Immuno-Oncologia: verso una immunoterapia di precisione?

Transcription

1 MEDICINA E ASSISTENZA DI PRECISIONE Firenze 22 Novembre 2017 Immuno-Oncologia: verso una immunoterapia di precisione? Anna Maria Di Giacomo Medical Oncology and Immunotherapy Center for Immuno-Oncology SIENA, ITALY

2 Cancer immunotherapy, a very long standing concept The concept that a vaccine could be useful in the treatment of cancer is a long-held hope coming from the observation that patients with cancer who developed bacterial infections experienced remission of their malignancies. The earliest mention of cancer-fighting infections dates to a citation from Ebers papyrus (1550 B.C.) attributed to the Egyptian physician Imhotep (2600 B.C.), who recommended to treat tumors (swellings) with a poultice followed by an incision which would result in infection of the tumor and therefore its regression. In 1896, the surgeon William Coley locally injected streptococcal broth cultures to induce erysipelas in an Italian patient (Mr. Zola) with an inoperable neck sarcoma, obtaining a tumour regression. Although therapy was toxic, the patient's tumour ultimately regressed, and he lived disease-free for 8 years before succumbing to his cancer. Venuti A. J Exp Clin Cancer Res

3 Evolving Therapeutic Options for Cancer Treatment Surgery Chemotherapy Radiotherapy

4 Evolving Therapeutic Options for Cancer Treatment Surgery Chemotherapy Radiotherapy Immunotherapy

5 T-cell Checkpoint and Co-stimulatory Pathways APC/ Tumor T cell CD40 CD40L Activation CD137L OX40L B7-2 (CD86) CD137 OX40 CD28 Activation Activation Activation These pathways can be activated via I-O agents to counteract tumor-mediated inhibition B7-1 (CD80) CTLA-4 Inhibition PD-L1 PD-L2 PD-1 B7-1 (CD80) Inhibition Inhibition LAG-3 Inhibition MHC TCR These pathways can be blocked via I-O agents to counteract tumormediated inhibition Adapted from Pardoll DM APC=antigen-presenting cell; CTLA-4=cytotoxic T-lymphocyte antigen-4; LAG-3=lymphocyte activation gene-3; MHC=major histocompatibility complex; PD-1=programmed death-1; PD-L1=PD ligand-1; PD-L2=PD ligand-2; TCR=T-cell receptor. Pardoll DM. Nat Rev Cancer. 2012;12:

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7 Melanoma as a tool for cancer research Tissue samples readily accessible Adaptable to tissue culture Amenable to testing of novel therapies

8 Immune Checkpoint Inhibitors Provide Durable Longterm Survival for Patients with Advanced Melanoma Overall Survival (%) N=210 N=107 IPI (Pooled analysis) 1 NIVO Monotherapy (Phase 1 CA ) 2 NIVO Monotherapy (Phase 3 Checkmate 066) 3 N=1, Years 1. Schadendorf et al. J Clin Oncol 2015;33: ; 2. Current analysis; 3. Poster presentation by Dr. Victoria Atkinson at SMR 2015 International Congress. 8

9 Immune Checkpoint Pathways CTLA-4 Blockade (ipilimumab) PD-1 Blockade (nivolumab) CTLA-4 = cytotoxic T-lymphocyte-associated antigen 4 ; MHC = major histocompatibility complex; PD-1 = programmed death-1; PD-L1 = programmed death ligand 1; TCR = T-cell receptor.

10 Kaplan Meier Estimates of Survival. Wolchok JD et al. N Engl J Med DOI: /NEJMoa

11 A C E * * * B Baseline 3 weeks after the first dose 20 weeks after the first dose D F * * * Baseline 9 weeks after the first dose 20 weeks after the first dose Danielli R et al, unpublished

12 Immunotherapy in solid tumors with immunomodulating antibodies

13 NSCLC Kaplan Meier Estimates of OS (3 Years Minimum Follow-up) CheckMate 017 (SQ NSCLC) CheckMate 057 (non-sq NSCLC) Nivolumab (n = 135) Docetaxel (n = 137) Nivolumab (n = 292) Docetaxel (n = 290) HR (95% CI): 0.62 (0.48, 0.80) HR (95% CI): 0.73 (0.62, 0.88) OS (%) 1-y OS = 42% OS (%) 1-y OS = 51% 40 Δ18% 2-y OS = 23% 40 1-y OS = 39% Δ12% 2-y OS = 29% 20 1-y OS = 24% 3-y OS = 16% 20 Δ13% 3-y OS = 18% Δ15% Δ10% 2-y OS = 8% 3-y OS = 6% y OS = 16% Δ9% 3-y OS = 9% Months Months No. of patients at risk No. of patients at risk Nivolumab Docetaxel CI = confidence interval; HR = hazard ratio Nivolumab 29 Docetaxel ASCO 2016 Felip E, ESMO Felip E, ESMO 2017

14 Presented By Julie Brahmer at 2017 ASCO Annual Meeting

15 Lawrence et al, Nature 2013

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17 Mutational landscape of tumor according to Clinical Benefit from ipilimumab therapy (Snyder et al., 2014)

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20 Clinical Benefit of Pembrolizumab Treatment According to Mismatch-Repair Status Le DT et al. N Engl J Med 2015; 372:

21 A historical view of immunotherapy Coley in 1891: observation of a tumour regression in a pt who developed a post op infection 1 st tumour associated antigen cloned IFN adjuvant melanoma US (1995) 2010 Provenge US Anti PD 1/ PD L1 for metastatic melanoma, NSCLC, RCC, Bladder, HNSCC, Hodgkin, Merkel, MSI H. Ipilimumab in adjuvant melanoma. Nivolumab + ipilimumab, T VEC in melanoma 1970s 1980s 1990s 2010s 2017 Spontaneous regressions in melanoma: immune component? IL 2 approved in the US for melanoma (1992) 2011 Ipilimumab approved for advanced melanoma Italy 2017 Anti PD 1 in: RCC Hodgkin Melanoma NSCLC...

22 The future of Cancer Immunotherapy Targeting and modulating multiple compartments TUMOR MICRO ENVIRONMENT ICOS GITR LAG3 4 1BB OX 40 TIM3.... IMMUNE SYSTEM Dendritic cell Active T cell Antigens BLOOD VESSELS LYMPH NODE Apoptotic cancer cell Active T cell TUMOR MICROENVIRONMENT Cancer cell TUMOR

23 LAG-3 in T-Cell exhaustion and anti PD-1 resistance + Nivolumab + Anti LAG-3 IO therapy naïve: LAG-3 limits IO response PD-1 PD-L1 Tumor or other infiltrating cell 1 In therapy-naïve patients, constitutive LAG-3 expression may limit the antitumor activity of PD-1 pathway blockade. Anti LAG-3 combined with nivolumab may deepen or increase the durability of responses 1 LAG-3 MHC II Effector CD4 + /CD8 + T cell + Antigen 2 PD-1 + Nivolumab PD-L1 PD-1 MHC II LAG-3 + Nivolumab + Anti LAG-3 2 In patients exposed to PD-1 pathway blockade, adaptive upregulation of LAG-3 expression may lead to treatment resistance and tumor progression. Anti LAG-3 combined with nivolumab may restore T-cell activation and tumor response IO therapy exposed: LAG-3 contributes to resistance Acquires resistance Nivolumab Anti LAG-3 (BMS )

24 Anti-Lymphocyte Activation Gene-3 (anti LAG-3; BMS ) in Combination With Nivolumab in Patients With Melanoma Previously Treated With Anti PD-1/PD-L1 Study design and endpoints BMS Nivolumab (N = 212) Endpoints (dose expansion) Dose-Escalation Phase (advanced solid tumors) Dose-Expansion Phase Melanoma After Prior IO (n = 55) (other tumor-specific cohorts) Preliminary efficacy a (co-primary) Safety/tolerability b (co-primary) Pharmacokinetics and pharmacodynamics Immunogenicity and QTc (secondary) Biomarkers (LAG-3 and PD-L1; exploratory) c a Tumor response evaluated per Response Evaluation Criteria in Solid Tumors (RECIST) v (investigator assessment). b Safety evaluated per Common Terminology Criteria for Adverse Events v during treatment and up to 135 days after discontinuation. c LAG-3 and PD-L1 expression (percent of positive cells within invasive margin, tumor, and stroma) evaluated using immunohistochemistry (IHC) assays on formalin-fixed, paraffin-embedded tumor sections. Immune cell LAG-3 expression ( 1% or < 1%) determined using mouse antibody clone 17B4; tumor cell PD-L1 expression ( 1% or < 1%) determined using Dako PD-L1 IHC 28-8 kit. Ascierto P et al., ASCO 2017

25 Results Efficacy in the Melanoma Prior IO Cohort Table 4. Preliminary evidence of antitumor activity Patients, n (%) Mel Prior IO (n = 48 a ) BOR CR 0 PR b 6 (13) SD 20 (42) PD 16 (33) Clinical progressions c 6 (13) ORR, 95% CI b 6 (13), 4.7, 25 LAG-3 1% (n = 25) 5 (20), 6.8, 41 LAG-3 < 1% (n = 14) 1 (7.1), 0.2, 34 DCR (CR + PR + SD) b 26 (54) LAG-3 1% (n = 25) 16 (64) LAG-3 < 1% (n = 14) 5 (36) BOR, best overall response; DCR, disease control rate. a All response-evaluable patients; all progressed on prior anti PD-1/PD-L1 therapy. b Two responses were unconfirmed. coccurred prior to first radiographic scan.

26 Figure 5. Ongoing clinical follow-up Results Efficacy in the Melanoma Prior IO Cohort Melanoma prior-io cohort * * * * * * 46% (22/48) of patients were still on treatment at data cutoff a Ongoing progression-free survival b Time to progression or death *Patients with an objective response Weeks c asix patients had clinical progression prior to their first scan and are not included in the plot. b Censored on last visit. c Evaluations are planned for every 8 weeks.

27 ICOS Mechanism of Action T cell Priming / Periphery Local Antigen Re-challenge IFN-γ CXCR5, CD40L Proliferation ICOS ICOS-L

28 Activation status of T cells Increased levels of CD4+ICOS+ T cells in patients with different tumor types treated with Ipilimumab A Week 7 mos = 118 wks log-rank test, p = mos = 27 wks CD4+ICOS+ > 4 fold increase; CD4+ICOS+ 4 fold increase Kaplan Meyer curves of overall survival according to the circulating CD4+ICOS+ in A) metastatic melanoma pts treated with ipilimumab at 10mg/Kg within an EAP Di Giacomo et al CII, 2013

29 Summary of GSK anti-icos agonist antibody GSK A humanized, engineered IgG4 anti-icos agonist monoclonal antibody (mab) For the treatment of cancer First-in-class ICOS agonist antibody in development Binds with high affinity to human ICOS Enhances the proliferation, survival and function of antigen activated effector T cells Well tolerated safety profile in pre-clinical studies Strong rationale for combination with other anticancer agents Enhanced survival and function T cell APC ICOS agonist mab (GSK ) ICOS

30 Preclinical Evidence of ICOS Agonist Combination Potential Combination of GSK with Pembrolizumab in human PBMCs induces synergistic IFN-γ production Synergistic combination of surrogate ICOS agonist antibody with checkpoint mabs in mouse tumor models CT26 Tumor Model ICOS + PD1 PD1 ICOS

31 GSK (INDUCE-1) Study Design Part 1A: Monotherapy Dose Escalation N~36 Multiple selected solid tumors Part 1B: Monotherapy Expansion Cohort 1 N~20 Cohort 2 N~20 Cohort 3 N~20 Cohort 4 N~20 Biomarker cohort N~30 Steering Committee Decision Points 1 2 Part 2A: Combination Dose Escalation N~24 N~24 Multiple selected solid tumors Part 2B: Combination Expansion Cohort 1 N~20 Cohort 2 N~20 Cohort 1 N~20 Cohort 2 N~20 Biomarker cohort N~30

32 The future of Cancer Immunotherapy Targeting and modulating multiple compartments TUMOR MICRO- ENVIRONMENT ICOS GITR LAG3 4 1BB OX 40 TIM3.... IMMUNE SYSTEM Dendritic cell Active T cell Antigens BLOOD VESSELS LYMPH NODE Cancer cell Apoptotic cancer cell Active T cell TUMOR MICROENVIRONMENT TUMOR HLA I/II Tumor Associated Antigens Antigen Processing Machinery Co stimulatory Molecules....

33 EPIGENETICS Heritable changes in gene expression not based on modifications of the DNA sequence

34 EPIGENETIC MODIFICATIONS Histone modifications DNA methylation PHARMACOLOGICALLY REVERSIBLE HDAC inhibitors (HDACi) MicroRNA gene silencing DNMTs inhibitors (DNMTi) Maio et al, unpublished

35 Epigenetic Immunomodulation of Cancer cell Maio M. et al., CCR 2015

36 Can epigenetic modulation of neoplastic cells be used to design novel immunotherapeutic approaches in cancer?

37 Epigenetic immuno-sequencing COMBOS Improve host s immune system activity HOST Modulate tumor immunogenicity and immune recognition TUMOR Check-point mab Epigenetic drugs

38 Epigenetic immuno sequencing: the NIBIT M4 Study EUDRACT Tumor Biopsy PBMC Tumor Biopsy PBMC Tumor Biopsy PBMC Guadecitabine W0 W3 W6 W9 5 days q21 W12 TA WK Ipilimumab 4 x q21 W1 W4 W7 W10 FPFV October 12, 2015 A.M. Di Giacomo et al. Semin Oncol, 2015

39 Epigenetic immuno sequencing: the NIBIT M4 Study NCT pts 15mg/m 2 /die 2 DLT 3 pts 30mg/m 2 /die 1 DLT +3 pts 30mg/m 2 /die No DLT 3 pts 45mg/m 2 /die Expand to 16 pts To date 11 out of 19 pts enrolled 2 DLT No DLT Amendment approved Jan 24rd, pts 60mg/m 2 /die 1 DLT +3 pts 60mg/m 2 /die

40 Epigenetic immuno sequencing: the NIBIT M4 Study NCT W0 W3 W6 W9 W12 TA Guadecitabine 5 days q21 WK Ipilimumab 4 x q21 W1 W4 W7 W10 Tumor biopsy PBMC Tumor biopsy PBMC NGS analyses Tumor biopsy PBMC Perifery and tumor immunophenotype Transcriptome RNA Methylome DNA Exome DNA Phenotipic, functional analyses of PBMC IMMUNOSCORE density, location, organization and functional orientation of tumor infiltrating immune cells FFPE

41 The future of Cancer Immunotherapy Targeting and modulating multiple compartments TUMOR MICRO- ENVIRONMENT IDO Arginase Suppressor cells VEGF ICOS GITR LAG3 4 1BB OX 40 TIM3.... IMMUNE SYSTEM Dendritic cell Active T cell Antigens BLOOD VESSELS LYMPH NODE Apoptotic cancer cell Active T cell TUMOR MICROENVIRONMENT Cancer cell TUMOR

42 IDO mediated immunesuppression

43 IDO1 Inhibition Correlates With Increases in TIL Number and Function Infiltrating cells Cytokines PD-1 expression IDO1 inhibition leads to increased number of TILs and decreased suppressor cells in tumors Enhanced IFN-γ secretion from TILs was observed following IDO1 inhibitor treatment IFN=interferon Koblish HK, et al. AACR Poster

44 Combinations of Epacadostat and Checkpoint Inhibition Showed Synergistic Inhibition in Preclinical Models Epacadostat + anti CTLA4 Epacadostat + anti PD-L1 Days Postinoculation Days Postinoculation Combinations of epacadostat and checkpoint inhibition were associated with enhanced T-cell proliferation and cytokine secretion in vivo 1. Spranger S, et al. J Immunother Cancer. 2014;2:3. Data on file, Incyte Corporation 44

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47 The future of Cancer Immunotherapy Targeting Patient-tailored and modulating immunotherapeutic multiple compartments approaches IMMUNE SYSTEM TUMOR TUMOR MICRO- ENVIRONMENT

48 Medical Oncology and Immunotherapy Center for Immuno Oncology University Hospital of Siena Italy Maresa Altomonte Erika Bertocci Luana Calabrò Ornella Cutaia Riccardo Danielli Anna Maria Di Giacomo Carolina Fazio Ester Fonsatti Carla Chiarucci Gianluca Giacobini Andrea Lazzeri Francesca Colizzi Sandra Coral Alessia Covre Elisabetta Fratta Hugues Nicolay Luca Sigalotti Maria Lofiego Patrizia Tunici Antonello Lamboglia Monica Valente Armida D Incecco