Michael Weller Department of Neurology & Brain Tumor Center University Hospital Zurich Frauenklinikstrasse 26 CH-8091 Zurich [email protected]ESMO Preceptorship Programme Immuno-Oncology From the essentials of tumour immunology to clinical application Glioblastoma 3 February 2017 – Madrid, Spain
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� 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)
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
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)