Glioblastoma and CNS tumors - OncologyPRO · Glioblastoma and CNS tumors. PRECEPTORSHIP PROGRAMME....
Transcript of Glioblastoma and CNS tumors - OncologyPRO · Glioblastoma and CNS tumors. PRECEPTORSHIP PROGRAMME....
Glioblastoma and CNS tumorsPRECEPTORSHIP PROGRAMME
IMMUNO-ONCOLOGYAmsterdam, 27 May 2017
Patrick RothDepartment of Neurology and Brain Tumor Center
University Hospital Zurich
Melanoma
Challenges in immunooncology
Successful implementation of immunotherapy
Glioblastoma
Blood-brain barrier
Gerstner et al. Nat Rev Clin Oncol 2009
Tumor-mediatedmechanisms:• VEGF• Nitric oxide (NO)• Leukotriens• Prostaglandins
Lymphatic vessels in the CNS
Schläger et al. Nature 2016
The CNS “macro“environment
• The CNS is not immunologically quiescent, activated
lymphocytes can cross the BBB
• Parts of the brain lack a BBB
• The BBB gets partially disrupted in gliomas
• A true lymphatic drainage system exists in the meninges of the
dural venous sinuses
Potent immune cell infiltration and activity is possible
J Immunol 2012; 189:1920-1927
GlioblastomaInfiltrating immune cells
How can we activate the immune system?
• Various approaches: tumor cell lysate, RNA, peptides…
• Best adjuvant remains to be defined
• Focus on peptide vaccines which may activate the immune system very specifically
• Promising data from preclinical models
Vaccination
Surv
ival
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 = <0.0001ACT II (n=22) 24.4 50% 23% p = 0.0034ACTIVATE (n=18) 24.6 50% 33% p = 0.0003Matched historical control (n=17)
15.2 6% 6%
Vaccinations begin approximately 3 months after diagnosis
OS from Diagnosis (Months)
p = 0.46
Median duration of follow-up: ACT III: 48.7 monthsACT II: 71.8 monthsACTIVATE: 99.3 months
RindopepimutPeptide vaccine targeting EGFRvIII
• RT/TMZ completed• EGFRvIII mutation
Adjuvant TMZ/Placebo ►P maintenance
Adjuvant TMZ/Rindopepimut ► R maintenance
• Blinded study vaccine (rindopepimut/GM-CSF or KLH as control)• Priming: 2 injections, 2 weeks after RT/TMZ• During adjuvant TMZ: 1 injection on day 22 of every cycle• Maintenance: 1 injection per month
ACT-IV: trial designNewly diagnosed glioblastoma
Weller et al., SNO meeting 2016
ACT-IV outcomeOverall surival
ReACT (Ctl)
0 1 2 3 4 5 6 7 8 9 10 11 12
Month
107
106
105
104
103
102
101
Geom
etric
Mea
n Ti
ter (
95%
CI)
Anti-EGFRvIII Humoral Response
ACT-IV outcomeHumoral immune response
Weller et al., SNO meeting 2016
ICT-107: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
• Targeting multiple antigens may minimize tumor immune escape
• Promising data in a randomized phase II trial• Phase III trial ongoing: ICT-107 or placebo in addition to
temozolomide-based radiochemotherapy in patiens with newly diagnosed glioblastoma
Targeting the microenvironmentMultiple immunosuppressive mechanims
Glioma cells
Microglial cells
T cells
NK cells
Antigen presentation
cytotoxicityproliferation
TGF-β
+ TGF-β
+ TGF-β
Tumor-derived immunosuppressionIdentification of TGF-β
Time [days]
Sur
vivo
rs [%
]
20
40
60
80
100
0 10 20 30 40
VehicleSD-208
TGF-βMaster immunosuppressive cytokine
vehicle SD-208
HE
CD8
CD11b
Uhl et al., Cancer Res 2004
Conclusions: Galunisertib alone or galunisertib + lomustine failed to demonstrate improved OS relative to lomustine alone. Efficacy outcomes were similar in all 3 arms.
TGF-β inhibitionNot working in human patients…?
Glioma immunobiologyMultiple immunosuppressive mechanims
Glioma cells
Microglial cellsAntigen presentation
cytotoxicityproliferation
CTLA-4
TGF-βLLT-1
GDF-15IL-10Prg-E
Galectin-1PD-L1
PD-1
PD-L1
T cells
NK cells
HLA-E/G
FasL
IDO/TDO
IDO/TDO
STAT3
• Immune checkpoint inhibitors may exert strong anti-tumor activity:
=> Melanoma: anti-CTLA-4 alone vs. anti-PD-1 alone vs. combined treatment
=> Pembrolizumab and nivolumab have been approved for advanced melanoma and other tumor entities
• May these drugs also mount anti-tumor immune responses against neoplasms in the CNS?
Immune checkpoint inhibitors
Checkpoint inhibitors are activeagainst brain metastases
Berghoff et al., Neuro Oncol 2015
Expression of PD-1 and PD-L1 in glioblastoma tissue
• PD-1 expression on tumor-infiltrating lymphocytes (TIL)
– 34/117 (29.1%) specimens with scattered PD1+ TIL infiltration
• Different PD-L1 staining patterns
– Diffuse/fibrillary PD-L1 expressionthroughout the tumor tissue
– Distinct membranous PD-L1 expression in tumor cell aggregates
CheckMate 143Randomized phase III trial
Treatment Phase Follow-up PhaseScreening/Randomization Phase
Treatment until:• Confirmed progression• Unacceptable toxicity• Discontinuation due to
other reason
Follow-up:• Safety for ≥ 100 days• Progression• Survival every 3 months
Patients (N = 369)• First recurrence of GBM• Prior 1L treatment with at least
RT and TMZ
Nivolumab 3 mg/kg Q2Wn = 184
Bevacizumab 10 mg/kg Q2Wn = 185
Randomized 1:1 • Stratified by
measurable disease at baseline (yes/no)
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• The most common AEs leading to discontinuation (> 2 patients in either arm [nivolumab; bevacizumab]) were cerebrovascular accident (0%; 2%) and pulmonary embolism (< 1%; 2%)
• No patient in either arm died due to study drug toxicity
Nivolumabn = 182a
Bevacizumabn = 165a
Any Grade Grade 3/4 Any Grade Grade 3/4
Overall frequencies of AEs, n (%)
AEs leading to discontinuation 18 (9.9) 15 (8.2) 24 (14.5) 13 (7.9)
Serious AEs 84 (46.2) 52 (28.6) 58 (35.2) 39 (23.6)
Neurological AEs 135 (74.2) 41 (22.5) 114 (69.1) 33 (20.0)
Deaths, n (%)DiseaseUnknownOther
152 (83.5)146 (80.2)
4 (2.2)2 (1.1)
137 (83.0)130 (78.8)
5 (3.0)2 (1.2)
CheckMate 143Safety summary
Reardon et al., WFNOS meeting 2017
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Events, n
Median OS [95% CI], months
12-Month OS Rate [95% CI], months
Nivolumab 154 9.8 [8.2, 11.8] 41.8 [34.7, 48.8]
Bevacizumab 147 10.0 [9.0, 11.8] 42.0 [34.6, 49.3]
Events, n
Median PFS [95% CI], months
12-Month PFS Rate [95% CI], months
Nivolumab 171 1.5 [1.5, 1.6] 10.5 [6.5, 15.5]
Bevacizumab 146 3.5 [2.9, 4.6] 17.4 [11.9, 23.7]
Progression-Free Survival
HR = 1.97 [95%CI: 1.57, 2.48]P < 0.0001
NivolumabBevacizumab
Months
0 3 6 9 12 15 18 21 24 27
Prob
abili
ty o
f Pro
gres
sion
-Fre
e Su
rviv
al
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
184 41 27 19 18 12 10 7 1 0185 88 46 32 27 19 12 3 1 0
NivolumabBevacizumab
No. at Risk
Censored
Overall Survival
HR = 1.04 [95%CI: 0.83, 1.30]P = 0.76
NivolumabBevacizumab
Months
Prob
abili
ty o
f Ove
rall
Surv
ival
0 3 6 9 12 15 18 21 24 270.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
184 168 133 96 77 59 39 24 9 0185 169 135 99 72 48 37 14 5 0
NivolumabBevacizumab
No. at Risk
Censored
CheckMate 143Progression-free and overall survival
PFS OS
Reardon et al., WFNOS meeting 2017
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Treatment until progression /
unacceptable toxicity
Patients• Newly diagnosed GBM• MGMT methylated or
indeterminate status
Randomized
Nivolumab + RT + TMZNivolumab
+RT and TMZ
Nivolumab+
TMZ
Placebo + RT + TMZPlacebo
+RT and TMZ
Placebo+
TMZ
CheckMate 548: Nivolumab or placebo in combination with RT + TMZ in newly diagnosed patients with MGMT-methylated or indeterminate GBM
Treatment until progression /
unacceptable toxicity
Patients• Newly diagnosed GBM• MGMT unmethylated
status
Randomized
Nivolumab + RTNivolumab
+RT
Nivolumab
RT + TMZRT+
TMZTMZ
CheckMate 498: Nivolumab or TMZ in combination with RT in newly diagnosed patients with MGMT-unmethylated GBM
PD-1 inhibitionOngoing trials
MMR-deficient tumors may respond better to PD-1 inhibition
Startnivolumab
11/2014 6/20153/20159/2014 10/2015 2/20168/2015 9/2016
Challenges associated with the use of immune checkpoint inhibitors
Pseudoprogression vs. (true) progression61 yo man, recurrent glioblastoma
Roth et al., Neuro Oncol 2017
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Novel approachesCAR T cells
Glioblastoma and CNS tumorsTake home messages
• The particular immunological situation in the CNS does not preclude anti-tumor immune responses
• 2 negative phase III trials with rindopepimut andnivolumab in glioblastoma patients
• Advanced vaccines, checkpoint inhibitors in combination with conventional treatmentmodalities and CAR T cells are currently beingexplored in clinical trials