Combinations in Immunotherapy. George Coukos, MD, PhD Ludwig Center & Department of Oncology University of Lausanne Lausanne, Switzerland

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1 Combinations in Immunotherapy George Coukos, MD, PhD Ludwig Center & Department of Oncology University of Lausanne Lausanne, Switzerland

2 The Promise Control Chemotherapy/Targeted therapies Immune checkpoint blockade Immunotherapy combinations Enriched population Survival Time 1. Adapted from Ribas A, presented at WCM, Ribas A, et al. Clin Cancer Res 2012;18: Drake CG. Ann Oncol 2012;23(suppl 8):viii41 viii46

3 Immunotherapy outperforms SOC chemotherapy CheckMate 017: 2L SQ-NSCLC nivolumab docetaxel

4 Immune checkpoint inhibitors have demonstrated responses across several tumour types Breast cancer treated with pembrolizumab 1 NSCLC treated with durvalumab 2 Change from baseline in sum of longest diameter of target lesion, % * ORR 19% PD 44% Confirmed complete response (nodal disease) Confirmed partial response Stable disease Progressive disease Best change from baseline (%) PD-L1+ ORR 27% PD NA PD-L1- ORR 5% PD NA Not all patients respond to anti-pdl1/pd1 monotherapy NA = not available; ORR = objective response rate PD-1 = programmed death 1 1. Nanda, et al. SABCS 2014; 2. Rizvi, et al. ASCO 2015; 3. Rosenberg, et al. ECC 2015 Maximum SLD reduction from baseline (%) 100 * UC IC2/3 treated with atezolizumab 3 ORR 27% PD 43% Complete response Partial response Progressive disease Stable disease

5 Broad Pan-Tumor Potential with anti-pd-l1/pd-1 inhibitors: Approximate Monotherapy ORR in All-comers Modified from D. Chen, BioScience Forum, 2015

6 IO-IO Trials summary MEL NSCLC RenCa OvCa SCLC CRC Sarcoma PancrCa SolTu Total Trials Screened Chk+Chk % Chk+V % Chk+V+RT 1 1 1% Chk+A 1 1 1% Chk+IR % Chk+IR+Chemo 2 2 2% V+IR % 85% V+IR+Chemo 1 1 1% V+IR+RT 1 1 1% A+V % A+IR 1 1 1% A+V+IR 2 2 2% IO-IO Trials % % 37% 7% 8% 6% 5% 2% 3% 3% 27% 100% A: ACT IO-IO Trials by status (March 2016) Chemo: Chemotherapy Total 95 Chk: Checkpoint inhibitor Completed 20 IR: Immuno-regulator Terminated 4 RT: Radiotherapy Suspended 5 V: Vaccine Withdrawn 2 Unknown 1 Active, not recruiting 14 Note: V+Cy studies are not included Recruiting 34 in V+IR (considered as Vaccine SOC); Not yet recruiting 15 IR includes IFN, Imiquimod, Sirolimus, IDO-inh, COX2-inh, Bevacizumab, Sunitinib (The list is not exhaustive)

7 IO-IO Trials by starting year IO-IO Trial status by starting year Total 95 Completed Active, not recruiting Recruiting Not yet recruiting < (first in 1991)

8 Clinical Trials testing combinations of Checkpoint inhibitors plus Vaccines (status in March 2016) Country NCT Number Type Interventions Immunological agent used Conditions Phase Title USA NCT CTLA4,PD1+W TC-ALLO Drug: HyperAcute - ipilimumab Melanoma (HAM) Immunotherapy Drug: Ipilimumab Drug: Pembrolizumab Drug: Nivolumab Australia NCT CTLA4+BCG Biological: Bacillus ipilimumab Calmette-Guérin (BCG) anti-ctla-4 Ab vaccine Drug: BCG vaccine Ipilimumab USA NCT CTLA4+DC- PEP Belgium NCT CTLA4+DC- RNA USA NCT CTLA4+PEP- MIX USA NCT CTLA4+PEP- MIX USA NCT CTLA4+PEP- MIX USA NCT CTLA4+PEP- MIX USA NCT CTLA4+PEP- MIX MultiC NCT CTLA4+PEP- MIX anti-ctla-4 Ab pembrolizumab Anti-PD-1 Ab nivolumab (BMS ) Anti-PD-1 Ab HyperAcute Cellular Immunotherapies use allogeneic (disease-specific, not patient-specific), tumor-specific human cell lines that have been modified to express alpha-gal. Biological: maximum CP-675,206 (CTLA4-Blocking Monoclonal Antibody) tolerated dose of anticytotoxic T- MART-1 Peptide-Pulsed Dendritic Cells lymphocyteassociated antigen-4 monoclonal antibody Biological: TriMix-DC and ipilimumab Stage IV Melanoma Metast atic Melanoma Metastatic Melanoma ipilimumab Malignant anti-ctla-4 Ab Melanoma Stage TriMix-DC III Malignant Dendritic cells (DCs) electroporated with mrna encoding Melanoma Stage IV CD70, CD40L and a constitutively active toll-like receptor 4 Biological: MART-1 ipilimumab antigen Biological: anti-ctla-4 Ab gp100 Tyrosinase/gp100/MART-1 Peptides antigen Biological: incomplete Freund's adjuvant Biological: ipilimumab Biologica l: tyrosinase peptide Procedure: adjuvant therapy Biological: MDX-CTLA4 MDX-CTLA4 Antibody Antibody; Tyrosinase/gp100/MART-1 Peptides Melanoma Vaccine Tyrosinase/gp100/MA RT-1 Peptides Melanoma Vaccine Biological: gp100 antigen Biological: incomplete Freund's adjuvant Biological: ipilimumab Biological: gp100 antigen Biological: incomplete Freund's adjuvant Biological: ipilimumab ipilimumab anti-ctla-4 Ab gp100 Peptides Emulsified With Montanide ISA 51 ipilimumab anti-ctla-4 Ab gp100 Peptides Plus Montanide ISA-51 Biological: ipilimumab ipilimumab Biologica anti-ctla-4 Ab l: Tyrosinase/gp100/MART-1 Peptides Tyrosinase/gp100/MA RT-1 Peptides Drug: MDX-010 (anti- CTLA4) monoclonal antibody Biological: MDX-1379 (gp100) Melanoma Peptide Vaccine MDX-010 (anti-ctla4) monoclonal antibody MDX-1379 (gp100) Melanoma Peptide Vaccine MDX-1379 vaccine consists of two gp100 melanoma peptides. Phase 2 Phase 1 Immunotherapy Study for Patients With Stage IV Melanoma A Phase I Study of Intralesional Bacillus Calmette-Guerin (BCG) and Followed by Ipilimumab Therapy in Patients With Advanced Metastatic Melanoma Melanoma (Skin) Phase 1 CP-675,206 (CTLA4-Blocking Monoclonal Antibody) Combined With Dendritic Cell Vaccine Therapy in Treating Patients With Stage III or Stage IV Melanoma That Cannot Be Removed With Surgery Phase 2 Intraocular Phase 1 Melanoma Melano ma (Skin) Autologous TriMix-DC Therapeutic Vaccine in Combination With Ipilimumab in Patients With Previously Treated Unresectable Stage III or IV Melanoma Monoclonal Antibody and Vaccine Therapy in Treating Patients With Stage III or Stage IV Melanoma That Has Been Removed During Surgery Melanoma Phase 1 Novel Adjuvants for Peptide- Based Melanoma Vaccines Intraocular Phase 2 Melanoma Melano ma (Skin) Vaccine Therapy and Monoclonal Antibody Therapy in Treating Patients With Stage IV Melanoma Melanoma (Skin) Phase 2 Monoclonal Antibody With or Without gp100 Peptides Plus Montanide ISA-51 in Treating Patients With Stage IV Melanoma Intraocular Phase 2 Melanoma Melano ma (Skin) Melanoma Metast ases Phase 3 Monoclonal Antibody Therapy and Vaccine Therapy in Treating Patients With Resected Stage III or Stage IV Melanoma MDX-010 Antibody, MDX-1379 Melanoma Vaccine, or MDX- 010/MDX-1379 Combination Treatment for Patients With Unresectable or Metastatic Melanoma Estimated Enrollment Start Date 100 June April April February October August 2001 null January March May September 2004

9 Clinical Trials testing combinations of Vaccines plus Immune Regulators (status in March 2016) Country NCT Number Type Interventions Immunological agent used Conditions Phase Title USA NCT DC-PEP+IR Biological: MART-1 antigen Biological: aldesleukin Biological: gp100 antigen Biological: recombinant CD40-ligand Biological: recombinant interferon gamma Biological: recombinant interleukin-4 Biological: sargramostim Biological: therapeutic autologous dendritic cells Biological: therapeutic tumor infiltrating lymphocytes Biological: tyrosinase peptide Radiation: Candida albicans skin test reagent MART-1/gp100/Tyrosinase Peptide-Pulsed Dendritic Cell Vaccine Treated With CD40 Ligand/Gamma Interferon With Subcutaneous IL-2 USA NCT PEP-MIX+Flt3 Drug: flt3 ligand Drug: gp100 antigen Drug: MART-1 antigen Drug: Montanide ISA-51 Drug: tyrosinase peptide USA NCT PEP- MIX+Flt3L USA NCT PEP-MIX+IFN- A USA NCT PEP-MIX+IFN- G USA NCT PEP- MIX+IMIQ USA NCT PEP- MONO+IR France NCT PEP- MONO+IR Drug: flt3 ligand Drug: gp100 antigen Drug: MART-1 antigen Drug: Montanide ISA-51 Drug: tyrosinase peptide Biological: MART-1 antigen Biological: gp100 antigen Biological: incomplete Freund's adjuvant Biological: recombinant interferon alfa Biological: sargramostim Biological: tyrosinase peptide Biological: A combination of intratumoral IFN-gamma plus systemic vaccination with MELITAC 12.1 Biological: MELITAC 12.1 Drug: Imiquimod Drug: Pegylated Interferon-Alfa 2b (PEG Intron) Drug: GP-100 Peptide Vaccine Drug: Vaccine MAGE-3.A1 peptide, or the NA17.A2 peptide + IL-2, IFN-α and GMCSF, Imiquimod. Flt3 Ligand Flt3 ligand binds to the Flt3 tyrosine kinase receptor and, synergistically with other growth factors, stimulates the proliferation and mobilization of certain bone marrow precursor cells, including CD34+ cells, and dendritic cells Melanoma Peptide Immunization Flt3 ligand binds to the Flt3 tyrosine kinase receptor and, synergistically with other growth factors, stimulates the proliferation and mobilization of certain bone marrow precursor cells, including CD34+ cells, and dendritic cells. melanoma peptide immunization (MART-1, gp100: , gp100: , and tyrosinase) HLA-A2 Multi-Epitope Peptide Vaccine Containing MART-1 (NSC #672643), gp100 (NSC #683472), and Tyrosinase (NSC #699048) Peptides Alone or in Combination With GM-CSF, IFN Alpha-2b, or GM-CSF + IFN Alpha-2b MELITAC 12.1 peptide vaccine A peptide cancer vaccine consisting of an emulsion of a mixture of 12 class I MHCrestricted melanoma peptides and a class II MHC-restricted tetanus toxoid helper peptide Pegylated Interferon-Alfa 2b (PEG Intron) GP-100 Peptide Vaccine Vaccine MAGE-3.A1 peptide, or the NA17.A2 peptide + IL-2, IFN-α and GMCSF, Imiquimod. Melanoma (Skin) Phase 2 Stage IV Phase 2 Melanoma St age IV Renal Cell Cancer Recur rent Renal Cell Cancer Recur rent Melanoma Stage IV Melanoma St age IV Renal Cell Cancer Recur rent Renal Cell Cancer Recur rent Melanoma Melanoma (Skin) Phase 2 Phase 2 Vaccine Therapy Followed by Biological Therapy in Treating Patients With Stage III or Stage IV Melanoma flt3l With or Without Vaccine Therapy in Treating Patients With Metastatic Melanoma or Renal Cell Cancer flt3l With or Without Vaccine Therapy in Treating Patients With Metastatic Melanoma or Renal Cell Cancer Vaccine Therapy With or Without Biological Therapy in Treating Patients With Metastatic Melanoma Melanoma 0 Evaluating the Safety and the Biological Effects of Intratumoral Interferon Gamma and a Peptide- Based Vaccine in Patients With Melanoma Melanoma 0 Combination Therapy of Topical Imiquimod Plus Multipeptide Vaccination for Cutaneous Metastases of Melanoma Melanoma Phase 1 Adjuvant Therapy of Pegylated Interferon- 2b Plus Melanoma Peptide Vaccine Metastatic Melanoma Phase 1 Phase 2 Peptide Vaccination Associated With Tumoral Immunomodulation in Patients With Advanced Metastatic Melanoma Estimated Enrollment Start Date 25 June 1999 null null null February 1998 February 1998 September November January March August 2010

10 Combinations

11 IMA901: A multi-peptide cancer vaccine for treatment of renal cell cancer Phase II Walter et al. Nature Medicine 18, (2012) doi: /nm.2883

12 Immatics announces results of IMPRINT phase 3 clinical trial investigating the addition of IMA901 to standard first-line therapy with sunitinib for advanced/metastatic RCC by Immatics Sep 27, 2015 News, Press Releases IMA901: therapeutic vaccine for renal cell cancer (RCC) consisting of multiple tumor-associated peptides (TUMAPs) confirmed to be naturally presented in human cancer tissue. n=339 R (3:2) 10 x IMA901+ GM-CSF i.d. 10 x IMA901+ GM-CSF i.d. + sunitinib a single infusion of cyclophosphamide (300mg/m2) was given three days prior to the first vaccination to reduce the patient s regulatory T cells The primary endpoint of the phase 3 study was OS with progression free survival (PFS), overall response rate (ORR), safety, with biomarker and immune analyses being secondary endpoints.

13 Conclusions from the Phase III study IMA901 +/- sunitinib No significant difference in OS was found when IMA901 was added to sunitinib standard first line treatment for patients with metastatic RCC. The study did not demonstrate an association between T-cell responses and clinical outcomes in contrast to the phase 2 trial with IMA901, which demonstrated a clear link between the patient s T cell response and OS. The intensity of the immune responses observed in the phase 3 trial when combined with sunitinib was shown to be 3-fold lower than those observed in the previous phase 2 trial, when IMA901 was investigated as single agent.

14 CD3 + Stroma TIL present 55% Islet TIL absent 40% Zhang, et al. N Engl J Med 2003

15 100 P<0.001 CD3 + Stroma Overall survival (%) Immunogenic Intra-tumoural T cells No intra-tumoural T cells Month Non-immunogenic Zhang, et al. N Engl J Med 2003

16 T cell infiltrate is associated with better prognosis in most cancer types Fridman et al, Nature Review Cancer, 2012

17 Absence of TILs predicts failure of PD-L1 blockade Duraiswamy J et al. Cancer Res 2014;74:

18 Tumeh, et al. Nature 2014

19 Mutational load predicts response to pembrolizumab in NSCLC All tumors All tumors P= HR % CI ( ) P= Rizvi, Hellmann, Snyder, Science 2015

20 Mismatch-repair deficient tumors treated with pembrolizumab Le et al, NEJM 2015

21 Immunogenic How do we improve response to PD-1/PD-L1 blockade? What Opportunities for Combinations? Push TILs harder Eliminate more breaks Expand the pool of tumor-reactive T cells

22 New Opportunity Targets for Inflamed/Immunogenic Tumors - T cell (Checkpoint) Targets Agonist and antagonist antibodies 22 Mellman I, Coukos G, Dranoff G (2011) Nature 480

23 New Opportunity Targets for Inflamed/Immunogenic Tumors - T cell (Checkpoint) Targets Agonist and antagonist antibodies PD-L1 and CTLA-4 Ab (Ludwig AZ/Medimmune) PD-1 and LAG-3 Ab (BMS) PD-L1 / CTLA-4 + IL-2 (Ludwig AZ) 23 Mellman I, Coukos G, Dranoff G (2011) Nature 480

24 Park, Rosenberg & Morgan, Trends Biotechnol 2011

25 Success of Adoptive Therapy Using TILs From July 2002 to July 2007, 787 tumors from 402 patients Melanoma were processed for TIL. Active, specific TILs Lung were identified in 269 patients (67%), Head leading & to Neck the eventual treatment of 107 patients (27%). Cervical Ovarian Breast Goff SL et al. J Immunother 2010 Gastric Hepatocellular Pancreatic Colon Multiple myeloma Rosenberg S A et al. Clin Cancer Res 2011

26 Two (or three) immunophenotypes of cancer Immunogenic Immune exclusion Non-Immunogenic Immune ignorance

27 Immune exclusion Opportunities Defeat mechanisms of exclusion PLUS Immune checkpoint blockade T cell activation Vaccines TILs Personalized T cell adoptive therapy

28 The endothelial barrier hypothesis part 1 Zhang, et al. N Engl J Med 2003 Tothill, et al Clin Cancer Research 2008

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30 Blockade of PGE2 + VEGF-A and PD-1 results in positive interactions Tumour volume (mm 3 ) Tumor Volume (mm 3 ) P<0.001 Control ASA+Bev apd1 ASA+Bev+aPD1 Anita Wolfer Lana Kandalaft EORTC / Roche

31 Phase II trial of bevacizumab + aspirin + atezolizumab in platinum-resistant ovarian cancer: trial design Continue treatment until PD Upon progression: continue tumour assessment q9w until PFS2 Bevacizumab 15mg/kg q3w Atezolizumab 1,200mg q3w Bevacizumab 15mg/kg q3w + atezolizumab 1,200mg q3w Recurrent, platinum-resistant ovarian, fallopian tube or primary peritoneal cancer Mandatory biopsy 1:1:1:1 Atezolizumab 1,200mg q3w + aspirin 325mg/day Bevacizumab 15mg/kg q3w + atezolizumab 1,200mg q3w Investigator s choice Optional biopsy Bevacizumab 15mg/kg q3w + atezolizumab 1,200mg q3w + aspirin 325mg/day Pre-cycle 3 Anita Wolfer Lana Kandalaft

32 A PILOT CLINICAL TRIAL OF DENDRITIC CELL VACCINE LOADED WITH AUTOLOGOUS TUMOR FOR RECURRENT OVARIAN, PRIMARY PERITONEAL OR FALLOPIAN TUBE CANCER * Immune Monitoring Cohort 1: OC-DC vaccine alone q 2 weeks Cohort 2: OC-DC vaccine + Bevacizumab (10 mg/kg) q 2 weeks Cohort 3: OC-DC vaccine + Bevacizumab (15 mg/kg) + Cyclophosphamide (200 mg/m 2 ) q 3 weeks Cohort 4: OC-DC vaccine + Bevacizumab (15 mg/kg) + Cyclophosphamide (200 mg/m 2 ) q 3 weeks + Daily 325 mg Enteric Coated Aspirin Lana Kandalaft Dan Powell

33 How do we convert an non-immunogenic to immunogenic tumor?? Opportunities for targeted therapy Pro-inflammatory agents STING agonists TLR agonists Bispecific CD3 Abs Immunocytokine conjugates Potent CAR therapy? DO/H/gc/dds/jul-15 RT Molecular therapy Pathways that sustain EMT, stemness Epigenetic drugs

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35 SBRT + IL-2 in metastatic melanoma Seung et al. Science translational medicine. (2012) 4(137):137ra74.

36 De Palma, Coukos, Hanahan, Cancer Cell 2014

37 Critical components of immune therapy Disruption of homeostatic regulatory mechanisms Vasculature/stroma reprogramming Tumor cell reprogramming Expansion of tumour-reactive T cells

38 CAR T cells comprise scfv-mediated Tumor Cell Specificity Along with Signal 1 (CD3z) and Signal 2 (costimulatory domains) Borrowed from Natural T cell Activation Kershaw et al, Nat Rev Cancer, 2013

39 Strategies to Improve Adoptive Transfer of Tumor Specific T Cells Using Genetic Modification Ho, Greenberg et al, Cancer Cell (2003)

40 THANK YOU