Immunterapi ved kreft hva er status? Steinar Aamdal, Professor Avdeling for Kreftbehandling Oslo Universitetssykehus

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1 Immunterapi ved kreft hva er status? Steinar Aamdal, Professor Avdeling for Kreftbehandling Oslo Universitetssykehus

2 Evidence for the role of immune system in tumor rejection Spontaneous regression Regression of metastases after removal of primary tumor Infiltration of tumors by lymphocytes and macrophages Lymphocyte proliferation in draining lymph nodes Higher incidence of cancer after immunosuppression/- immunodeficiency (AIDS, neonates, aged, transplant patients)

3 Evidence for the role of immune system in tumor rejection Spontaneous regression Regression of metastases after removal of primary tumor Infiltration of tumors by lymphocytes and macrophages Lymphocyte proliferation in draining lymph nodes Higher incidence of cancer after immunosuppression/- immunodeficiency (AIDS, neonates, aged, transplant patients)

4 Overall survival (%) Prognostic a tumour infiltrating lymphocytes are identified in many tumour types Example: presence of intratumoural T cells correlates with improved clinical outcome in advanced ovarian carcinoma 1 Also seen in NSCLC, 2 CRC, 3 breast, 4,5 melanoma, 6,7 renal, 8,9 prostate, 10 head and neck, 11 cervical P<0.001 Intratumoural T cells (n=102) Median OS = 50.3 months T cells infiltrating tumour cells 25 0 No intratumoural T cells (n=72) Median OS = 18 months Month No intratumoural T cells: T cells restricted to tissue surrounding tumour a Correlation with improved overall or progression-free survival, disease stage, or therapy outcome; type of lymphocyte dictates where there is a correlation with improved or worsened outcome Figures adapted from Zhang L, et al. N Engl J Med 2003;348(3): , Copyright 2003 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. 1. Zhang L, et al. N Engl J Med 2003;348(3): ; 2. Hiraoka K, et al. Br J Cancer 2006;94(2): ; 3. Galon J, et al. Science 2006;313(5795): ; 4. Mahmoud SM, et al. J Clin Oncol 2011;29(15): ; 5. Loi S, et al. J Clin Oncol 2013;31(7): ; 6. Piras F, et al. Cancer 2005;104(6): ; 7. Azimi F, et al. J Clin Oncol 2012;30(21): Siddiqui SA, et al. Clin Cancer Res 2007;13(7): ; 9. Donskov F, et al. Br J Cancer 2002;87(2): ; 10. Flammiger A, et al. APMIS 2012;120(11): Badoual C, et al. Clin Cancer Res 2006;12(2): ; 12. Piersma SJ, et al. Cancer Res 2007;67(1):

5 The immune system matters

6 First cancer immunotherapy Colye`s toxins William Coley, surgeon in 1888 observed remission of sarcoma in a patient after infection with Streptococcus pyogenes Coley`s toxins: Mixture (Parke Davies)of killed S.pyogens and Serratia, used until 1953.Finally tested out in a clinical trial 1000 cancer patients inconsistent results and sometimes dangerous - Coley ridiculed as a quack But! Contained lipopolysaccarides stimulating: interferon production, NK cells, macrophages, and contained CpG stimulating Toll-Like Receptors (TLR) 9 inducing TH1 immune response. Coley Pharmaceutical acquired by Pfizer (2010) - develop drugs targeting TLR`s

7 History of cancer immunotherapy: key milestones Enthusiasm Phase Skeptisism Phase Renaissance Phase Discovery of the dendritic cell Tumour specific mabs BCG approved for bladder cancer Adoptive T cell immunotherapy IFN-α as adjuvant therapy for melanoma Discovery of checkpoint inhibitor! First immunotherapy approved for prostate cancer (Provengesipuleucel-T, FDA 2011, EMA Sept 2013) 1970s 1980s 1990s 2000s 2011 Immune component to spontaneous regressions in melanoma First tumourassociated antigen cloned (MAGE-1) IL-2 approved for RCC and melanoma (FDA 98) First checkpoint inhibitor (ipilimumab) approved for advanced melanoma (March 2011 FDA, July 2011 EMA, Norway March 2013) Figure adapted with permission from Kirkwood JM. Ca J Clin 2012;62:309 35, Copyright 2012 American Cancer Society; George S, et al. JNCCN 2011;9: ; Garbe C, et al. The Oncologist 2011;16:2 24; Rosenberg SA. Sci Transl Med 2012;4:127ps8; Cheeve, et al. Clin Cancer Res 2011;17: ; Kantoff PW, et al. N Engl J Med 2010;363; Mansh M. Yale J Biol Med 2011;84:381 89; Hodi FS, et al. N Engl J Med 2010;363:711 23

8 First cancer vaccine approved by EMA Sept Sipuleucel-T, Provenge, in prostate cancer Day 1 Leukapheresis Day 1-2 Sipuleucel-T is manufactured Day 2 Patient is infused Apheresis Center ml mononuclear cells Dendreon COMPLETE COURSE OF THERAPY: 3 CYCLES WEEKS 0, 2, and 4 Doctor s Office # cells infused was the maximum # of cells that could be prepared from the leukapheresis product. Median # of nucleated cells per infusion = 3.65 x 10 9 and median # of CD54+ bright cells per infusion = 7.45 x Patients premedicated 30 minutes before each infusion with Tylenol (650 mg) and Benadryl (50 mg). Sipuleucel-T or placebo administered IV over 30 minutes, and patients observed 30 minutes

9 Active immunotherapy using sipuleucel-t in patients with metastatic castrate-resistant prostate cancer Probability of survival (%) In a phase 3 trial, sipuleucel-t prolonged overall survival compared with placebo (median overall survival was 25.8 months with sipulecel-t versus 21.7 months with placebo) Adverse events more frequently reported in the sipuleucel-t group than in the placebo group included chills, fever, and headache Hazard ratio 0.78 ( ) P=0.03 Sipuleucel-T (n=341) 60 Placebo (n=171) Years since randomisation Adapted from Kantoff PW, et al. N Engl J Med 2010;363:

10 Cellular immune response to tumour derived antigens

11 T-celle Priming and Activation

12 T-cell Primiing T-cell activation T-cell inactivation

13 Anti-CTLA-4 1, Ipilimumab, mechanism of action Immune checkpoint inhibitor CTLA-4: Cytotoxic T- Lymphocyte-Antigen-4

14 Immune Checkpoint Inhibitors

15 Proportion of patients alive (%) Immunotherapy using ipilimumab in patients with advanced melanoma Ipilimumab was the first therapy for unresectable or metastatic melanoma ever to improve overall survival in a phase 3 trial Median OS, months 95% CI HR P value Survival rate (%) 1-year 2-year Ipilimumab + gp < Ipilimumab gp Years In clinical trials, most adverse events associated with ipilimumab were immune related and were managed using ipilimumab-specific treatment algorithms 2 The most frequently reported immune-related adverse events associated with ipilimumab monotherapy ( 10%, all grades) in a phase 3 trial were: diarrhea (28%), pruritus (24%), and rash (19%) 1 1. Adapted from Hodi FS, et al. N Engl J Med 2010;363: ; 2. Data on file; Bristol-Myers-Squibb Company, Princeton, NJ

16 Proportion of patients alive (%) Active immunotherapy using ipilimumab in patients with advanced melanoma Ipilimumab was the first therapy in advanced melanoma ever to improve overall survival in a phase 3 trial Median OS, months 95% CI HR P value Survival rate (%) 1-year 2-year Ipilimumab + gp < Ipilimumab gp «tail of the curve» Years In clinical trials, most adverse events associated with ipilimumab were immune related and were managed using ipilimumab-specific treatment algorithms 2 The most frequently reported immune-related adverse events associated with ipilimumab monotherapy ( 10%, all grades) in a phase 3 trial were: diarrhea (28%), pruritus (24%), and rash (19%) 1 1. Adapted from Hodi FS, et al. N Engl J Med 2010;363: ; 2. Data on file; Bristol-Myers-Squibb Company, Princeton, NJ

17 Need special attention

18 Evolution of ipilimumab response: initial PD with durable CR Initial PD with durable late response CR NO iraes Corresponding CT-Scans - Ipilimumab 10mg/kg Screening Baseline Week 12 Week 16 Week 188 Week 188 total Durable & ongoing response Week 176 (-025) without signs of IRAEs Week 12 Initial increase in total tumour burden (mwho PD) Week 16 Responding Dr. Kaan Harmankaya Deptment of Dermatology, Medical University of Vienna, Austria Week 96 ongoing response Dr. Kaan Harmankaya Deptment of Dermatology, Medical University of Vienna, Austria Courtesy of K. Harmankaya, Vienna

19 [TITLE] Presented By Padmanee Sharma, MD, PhD at 2013 ASCO Annual Meeting

20 Long term ipilimumab results?

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23 [TITLE] INFγ IINF NF Presented By Jedd D. Wolchok, MD, PhD at 2013 ASCO Annual Meeting

24 [TITLE] Presented By Mario Sznol, MD at 2013 ASCO Annual Meeting

25 Proportion of patients alive (%) Targeting distinct and potentially complementary immune evasion pathways: anti-pd-1 plus anti-ctla-4 Clinical activity nivolumab a plus ipilimumab on a concurrent or sequenced regimen: phase 1 trial in patients with advanced melanoma year survival 82% 95% CI ( ) Censored 1 mg/kg nivolumab + 3 mg/kg ipilimumab n=17 n= Months Died/treated a Investigational compound; b Data from separate, non-comparative trials; use cross-trial comparisons with caution in the absence data from a randomised, comparative trial 1. Adapted from Wolchok J, et al. Presented at ASCO 2013: oral presentation 9012; 2. Hodi FS, et al. N Engl J Med 2010;363: Sznol M, et al. Presented at ASCO 2013: oral presentation CRA9006 2/17 All concurrent regimen 9/53 53% of patients had grade 3/4 AEs on the concurrent regimen; most were manageable using standard protocols 1 With ~13 months of follow-up, 90% of patients continue to respond 1 Historical 1-year survival rates with ipilimumab or nivolumab monotherapy in patients with advanced melanoma are 45.6% (phase 3) 2 and 62% (phase 1), respectively 3b

26 Regulating the T cell immune response 1,2a Activating receptors CD28 OX40 CD137 Agonistic antibodies T cell stimulation Inhibitory receptors CTLA-4 PD-1 TIM-3 LAG-3 Antagonistic (blocking) antibodies T cell responses are regulated through a complex balance of inhibitory ( checkpoint ) and activating signals Tumours can dysregulate checkpoint and activating pathways, and consequently the immune response Targeting checkpoint and activating pathways is an evolving approach to cancer therapy, designed to promote an immune response a The image shows only a selection of the receptors/pathways involved LAG-3 = lymphocyte-activation gene 3 1. Adapted from Mellman I, et al. Nature 2011:480; ; 2. Pardoll DM. Nat Rev Cancer 2012;12:

27 Pan-tumour potential for immunotherapies Therapies a are being studied for the potential for activity in many different types of cancer, irrespective of mutated genes or tumour histology Pembrolizumab (anti-pd-1) a Selected therapies and tumour types are shown: additional agents are, for example in phase 1 studies in patients with solid tumours accessed 19 August 2013

28 Rationale for combining immunotherapy with other therapeutic modalities Multiple mechanisms of potential synergy between the different treatment modalities Radiation Adhesion molecules (CAM-1) and death receptors (FAS) Peptide pools CD8 T cell Upregulation of MHCI Uploading of antigen processing machinery Chemotherapy Effector immune infiltrate Release of tumour antigens (cascade) Targeted therapies Vascular normalisation T cell initiation Cytokine release Translocation of calreticulin CD8 T cells TAA crosspresentation MDSC Tregs M2 macrophages Dendritic cell TAA Upregulates MHCI Adhesion molecules/ death receptors APM CD8 T cells (homeostatic peripheral expansion) MDSC Tregs Activation of apoptosis Blockage of cell cycle CD8 T cells T cell function 1. Adapted from Hodge JW. Semin Oncol 2012;39: ; 2. Drake CG Ann Oncol 2012;23 Suppl 8:viii41 6; 3. Ménard C, et al. Cancer Immunol Immunother 2008;57: ; 4. Hannani D, et al. Cancer J 2011;17: ; 5. Ribas A at al. Curr Opin Immunol 2013:25:

29 Immunotherapy targeted therapy Immunotherapy Target host Targeted Therapy Target tumor Single agent immunotherapies (ipilimumab) give low but durable response rates Combination? In CRC, EGFR mutations related to PDL-1 expression Single agent targeted therapies (vemurafenib, BRAF inhibitors) give high but nondurable responses

30 [TITLE] Presented By Padmanee Sharma, MD, PhD at 2013 ASCO Annual Meeting

31 [TITLE] Presented By Padmanee Sharma, MD, PhD at 2013 ASCO Annual Meeting

32 Other Immunotherapies Adaptive T-cell therapy with Tumor Infiltrating Lymphocytes - TIL and checkpoint inhibitor? Dendritic cell vaccines transfected with tumor mrna and checkpoint inhibitor? Peptide vaccines + checkpoint inhibitor? --- CAR (Chimeric Antigen Receptor) therapy retargeting T- cells T-VEC Herpes simplex derived oncolytic virus, local injections

33 Immunotherapy studies Avdeling for kreftbehandling OUS Checkpoint inhibitors Ipilimumab Phase II (3), melanoma (BMS) Ipilimumab + nivolumab versus ipilimumab, Phase III, melanoma (BMS) Ipilumumab, Phase III, adjuvant, melanoma (BMS) PD1 inhibitor, Nivolumab, Phase III, versus ipilimumab, melanoma (MSD) PD1 inhibitor, MK-3475, versus DTIC, Phase III, melanoma (MSD) PDI inhibitor, LGX, Phase I, melanoma (Novartis) PD1 inhibitor, MK-3475, Phase I, lung cancer (MSD) PD1 inhibitor, Nivolumab, Phase II, lymphoma (BMS) Dendritic celle vaccines (Section for Cell Therapy), Phase I/II studies Malignant melanoma 3 (OUS) Prostate cancer (OUS) Glioblastoma (OUS) (Ovarian carcinoma) (OUS) Peptide vaccines (Telomerase - and Ras peptide vaccines) Malignant melanoma, Phase I (OUS) Lung cancer (2), Phase I and II (OUS) Pancreatic cancer, Phase I-II (Targovax) Lung cancer, Phase I-II (Ultimovax) Prostate cancer Phase I-II (Ultimovax) Ipilimumab, National Phase IV, malignant melanoma (HOD) Intratumoral injection of LTX -315, solid cancer, Phase I, (Lytix) Radio-immunconjugate, Betalutin, lymphoma (Nordic NanoVector) Lymvac, intratumoral injection of DC, Rituximab + local radiation, lymphoma(ous)

34 Challenges PREDICTIVE MARKERS FOR RESPONSE? DRUG COSTS?

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36 [TITLE] Immunotherapy Checkpoints Presented By Padmanee Sharma, MD, PhD at 2013 ASCO Annual Meeting

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39 Phase III, randomized, Double-Blind study of Nivolumab or Nivolumab + Ipilimumab versus Ipilimumab in advanced melanoma (ongoing) R Ipilimumab Ipilimumab + Nivolumab Nivolumab Protocol CA209067

40 Prostate Cancer Vaccine, Provenge Provenge (DC and fusion protein PAP + GM- CSF) in metastatic asymtomatic/minimal symptomatic androgen independent prostate cancer- survival benfit of 4.1 months from median 21.7 to 25.8 months. First therapeutic cancer vaccine ever approved by FDA (2011) EMA approval in Sept 2013

41 [TITLE] Immunotherapy Checkpoints Presented By Padmanee Sharma, MD, PhD at 2013 ASCO Annual Meeting