW Biotherapeutics)• Personalized multipeptide vaccination (IMA950, Immatic s→GAPVAC)
• DC/CMV-targeted immunotherapy (Duke)
• IDH-targeted immunotherapy (Heidelberg, and others)
• Chimeric antigen receptor (CAR) therapy (e.g., EGFR vIII)
Coexpression of wild-type EGFR and EGFRvIII expression in
glioblastoma
EGFRvIII (L8A4)
EGFRwt (3C6)
Overlap
GB 1097
GB 1097
GB 1122
Rindopepimut (CDX -110)
• Vaccine designed to generate a specific immune response against EGFRvIII-expressing tumors
– “Off the shelf” vaccine recognized across HLA types
– Consists of the EGFRvIII antigen (unique 13 amino acid peptide sequence) chemically conjugated to Keyhole Limpet Hemocyanin
– Delivered as intradermal injection of 500ug rindopepimut with 150ug GM-CSF as an adjuvant
– Stable, lyophilized formulationNOO OS
LEEKKGNYVVTDHC
>30
N KLH
Median (months)
Comparison to Historical Control
ACT III (n=65) 12.3 p = 0.0063
ACT II (n=22) 15.3 p = 0.0029
ACTIVATE (n=18) 14.2 p = 0.0112
Matched historical control (n=17)
6.4
Progression -free survival(from diagnosis)
PFS from diagnosis (months)
Sur
viva
l Pro
babi
lity
ACT III Primary EndpointProgression-free survival (PFS) at 5.5 months from vaccination (≈ 8.5 months from diagnosis):•PFS = 66%•p = 0.0168 vs. null hypothesis (H0) ≤ 53%
Vaccinations begin approximately 3 months after dia gnosis
p = 0.44
Overall survival(from diagnosis)
Sur
viva
l Pro
babi
lity
Median (months)
OS at 24
Months
OS at 36
Months
Comparison to Historical
Control
ACT III (n=65) 24.6 52% 31% p = <0.0001
ACT II (n=22) 24.4 50% 23% p = 0.0034
ACTIVATE (n=18) 24.6 50% 33% p = 0.0003
Matched historical control (n=17)
15.2 6% 6%
Vaccinations begin approximately 3 months after dia gnosis
OS from diagnosis (months)
p = 0.46
Median duration of follow-up: ACT III: 48.7 monthsACT II: 71.8 monthsACTIVATE: 99.3 months
Does Rindopepimut mediate EGFRvIII elimination at
recurrence?
� EGFRvIII was selectively eliminated in recurrent tu mors for 26/32 (81%) patients across all three studies− 15/15 control patients treated with RT/TMZ (+/- CPT- 11,
bevacizumab or erlotinib) were EGFRvIII(+) at recur rence� Robust anti-EGFRvIII titers in most patients; titer s maintained for >
6 months following cessation of treatment
Pre-Vaccine Primary Tumor Post Vaccine Recurrent Tu mor
1. Mehta, et. al. JCO 2011
ACT IV Study DesignAdjuvant Temozolomide and Vaccine
Therapy (TMZ-V, 6-12 cycles)Vaccine Priming
RANDOMIZATION
Vaccine Maintenance
Therapy (VMT)
Follow Up
• Vaccine or control (KLH) is administered Day 22 of each TMZ cycle
• Begin TMZ no sooner than 6 days after administration of the second vaccine priming dose
• Begin TMZ no sooner than 28 days after completion of CRT
• Begin TMZ when ANC ≥ 1000/µL and platelets ≥ 100,000/µL
• TMZ dosed days 1-5 of each 28 day cycle
• Dose vaccine days 1 and 15 of Vaccine Priming cycle
• Start cycle within 4 days after randomization and within 7-14 days after completion of CRT
If no disease progression after TMZ, continue dosing vaccine every 28 days (Day 1 ±3 days of each 28 day cycle) until intolerance or disease progression
Follow-up for overall survival every 12 weeks after disease progression
Temozolomide DosingVaccine or Control (KLH) Dosing
CRT Chemoradiation Therapy
Treatment will be discontinued upon disease progression, unacceptable treatment-related toxicity, or patient refusal to continue study treatment
D1 D15 C1D1 C1D22 C2D22 C3D22 etc…. C1D1 C2D1 etc…
Baseline Patient Characteristics
MRD Population
(Primary Analysis)
ITT Population
(All Randomized)
“Bulky Disease”
Population
Rindopepimut
(n=195)
Control
(n=210)
Rindopepimut
(n=371)
Control
(n=374)
Rindopepimut
(n=175)
Control
(n=163)
Age, years (median [range])
≥65 years
59 (25-80)
24%
57 (19-85)
24%
59 (25-80)
23%
58 (19-85)
23%
58 (33 - 80)
23%
59 (29 - 83)
23%
Male 68% 58% 68% 61% 67% 65%
ECOG PS 0
1
2
51%
44%
5%
49%
46%
5%
45%
51%
5%
45%
50%
6%
37%
58%
5%
40%
54%
6%
MGMT Methylated
Unmethylated
Unknown
35%
55%
10%
35%
57%
9%
33%
60%
6%
35%
58%
7%
31%
66%
2%
35%
60%
5%
RPA class III
IV
V
13%
71%
16%
13%
75%
12%
12%
69%
19%
10%
73%
17%
12%
66%
22%
6%
72%
23%
Time since diagnosis,
months (median [range])
2.8 (2.1-5.3) 2.8 (2.1-4.2) 2.9 (1.7-5.3) 2.8 (2.1-5.4) 2.9 (1.7 - 5.1) 2.9 (2.1 - 5.4)
Prior RT dose, Gy(median [range])
60 (59 - 72) 60 (56 - 66) 60 (40-75) 60 (54-66) 60 (40 - 75) 60 (54 - 65)
Prior TMZ dose, mg/m2
(median [range])
3225
(600 - 4200)
3225
(624 - 4500)
3225
(600-6075)
3225
(624-4575)
3225
(1435 - 6075)
3225
(1470 - 4575)
28
Confidential. For internal, non-promotional use only. Do not distribute.
0 6 12 18 24 30 36 42 480
10
20
30
40
50
60
70
80
90
100
Months from Randomization
.
.
Overall Survival - ITT Population
Median (Mo) (95% CI)
Rindopepimut 17.4 (16.1, 19.4)
Control 17.4 (16.2, 18.8)
HR (95% CI): 0.89 (0.75, 1.07)
Logrank p: 0.22
29
Number at Risk
Rindopepimut 371 345 261 159 72 32 12 7 0
Control 374 347 268 149 73 25 8 4 0
Ov
era
ll S
urv
iva
l (%
)
Primary Endpoint:
Overall Survival - MRD Population
Median (Mo) (95% CI)
Rindopepimut 20.1 (18.5, 22.1)
Control 20.0 (18.1, 21.9)
HR (95% CI): 1.01 (0.79, 1.30)
Logrank p: 0.93
30
Number at Risk
Rindopepimut 195 190 150 102 42 21 7 4 0
Control 210 210 169 101 53 21 7 4 0
Median survival from diagnosis:
Rindopepimut 23.0 (21.4, 25.2)
Control 22.9 (21.0, 24.6)
Ov
era
ll S
urv
iva
l (%
)
Overall Survival - “Bulky Disease” Population
Overall survival by weighted log-rank test:*
Fleming (0,1): p=0.022
Fleming (0,2): p=0.017
* Prespecified exploratory analysis using Harrington and Fleming (1982) method; weight function parameters (r1 = 0, r2 = 1, 2)31
Number at Risk
Rindopepimut 175 155 111 57 30 11 5 3 0
Control 163 145 98 47 19 4 1 0 0
Median (Mo) (95% CI) 2-year OS (95% CI)
Rindopepimut 14.8 (12.8, 17.1) 30% (95% CI 23-37)
Control 14.1 (12.6, 15.7) 19% (95% CI 13-26)
HR (95% CI): 0.79 (0.61, 1.02) p: 0.029
Logrank p: 0.066
ACT IV: MRD Population
Rindopepimut
Control
ACT IV: “Bulky Disease” Rindopepimut
Control
ACT III Study*Rindopepimut
ReACT Study**Rindopepimut
Control
0 1 2 3 4 5 6 7 8 9 10 11 12
Month
107
106
105
104
103
102
101
Ge
om
etr
ic M
ea
n T
ite
r (9
5%
CI)
EGFRvIII expression
• Intensity of baseline EGFRvIII
expression (in this EGFRvIII+
population) did not consistently
correlate with treatment effect
• In small subset with post-
treatment tumor issue, EGFRvIII
elimination rate was similar
across treatment arms, and did
not significantly correlate with
duration on treatment,
magnitude of anti-EGFRvIII titer,
or outcome.
EGFRvIII Expression and Anti-EGFRvIII Immune Response
32
Rindopepimut Control
MRD
Population
16/28 (57%) 17/26 (65%)
“Bulky Disease”
Population
5/9 (56%) 6/13 (46%)
Post-treatment conversion to
EGFRvIII(-) status
Patients providing post-treatment tumor tissue
for PCR analysis.
• Robust response (with median peak titer of 1:25,600) for
rindopepimut-treated patients
• MRD and “bulky disease” populations with similar
magnitude of titers
− Consistent with prior studies in newly diagnosed GBM
• Magnitude of titers did not consistently correlate with
treatment effect
Anti-EGFRvIII Humoral Response
* newly diagnosed GBM, rindopepimut with TMZ (n=65)
** recurrent GBM, rindopepimut with bevacizumab (n=35) or control with bevacizumab (n=37)
Open-label treatment
Randomization (1:1)
Double-blind treatment
ReACT
Bevacizumab refractory (Initial cohort: n=25
Expansion cohort: n=up to 73) Progression during or within two
months of bevacizumab
Bevacizumab naïve (n=70)
No prior bevacizumab or VEGF/ VEGF receptor-targeted agents Control +
bevacizumab
Study vaccine + bevacizumab
Study vaccine + bevacizumab
34 34
HR = 0.53 (0.32, 0.88)p = 0.0137*
Overall Survival
Five patients in the rindopepimut + BV arm, and 1 patient in the control + BV arm, continue survival follow-up without progression per expert review.
* Log-rank test (2-sided) 35
Median, months (95% CI)
OS 12 OS 18 OS 24
Rindopepimut + BV 11.3 (9.9, 16.2) 44% 32% 25%
Control + BV 9.3 (7.1, 11.4) 32% 13% 0%
Per-protocol population analyses: HR = 0.53 (0.31, 0.90)p = 0.0177*
Where do we go from here?
Bevacizumab
Rindopepimut
Current approaches of immunotherapy for glioblastoma
• Ipilimumab (anti-CTLA-4) (Yervoy , BMS)
• Pembrolizumab (anti-PD-1) (Keytruda , MSD)
• Nivolumab (anti-PD-1) (Opdivo , BMS)
• Atezolizumab (anti-PD-L1) (Roche)
• TGF-β antisense oligonucleotide (Trabedersen®, Antisense P harma/Isarna)
• TGF-β receptor antagonists (LY2157299, Galunisertib®, Lill y)
• Vaccination against EGFRvIII (Rindopepimut, Rintega®, Celldex)
• DC/peptide-based immunotherapy (ICT-107, Immunocellul ar)
• DC/lysate-based immunotherapy (DCVax, NW Biotherapeutics)• Personalized multipeptide vaccination (IMA950, Immatic s→GAPVAC)
• DC/CMV-targeted immunotherapy (Duke)
• IDH-targeted immunotherapy (Heidelberg, and others)
• Chimeric antigen receptor (CAR) therapy (e.g., EGFR vIII)
ICT-107:an autologous six -antigen DC vaccine
Six 9-10 amino acid antigen epitopes• MAGE-1 (HLA - A1)• AIM-2 (A1)• gp100 (HLA - A2)• IL-13Rα2 (A2)• HER2/neu (A2)• TRP-2 (A2)
MHC Class I
Matured, Activated, Peptide-loaded DC
Rationale for antigen choice• Targeting multiple antigens minimizes tumor escape• High expression levels for all antigens on GBM samp les• Bias toward TAA associated with cancer stem cells
Control used in Ph II• Matured, activated DC without peptide loading
A phase III randomized double-blind, controlled stu dy of ICT-107 with maintenance temozolomide (TMZ) in newly diagnosed glioblastoma following resection and concomitant TMZ chemoradiotherapy (STING - EORTC 150 7 – Alliance - ICT)
SurgeryScreen
MRIMGMT
and enroll
TMZ/RTEligibility
ConfirmationMRI
Vac
cine
Indu
ctio
n P
hase
Patient-Specific Vaccination• ICT-107 or Control• 1/wk for 4 wks
Mai
nten
ance
P
hase
ConsentHLA-A2 typing
Apheresis Randomize
Week – 2Rest Week
•DC therapy Maintenance Phase:Maintenance with monthly ICT-107 (patient-specific DC therapy) for 11 months, and once every 6 months thereafter until depletion or confirmation of progressive disease. CT-107 and TMZ will be administered two weeks apart during cycle 1 to cycle 6 maintenance TMZ. TMZ will be given Days 1-5 ± 2 days on a 28-day cycle. Study DC therapy will be given on Day 21 ± 2 days.
41
• No vs residual < 1 cm
Stratifications• MGMT• Age• No vs residual < 1 cm3 tumor
Current approaches of immunotherapy for glioblastoma
• Ipilimumab (anti-CTLA-4) (Yervoy , BMS)
• Pembrolizumab (anti-PD-1) (Keytruda , MSD)
• Nivolumab (anti-PD-1) (Opdivo , BMS)
• Atezolizumab (anti-PD-L1) (Roche)
• TGF-β antisense oligonucleotide (Trabedersen®, Antisense P harma/Isarna)
• TGF-β receptor antagonists (LY2157299, Galunisertib®, Lill y)
• Vaccination against EGFRvIII (Rindopepimut, Rintega®, Celldex)
• DC/peptide-based immunotherapy (ICT-107, Immunocellul ar)
• DC/lysate-based immunotherapy (DCVax, NW Biotherapeutics)• Personalized multipeptide vaccination (IMA950, Immatic s→GAPVAC)
• DC/CMV-targeted immunotherapy (Duke)
• IDH-targeted immunotherapy (Heidelberg, and others)
• Chimeric antigen receptor (CAR) therapy (e.g., EGFR vIII)
Heczey, Discov Med 16:287-294, 2013
CD3ζ
CD284-1BB
Chimaeric antigen receptor (CAR) therapy:the molecular concept
Does immunotherapyfor glioblastoma have a future?
• Most promising field of cancer therapy globally
• Immunotherapy requires sophisticated logistics
• Immunotherapy is expensive
• Immunotherapy may only work in young patients with minimal residual tumor (?)
Quadrennial Meeting of the World Federation of Neuro-Oncology WFNO 2017
in conjunction with the Meeting of the European Association of Neuro-Oncology (EANO)
WF
NO
201
7 &
EA
NO
ZURICH, SWITZERLANDKongresshaus Zürich May 4-7, 2017
INVITATION www.eano.eu