ESMO Preceptorship Programme Immuno-Oncology · ESMO Preceptorship Programme ... Glioblastoma 3 February 2017 – Madrid, Spain. Disclosures Research grants: Acceleron, Actelion,

Michael WellerDepartment of Neurology

& Brain Tumor CenterUniversity Hospital Zurich

Frauenklinikstrasse 26CH-8091 Zurich

[email protected]

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


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


Newly diagnosed glioblastomaUnmethylated MGMT promoter

Experimental: RT + nivolumabComparator: TMZ/RT�TMZ

III OS Not yet recruiting


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














TGF-β and immunosuppression in glioblastoma: clinical studies














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)


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:


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














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














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

Documents

ESMO Preceptorship Programme Immuno-Oncology · ESMO Preceptorship Programme ... Glioblastoma 3 February 2017 – Madrid, Spain. Disclosures Research grants: Acceleron, Actelion,