CHECKPOINT INHIBITORS IN GLIOBLASTOMA

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1 VII Symposium Educacional GEINO Madrid, 3-4 diciembre 2015 CHECKPOINT INHIBITORS IN GLIOBLASTOMA Juan M Sepúlveda Sánchez Unidad Multidisciplinar de Neurooncología Hospital 12 de Octubre

2 Cancer Inmunotherapy Timeline

3 Proportion Alive Ipilimumab, gp100, or Both in Advanced Melanoma (MDX010-20): Survival Comparison HR P Value Arms A vs C Arms B vs C Hodi FS, et al. N Engl J Med. 2010;363: OS, % Ipi + gp100 (n = 403) Yrs Ipilimumab + gp100 (A) Ipilimumab alone (B) gp100 alone (C) Ipi + Placebo (n = 137) gp100 + Placebo (n = 136) Year Year

4 Proportion Alive Ipilimumab: Pooled Survival Analysis from Phase II/III Trials in Advanced Melanoma Ipilimumab CENSORED N = 1861 Median OS (95% CI): 11.4 mo ( ) 3-year OS Rate (95% CI): 22% (20% to 24%) Months Patients at Risk Ipilimumab Schadendorf D, Hodi FS, Robert C, et al. Pooled Analysis of Long-Term Survival Data From Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma. J Clin Oncol 2015;33:

5 Tumor Immunology: Overview perforin granzyme cytokines Activated T cell Resting T cell TUMOR Tumor antigen T cell clonal expansion TCR CD28 LYMPH NODE MHC B7 Dendritic cell

6 Tumor-Derived Immune Suppression Tumors go to great lengths to evade the immune response Systematic studies have identified multiple mechanisms cancers employ to defeat the immune response Immunosuppressive cytokines: TGF-β, IL-4, -6, -10 Immunosuppressive immune cells: T-regs, macrophage Disruption of immune activation signaling: loss of MHC receptor, PDL1,2 expression Goal: therapy strategies that liberate underlying anticancer immune responses Immune checkpoints not even in the picture in 2008! Weiner LM. N Engl J Med. 2008;358:

7 Major Issues of Inmunotherapy in Cancer Treatment -ANTIGEN RECOGNITION BY IMMUNE SYSTEM -TUMOR-DERIVED INMUNOSUPRESION

8 Noninflamed Tumor Phenotype Cytotoxic T cell Poor migration X Endothelial cells Chemokines Macrophage Tumor Poor effector cell trafficking due to: High expression of vascular markers, macrophages, fibroblasts Low inflammation and chemokine expression, few lymphocytes Fibroblasts Gajewski TF, et al. Curr Opin Immunol. 2011;23:

9 Inflamed Tumor Phenotype T cell recruitment Migration PD-L1 High levels of innate immune signals Chemokine expression Cytotoxic T cell Chemokines Tumor Nevertheless, negative immune regulators dominate Inhibitory receptors Anergy Suppressive cells Suppressive enzymes T reg MDSC Gajewski TF, et al. Curr Opin Immunol. 2011;23: Spranger S, Gajewski T. J Immunother Cancer. 2013;1:16.

10 Hoos A, Ibrahim R, Korman A, et al. Development of ipilimumab: contribution to a new paradigm for cancer immunotherapy. Semin Oncol 2010;37: Ipilimumab a Member of Novel Class of Immunotherapeutic Abs: Anti CTLA Costimulation via CD28 binding transduces T-cell activating signals 2. CTLA-4 binding on activated T cells downregulates T-cell responses 3. Blocking CTLA-4 binding enhances T-cell responses T-cell activation T-cell inactivation T-cell activation T cell CTLA-4 T cell T cell TCR MHC CD28 B7 TCR MHC CD28 B7 CTLA-4 TCR MHC CD28 B7 CTLA-4 Ipilimumab APC APC APC

11 Summary of CTLA-4 Blockade Immune-Mediated Toxicities Toxicity appears to be dose related Toxicity-related death occurred in < 1% of cases Common (> 20%) Rash, pruritus Fevers, chills, lethargy Diarrhea/colitis Occasional (3% to 20%) Hepatitis/liver enzyme abnormalities Endocrinopathies: hypophysitis, thyroiditis, adrenal insufficiency Rare (< 2%) Episcleritis/uveitis Pancreatitis Nephritis Neuropathies, Guillain-Barré, myasthenia gravis Lymphadenopathy (sarcoid) Thrombocytopenia Toxic epidermal necrolysis, Stevens- Johnson syndrome Weber JS, et al. J Clin Oncol. 2012;30: Weber JS, et al. J Clin Oncol. 2015;[Epub ahead of print].

12 Inflamed Tumor Phenotype T cell recruitment Migration PD-L1 High levels of innate immune signals Chemokine expression Cytotoxic T cell Chemokines PD1 Tumor Nevertheless, negative immune regulators dominate Blocking PD1:PD-L1 binding might activate immunity within the tumor microenvironment Anergy T reg MDSC Gajewski TF, et al. Curr Opin Immunol. 2011;23: Spranger S, Gajewski T. J Immunother cancer. 2013;1:16.

PD-1 Adaptive Resistance to Immunotherapy Anti PD-1 Anti PD-L1 Tumor cell Interferons PD-L1 can be expressed on tumor cells either endogenously or induced by association with T cells (adaptive immune

13 PD-1 Adaptive Resistance to Immunotherapy Anti PD-1 Anti PD-L1 Tumor cell Interferons PD-L1 can be expressed on tumor cells either endogenously or induced by association with T cells (adaptive immune resistance) [1,2] PD-1:PD-L1 interaction results in T cell suppression (anergy, exhaustion, death) In RCC, melanoma, and other tumors, PD-L1 expression has been shown to be associated with adverse clinical/pathologic features, eg, more aggressive disease and shorter survival [3] 1.Topalian SL, et al. Curr Opin Immunol. 2012;24: Taube JM, et al. Sci Transl Med. 2012;4:127ra Thompson RH, et al. Proc Natl Acad Sci USA. 2004;101:

14 Clinical Development of Inhibitors of PD-1 Immune Checkpoint Target Antibody Molecule Development stage PD-1 PD-L1 Nivolumab (BMS ) Pembrolizumab (MK-3475) Pidilizumab (CT-011) Fully human IgG4 Humanized IgG4 Humanized IgG1 Phase III multiple tumors (melanoma, RCC, NSCLCa, HNSCC) Phase I-II multiple tumors Phase III NSCLC/melanoma Phase II multiple tumors MEDI-4736 Engineered human IgG1 Phase I-II multiple tumors MPDL-3280A Engineered human IgG1 Phase I-II multiple tumors Phase III NSCLC MSB C Fully human IgG1 Phase I solid tumors

15 Nivolumab: Clinical Activity Tumor Type MEL (n = 107) NSCLC (n = 129) RCC (n = 34) Dose, mg/kg ORR (CR/PR), n (%) SD 24 Wks, n (%) Median PFS, Mos Median OS, Mos 1 yr, % 2 yr, % (34) 7 (7) (17) 13 (10) or (29) 9 (27) 7.3 > responses (16 MEL, 6 RCC, and 6 NSCLC) lasted 1 yr among 54 patients with treatment initiation 1 yr before data analysis 13 patients (4 MEL, 6 NSCLC, 3 RCC) demonstrated nonconventional patterns of response but were not included as responders Topalian SL, et al. N Engl J Med. 2012;366: Hodi FS, et al. ASCO Abstract Brahmer JR, et al. ASCO Abstract 8112.

16 Nivolumab: Durability of ORR in Pts With Advanced NSCLC, MEL and RCC Squamous NSCLC Nonsquamous MEL RCC Maximum treatment duration Ongoing response Time to response 65 of 306 pts had ORR (CR/PR): 30 of 65 (46%) responses were evident at first tumor evaluation (8 wks) 42 of 65 (65%) pts had responses lasting > 1 yr 35 of 65 (54%) responses were ongoing at time of data analysis Responses persisted off drug Wks since treatment initiation Topalian SL, et al. ASCO Abstract 3002.

17 MPDL3280A: Tumor Burden Over Time in Urothelial Bladder Cancer Median time to first response was 42 days (range, 38 to 85 days) Median duration of response has not been reached 0.1+ to weeks IHC (IC) 2 or 3 and 0.1+ to 6.0+ weeks for IHC (IC) 0 or 1 Best response is not known for 7 patients. Patients dosed by Nov 20, 2013 ( 6 wk follow-up) with measurable disease at baseline and at least 1 post-baseline measurement. Clinical data cutoff was Jan 1, Powles T, et al. ASCO Abstract 5011.

18 Summary of PD-1/PD-L1 Blockade Immune-Mediated Toxicities Occasional (5-20%) Fatigue Rash: maculopapular and pruritus Topical treatments Diarrhea/colitis Initiate steroids early, taper slowly Hepatitis/liver enzyme abnormalities Infusion reactions Endocrinopathies: thyroid, adrenal, hypophysitis Infrequent (<5%) Pneumonitis Grade 3/4 toxicities uncommon 1. Topalian SL, et al. N Engl J Med. 2012;366: Patnaik A, et al. ASCO Abstract Brahmer JR, et al. N Engl J Med. 2012;366: Herbst RS, et al. ASCO Abstract 3000.

19 Proportion Alive and Progression Free Melanoma. IPI + NIVO Vs Nivo Vs IPI CheckMate 067: PFS Nivo + Ipi (n = 314) Nivo (n = 316) Ipi (n = 315) Median PFS, mos (95% CI) 11.5 ( ) HR (99.5% CI) vs Ipi 0.42 ( )* HR (95% CI) vs Nivo 0.74 ( ) 6.9 ( ) 0.57 ( )* _ 2.9 ( ) Nivo + Ipi Nivo Ipi Mos *Stratified log-rank P < vs Ipi. Exploratory endpoint. Study not powered to detect a statistical difference between Nivo + Ipi and Ni Wolchok JD, et al. ASCO Abstract LBA1. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med 2015;373:23-34.

20 Immune Privilege in the Brain: Old Paradigm Historical belief was that immune privilege in the brain was equivalent to immune isolation [1-3] Presence of BBB Absence of lymphatic drainage system Ability to tolerate foreign antigens without eliciting an inflammatory response Low baseline levels of MHC expression Altered expression of T-cell costimulatory molecules BBB, blood-brain barrier; MHC, major histocompatibility complex. 1. Jackson CM et al. Clin Cancer Res. 2014;20(14): Heimberger AB, Sampson JH. Neuro Oncol. 2011;13(1): Carson MJ et al. Immunol Rev. 2006;213:

21 The BBB is Not an Absolute Barrier to Immune Response Component Effect / Impact on the BBB Glioblastoma cells [1] Glioblastomaassociated vasculature [1-4] Activated T cells [5,6] Release factors that disrupt endothelial tight junctions Display abnormal structural features, including loss or abnormal morphology of tight junctions, as well as increased permeability High levels of Very Late Antigen-4 (VLA-4) and leukocytefunction-associated antigen (LFA-1) allow movement across BBB Can patrol the CNS for antigens in an unrestricted manner Peripheral immune system activation [6] BBB leakiness and movement of activated macrophages and dendritic cells across BBB BBB, blood-brain barrier; CNS, central nervous system; LFA-1, leukocyte-function-associated antigen-1; VLA-4, very late antigen Schneider SW et al. Acta Neuropathol. 2004;107(3): Rascher G et al. Acta Neuropathol. 2002;104(1): Abbott NJ et al. Neurobiol Dis. 2010;37(1): Wolburg H et al. Acta Neuropathol. 2003;105(6): Ransohoff RM et al. Nat Rev Immunol. 2003;3(7): Carson MJ et al. Immunol Rev. 2006;213:

Immune privilege is being redefined: Communication between the CNS and immune system exists Functional lymphatic vessels have been observed in the CNS [7] Microglia, macrophages, astrocytes, and

22 Immune privilege is being redefined: Communication between the CNS and immune system exists Functional lymphatic vessels have been observed in the CNS [7] Microglia, macrophages, astrocytes, and dendritic cells are found within the CNS and may have roles in immune surveillance [2-6] Glioblastoma microenvironment CNS antigens drain through CSF CNS antigens are circulated to cervical lymph nodes [1] Cervical lymph node Activated T cells: [2,3] Cross the BBB Patrol the CNS in an unrestricted manner Return to systemic circulation BBB, blood-brain barrier; CNS, central nervous system; CSF, cerebrospinal fluid. 1. Jackson CM et al. Clin Cancer Res. 2014;20(14): Heimberger AB, Sampson JH. Neuro Oncol. 2011;13(1): Glass R, Synowitz M. Acta Neuropathol. 2014;128(3): Carson MJ et al. Immunol Rev : Ransohoff RM, Engelhardt B. Nat Rev Immunol. 2012;12(9): Jackson C et al. Clin Dev Immunol. 2011: doi: /2011/ Louveau A et al. Nature. 2015;523(7560): doi: /nature

23 GBM-related Inmunosupression

24 Cancer Immunity Cycle Chen DS, et al. Immunity. 39:1-10, 2013.

25 Percent Survival PD-1 and CTLA-4 Blockade Prolonged Survival in a Preclinical Mouse Model GL261 murine glioma tumor-bearing mice were treated with anti-murine CTLA-4 and anti-murine PD-1 or anti-murine PD-L1 blocking antibodies: Days of Treatment IgG control α-ctla-4 α-pd-1 Combo CTLA-4, cytotoxic T-lymphocyte antigen-4; IgG, immunoglobulin G; PD-1, programmed death Reardon DA et al. Poster presentation at ASCO

Trial Design for CheckMate 143 (Nivolumab) CheckMate 143: Ph I/III study of nivolumab as monotherapy or in combination with ipilimumab in GBM [2,3] CD28 OX40 CTLA-4 PD-1 TIM-3 Key Eligibility

[1] LAG-3 Cohort 1 (randomized): Nivo Nivo + ipi Cohort 1c: Nivo + RT + TMZ Cohort 2 (randomized): Nivo Bev Start Date: January 2014 Cohort 1b (nonrandomized): Nivo + ipi Primary Endpoint: Safety and

26 Trial Design for CheckMate 143 (Nivolumab) CheckMate 143: Ph I/III study of nivolumab as monotherapy or in combination with ipilimumab in GBM [2,3] CD28 OX40 CTLA-4 PD-1 TIM-3 Key Eligibility Criteria 1st recurrence* Safety Phase (n=~100) Key Eligibility Criteria Newly diagnosed Phase III (n=340) Key Eligibility Criteria 1st recurrence* CD137 Adapted from Mellman I et al [1] LAG-3 Cohort 1 (randomized): Nivo Nivo + ipi Cohort 1c: Nivo + RT + TMZ Cohort 2 (randomized): Nivo Bev Start Date: January 2014 Cohort 1b (nonrandomized): Nivo + ipi Primary Endpoint: Safety and tolerability Cohort 1d (unmethylated: Nivo + RT Primary Endpoint: OS Secondary Endpoints: OS 12, PFS, ORR * After RT and TMZ. Bev, bevacizumab; GBM, glioblastoma; Ipi, ipilimumab; nivo, nivolumab; ORR, objective response rate; OS, overall survival; OS12, OS at 12 months; PFS, progression-free survival; PD-1, programmed death-1; RT, radiotherapy; TMZ, temozolomide. 1. Mellman I et al. Nature. 2011;480(7378): Sampson J et al. Poster presentation at ASCO Clinicaltrials.gov. NCT

27 Socienty for Neurooncology Nov 2015 Abstracts Related with Checkpoint inhibitors

28 Safety and Activity of Nivolumab Monotherapy and Nivolumab in Combination With Ipilimumab in Recurrent Glioblastoma: Updated Results from CHECKMATE-143 John Sampson, 1 Antonio Omuro, 2 Gordana Vlahovic, 1 Solmaz Sahebjam, 3 Joachim Baehring, 4 David A. Hafler, 4 Alfredo Voloschin, 5 Robert Latek, 6 Vlad Coric, 6a Timothy Cloughesy, 7 Michael Lim, 8 David A. Reardon 9 1 Duke University Medical Center, Durham, NC; 2 Memorial Sloan Kettering Cancer Center, New York, NY; 3 Moffitt Cancer Center, Tampa, FL; 4 Yale School of Medicine, New Haven, CT; 5 Emory University School of Medicine, Atlanta, GA; 6 Bristol-Myers Squibb, Lawrenceville, NJ; 7 University of California, Los Angeles, Los Angeles, CA; 8 The Johns Hopkins Hospital, Baltimore, MD; 9 Dana- Farber Cancer Institute and Harvard University School of Medicine, Boston, MA a At the time this work was conducted, Vlad Coric was affiliated with Bristol-Myers Squibb 28

Study Design and Eligibility Criteria Nivolumab 3 mg/kg Q2W (n=10) Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg Q3W x 4 doses, then nivolumab 3 mg/kg Q2W thereafter (n=10) Nivolumab 3 mg/kg + Ipilimumab 1

29 Study Design and Eligibility Criteria Nivolumab 3 mg/kg Q2W (n=10) Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg Q3W x 4 doses, then nivolumab 3 mg/kg Q2W thereafter (n=10) Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg Q3W x 4 doses, then nivolumab 3 mg/kg Q2W thereafter Eligible patients had no prior bevacizumab treatment and Karnofsky performance status 70 All patients in Cohort 1 had prior surgical resection, radiation, and temozolomide Patients received nivolumab for up to 2 years Imaging for disease assessment occurred every 6 weeks 29

30 Demographics and Clinical Characteristics Characteristic Median age (range), years Age, years, n (%) <65 65 <75 Gender, n (%) Male Female Race, n (%) White Black/African-American Karnofsky performance score, n (%) Histopathologic diagnosis, n (%) Glioblastoma Gliosarcoma MGMT gene promoter methylation status, n (%) Methylated Unmethylated Missing Nivolumab 3 mg/kg (n=10) 59 (42 73) 6 (60) 4 (40) 5 (50) 5 (50) 8 (80) 2 (20) 7 (70) 1 (10) 2 (20) 9 (90) 1 (10) 2 (20) 4 (40) 4 (40) Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg (n=10) 57 (37 68) 7 (70) 3 (30) 6 (60) 4 (40) 10 (100) 0 6 (60) 1 (10) 3 (30) 10 (100) 0 2 (20) 6 (60) 2 (20) 30

31 Patient Disposition Patients in the treatment period, n (%) Continuing on treatment Not continuing on treatment Reason for not continuing on treatment, n (%) Disease progression Study drug toxicity Death a Patient deaths in both treatment arms were due to disease Nivolumab 3 mg/kg (n=10) 1 (10) 9 (90) 9 (90) 0 0 Patients in the study, n (%) Continuing on study 3 (30) Died a 7 (70) Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg (n=10) 0 10 (100) 6 (60) 3 (30) 1 (10) 1 (10) 9 (90) At the time of data cutoff (September 9, 2015), one patient in the nivolumab monotherapy arm continues to receive nivolumab after 17.5 months of treatment No patients receiving nivolumab monotherapy discontinued treatment due to drug toxicity. There were no deaths due to drug toxicity in the monotherapy or combination treatment arms Three patients receiving nivolumab monotherapy remain on study 31

32 Treatment-Related AEs Occurring in 2 Patients in Either Treatment Arm Nivolumab 3 mg/kg (n=10) Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg (n=10) Any Grade Grades 3 4 Any Grade Grades 3 4 Any treatment-related AE, n (%) 9 (90) 0 10 (100) 9 (90) Fatigue 3 (30) 0 8 (80) 1 (10) Diarrhea 1 (10) 0 7 (70) 3 (30) Lipase increased 2 (20) 0 5 (50) 5 (50) AST increased (50) 1 (10) ALT increased (40) 2 (20) Maculopapular rash (40) 0 Vomiting 1 (10) 0 4 (40) 0 Amylase increased 1 (10) 0 3 (30) 1 (10) Headache 2 (20) 0 3 (30) 0 Hyperthyroidism 1 (10) 0 3 (30) 0 Nausea 3 (30) 0 3 (30) 0 Confusional state 1 (10) 0 2 (20) 1 (10) Hypothyroidism 2 (20) 0 1 (10) 0 Rash 2 (20) 0 1 (10) 0 No deaths occurred due to drug-related toxicities 32

33 Investigator-Assessed Objective Responses per RANO Criteria Best overall response, n (%) a Complete response Partial response Stable disease Progressive disease Unable to determine a per RANO criteria Nivolumab 3 mg/kg (n=10) 0 1 (10) 5 (50) 3 (30) 1 (10) Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg (n=10) (40) 6 (60) 0 The majority of patients (6/10) treated with nivolumab monotherapy experienced stable disease or better Four patients in the combination arm achieved best responses of stable disease 33

34 Exploratory Analysis of Overall Survival Median, months (95% CI) Nivolumab 3 mg/kg (n=10) 10.5 (4.1 NE) Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg (n=10) 9.3 ( ) Range, months month rate (95% CI) 9-month rate (95% CI) 12-month rate (95% CI) NE, not estimable 70.0% ( ) 60.0% ( ) 40.0% ( ) 80.0% ( ) 60.0% ( ) 30.0% ( ) 34

35 Baseline PD-L1 Expression a Patients with quantifiable PD-L1 expression at baseline, n (%) Nivolumab 3 mg/kg (n=10) Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg (n=10) 10 (100) 9 (90) 0 <1% 3 (30) 4 (44) 1 <5% 2 (20) 2 (22) 5 <20% 2 (20) 2 (22) 20% 3 (30) 1 (11) Patients without quantifiable PD-L1 expression at baseline, n (%) 0 1 (10) a Tumor PD-L1 assessment was measured in pre-treatment archival or fresh tumor biopsies using BMS/Dako immunohistochemistry assay (rabbit anti-human antibody, clone 28-8) PD-L1 expression 1% was detectable among the majority of patients 35

36 ORR by PD-L1 Expression in Patients with Solid Tumors Rx Antibody Testing Method N PD-L1 + RR PD-L1 - RR Nivolumab [1] Nivolumab [2] MPDL3280A [3] Ipi/Nivo [4] Manual staining 5H1 5% cutoff Tumor staining Dako automated 5% cutoff Tumor staining Automated Roche Dx IHC 1% cutoff Tumor immune cell staining Dako automated 5% cutoff Tumor staining /31 42% 7/17 41% 13/36 36% 8/14 57% 0/18 0% 3/21 14% 9/67 13% 17/42 40% 1. Topalian SL, et al. N Engl J Med. 2012;366: Grosso J, et al. ASCO Abstract Herbst RS, et al. ASCO Abstract Sznol M, et al. ASCO LBA9003.

37 Issues with PD-L1 as a Biomarker PD-L1 negativity an unreliable biomarker Assays are technically difficult, imperfect; results may differ depending on the antibody/assay (tumor vs immune cells) 5% expression, tumor heterogeneity, and inducible gene = sampling error (false negative) Archived tissue different than recent biopsy May be more useful in determining which tumors rather than which patients to treat PD-L1 expression may be less relevant for combination therapies PD-L1 expression might be constitutive (no immune infiltrate)

38 Clinical Trials of Inmune Checkpoint Inhibitors Primary BT and Brain Mets Preusser M, et al. Nat Cancer Rev 2015

39 Other Imnotherapies proposed in GBM

Trial Design for ACT IV (Rindopepimut) ACT IV: Ph III study investigating the addition of rindopepimut to standard of care in newly diagnosed GBM (N=700) EGFRvIII vaccine Key Eligibility Criteria

Start Date: November 2011 Primary Endpoint: OS Secondary Endpoints: PFS, safety and tolerability EGFRvIII, epidermal growth factor receptor variant III; GBM, glioblastoma; GM-CSF, granulocyte

40 Trial Design for ACT IV (Rindopepimut) ACT IV: Ph III study investigating the addition of rindopepimut to standard of care in newly diagnosed GBM (N=700) EGFRvIII vaccine Key Eligibility Criteria Newly diagnosed, EGFRvIII positive GBM Attempted surgical resection followed by conventional chemoradiation No PD after initial therapy Randomized: Rindopepimut (+ GM-CSF) + TMZ KLH (control) + TMZ Start Date: November 2011 Primary Endpoint: OS Secondary Endpoints: PFS, safety and tolerability EGFRvIII, epidermal growth factor receptor variant III; GBM, glioblastoma; GM-CSF, granulocyte macrophage colony-stimulating factor; KLH, keyhole limpet hemocyanin; OS, overall survival; PD, progressive disease; PFS, progression-free survival; TMZ, temozolomide. 1. Clinicaltrials.gov. NCT

$positive, 1st or 2nd relapse* No prior bev or VEGF/VEGFR therapy Single-Arm Portion (n=~100) Key Eligibility Criteria EGFRvIII positive, 1st or 2nd relapse* Bev-refractory Groups 1A and 1B$

41 Trial Design for ReACT (Rindopepimut) ReACT: Ph II study investigating rindopepimut with bevacizumab in relapsed GBM [1,2] EGFRvIII vaccine Randomized Portion (n=70) Key Eligibility Criteria EGFRvIII positive, 1st or 2nd relapse* No prior bev or VEGF/VEGFR therapy Single-Arm Portion (n=~100) Key Eligibility Criteria EGFRvIII positive, 1st or 2nd relapse* Bev-refractory Groups 1A and 1B (randomized): Rindopepimut (+ GM-CSF) + Bev KLH (control) + Bev Group 2/2C: Rindopepimut (+ GM-CSF) + Bev Start Date: December 2011 Primary Endpoint: PFS (Groups 1 and 2), ORR (Group 2C) Secondary Endpoints: Safety and tolerability, antitumor activity, EGFRvIII-specific immune response * Of de novo glioblastoma; for secondary glioblastoma, first diagnosis or first relapse. Bev, bevacizumab; EGFRvIII, epidermal growth factor receptor variant III; GBM, glioblastoma; GM-CSF, granulocyte macrophage colony-stimulating factor; KLH, keyhole limpet hemocyanin; ORR, objective response rate; PFS, progression-free survival; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor. 1. Clinicaltrials.gov. NCT Reardon DA et al. Oral presentation at ASCO

Trial Design for Phase III DCVax-L Trial NCT00045968: Ph III study investigating the addition of DCVax-L to standard of care in newly diagnosed GBM (N=300) DCs pulsed

Start Date: December 2006 Primary Endpoint: PFS Secondary Endpoints: OS, TTP DC, dendritic cell; GBM, glioblastoma; GTR, gross total resection; OS, overall survival; PD,

42 Trial Design for Phase III DCVax-L Trial NCT : Ph III study investigating the addition of DCVax-L to standard of care in newly diagnosed GBM (N=300) DCs pulsed with patient tumor lysate Key Eligibility Criteria Newly diagnosed GBM Received attempted GTR + SOC (RT + TMZ) No PD at end of RT course Randomized: DCVax-L Placebo Start Date: December 2006 Primary Endpoint: PFS Secondary Endpoints: OS, TTP DC, dendritic cell; GBM, glioblastoma; GTR, gross total resection; OS, overall survival; PD, progressive disease; PFS, progression-free survival; RT, radiotherapy; SOC, standard of care; TMZ, temozolomide; TTP, time to progression. 1. Clinicaltrials.gov. NCT

Trial Design for Phase III ICT-107 Trial NCT02546102: Ph III study investigating the addition of DCVax-L to standard of care in newly diagnosed GBM (N=414) Key Eligibility

November 2015 Primary Endpoint: OS Secondary Endpoints: OS by MGMT status, PFS, safety and tolerability DC, dendritic cell; GBM, glioblastoma; HLA, human leukocyte antigen;

43 Trial Design for Phase III ICT-107 Trial NCT : Ph III study investigating the addition of DCVax-L to standard of care in newly diagnosed GBM (N=414) Key Eligibility Criteria Newly diagnosed, HLA-A2 positive GBM Prior tumor resection followed by chemoradiation DCs pulsed with Tumor Antigens Randomized: ICT TMZ Control + TMZ Start Date: November 2015 Primary Endpoint: OS Secondary Endpoints: OS by MGMT status, PFS, safety and tolerability DC, dendritic cell; GBM, glioblastoma; HLA, human leukocyte antigen; MGMT, O6-methylguanine DNA methyltransferase; OS, overall survival; PFS, progression-free survival; TAA, tumor-associated antigen; TMZ, temozolomide. 1. Clinicaltrials.gov. NCT

44 Immunotherapeutic Approaches in GBM: Combination Therapy Several combination therapies are being assessed in glioblastoma and malignant brain tumors: [1,2] Vaccines + Adoptive Cell Transfer Vaccines + Chemotherapy, Targeted Therapy, and/or Radiotherapy Checkpoint Inhibitor Combinations (with other checkpoint inhibitors or other treatment modalities) GBM, glioblastoma. 1. Clinicaltrials.gov. 2. Preusser M et al. Nat Rev Neurol. 2015;11(9): doi: /nrneurol

45 Conclusions -The approval of the first CTLA4 inhibitor, IPILIMUMAB, has provided substantial improvement in cancer treatment. - Potential for inmune checkpoint inhibitors to benefit patients with GBM -Brain is not an imnuno privileged site -Glioblastoma cells express PD1L -Promising results from the first trials with nivolumab (CHECKMATE 143) -Other results with inmunotherapies are expected in 2016: ACT IV, DCVAX

46 VII Symposium Educacional GEINO Madrid, 3-4 diciembre 2015 Muchas Gracias Por su Atención

9/22/2016. Introduction / Goals. What is Cancer? Pharmacologic Strategies to Treat Cancer. Immune System Modulation

9/22/2016. Introduction / Goals. What is Cancer? Pharmacologic Strategies to Treat Cancer. Immune System Modulation Immunomodulatory Therapies in Cancer Treatment Bill O Hara, PharmD, BCPS, BCOP Advanced Practice Pharmacist, Oncology/BMT Thomas Jefferson University Hospital Introduction / Goals What is Cancer? How can