Glioblastoma and CNS tumors

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1 Glioblastoma and CNS tumors PRECEPTORSHIP PROGRAMME IMMUNO-ONCOLOGY Amsterdam, 1 October 2016 Patrick Roth Department of Neurology and Brain Tumor Center University Hospital Zurich

2 Immunology in the CNS The CNS as an immunologically privileged site: Limitations of leukocyte entry imposed by the bloodbrain barrier (BBB) Absence of immune cells/naive T cells in the CNS Lack of CNS lymphatics Does this preclude anti-tumor immune responses in the CNS?

3 Blood-brain barrier Tumor-mediated mechanisms: VEGF Nitric oxide (NO) Leukotriens Prostaglandins Gerstner et al. Nat Rev Clin Oncol 2009

4 Lymphatic vessels in the CNS Schläger et al. Nature 2016

5 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

6 Glioblastoma Infiltrating immune cells How can we activate the immune system? J Immunol 2012; 189:

7 Vaccination 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

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9 Rindopepimut Peptide vaccine targeting EGFRvIII Median (months) OS at 24 Months OS at 36 Months Comparison to Historical Control Survival Probability p = 0.46 ACT III (n=65) % 31% p = < ACT II (n=22) % 23% p = ACTIVATE (n=18) % 33% p = Matched historical control (n=17) % 6% OS from Diagnosis (Months) Vaccinations begin approximately 3 months after diagnosis Median duration of follow-up: ACT III: 48.7 months ACT II: 71.8 months ACTIVATE: 99.3 months

10 ACT-IV: trial design Newly diagnosed glioblastoma RT/TMZ completed EGFRvIII mutation Adjuvant TMZ/Placebo P maintenance Press release March 2016: Trial stopped: no signs of activity for rindopepimut compared to placebo (HR 0.99) 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

11 ICT-107: autologous six-antigen DC vaccine Matured, activated, peptide-loaded DC MHC Class I 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) Targeting multiple antigens may minimize tumor immune escape High expression levels for all antigens on GBM samples Promising data in a randomized phase II trial

12 STING phase III ICT-107 in newly diagnosed GBM Consent HLA-A2 typing Apheresis Randomize Stratifications MGMT Age No vs residual < 1 cm 3 tumor Surgery Screen MRI MGMT and enroll TMZ/RT Eligibility Confirmation MRI Vaccine Induction Phase Patient-Specific Vaccination ICT-107 or Control 1/wk for 4 wks Maintenance Phase DC therapy Maintenance Phase: Maintenance with monthly Week ICT (patient-specific DC therapy) or placebo vaccine for 11 Rest months, Week and once every 6 months thereafter until progression or intolerable toxicity

13 Targeting the microenvironment Multiple immunosuppressive mechanims NK cells TGF-β T cells proliferation cytotoxicity Glioma cells Microglial cells Antigen presentation

14 Tumor-derived immunosuppression Identification of TGF-β + TGF-β + TGF-β

15 TGF-β Master immunosuppressive cytokine vehicle SD HE Vehicle SD-208 Survivors [%] CD Time [days] CD11b Uhl et al., Cancer Res 2004

16 TGF-β inhibition Not working in human patients? Conclusions: Galunisertib alone or galunisertib + lomustine failed to demonstrate improved OS relative to lomustine alone. Efficacy outcomes were similar in all 3 arms.

17 Glioma immunobiology Multiple immunosuppressive mechanims NK cells FasL PD-L1 HLA-E/G STAT3 Glioma cells IDO/TDO TGF-β LLT-1 GDF-15 IL-10 Prg-E Galectin-1 CTLA-4 IDO/TDO T cells PD-L1 PD-1 proliferation cytotoxicity Microglial cells Antigen presentation

18 Immune checkpoint inhibitors 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?

19 Combined inhibition of PD-1 and CTLA-4 signaling in a syngeneic glioma mouse model Wainwright et al., Clin Cancer Res 2014

20 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 expression throughout the tumor tissue Distinct membranous PD-L1 expression in tumor cell aggregates Berghoff et al., Neuro Oncol 2015

21 CheckMate 143 Transition from phase II to III

22 Trial name / ClinicalTrials.go v Identifier Target population Treatment arms Phas e Primary endpoint Status (as per June 2016) CheckMate 143 NCT CheckMate 498 NCT CheckMate 548 NCT NCT NCT NCT First recurrence of glioblastoma Newly diagnosed glioblastoma Unmethylated MGMT promoter Newly diagnosed glioblastoma Methylated MGMT promoter Newly diagnosed or recurrent glioblastoma requiring surgery Newly diagnosed glioblastoma Recurrent high grade glioma Experimental: nivolumab Comparator: bevacizumab Experimental: RT + nivolumab Comparator: TMZ/RT TMZ Experimental: TMZ/RT TMZ + nivolumab Comparator: TMZ/RT TMZ + placebo Nivolumab (neoadjuvant, before surgery) Arm 1: TMZ + ipilimumab Arm 2: TMZ + nivolumab Arm 3: TMZ + ipilimumab + nivolumab Hypofractionated stereotactic re-rt + bevacizumab + pembrolizumab NCT Recurrent glioblastoma Cohort A: pembrolizumab + bevacizumab Cohort B: pembrolizumab III OS Accrual completed III OS Recruiting II OS Not yet recruiting II I I II PD-L1 expression (lymphocytes, tumor) MTD (ipilimumab, nivolumab, combination) MTD (pembrolizumab) Cohort A: PFS-6 Cohort B: MTD (pembrolizumab) Recruiting Recruiting Recruiting Not recruiting NCT Recurrent glioblastoma Pembrolizumab II PFS-6 Recruiting NCT Recurrent glioblastoma, hypermutator phenotype Pembrolizumab n/a Response rate Recruiting NCT Newly diagnosed or recurrent glioblastoma MEDI4736, Bevacizumab + MEDI4736, RT + MEDI4736 II OS-12, PFS-6, OS-6 Recruiting

23 Glioblastoma and CNS tumors Take home messages The particular immunological situation in the CNS does not preclude anti-tumor immune responses Rindopepimut failed to polong survival in patients with newly diagnosed glioblastoma Advanced vaccines and checkpoint inhibitors are currently being explored in clinical trials