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The Medical Need for an Immune Scoring/Profiling for Melanoma and Other Cancer Patients

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Tumor-infiltrating immune cells are heterogeneous between tumor types, and are different from patient to patient. It may includes macrophages, dendritic cells, natural killer cells, naïve and memory …

Tumor-infiltrating immune cells are heterogeneous between tumor types, and are different from patient to patient. It may includes macrophages, dendritic cells, natural killer cells, naïve and memory lymphocytes, B cells and T lymphocytes (which includes various subsets of T cell including regulatory T cells, and cytotoxic T cells). An immune-classification of tumors was proposed based on a simple immune score, quantifying the density and location of immune-cells within the tumor. Although firstly described in colorectal cancer (Galon et al. Science. 2006), the impact of the immune score needs to be evaluated more thoroughly in other tumor types given the universal importance of the immune system in cancers. These immunoscore, correlating with the prognosis of patients, may help to better identify the high-risk patients who would benefit from novel therapeutic approaches, including immunotherapy. For this reason, we hypothesize that the immune score along with other markers are important prognostic biomarkers for metastatic melanoma and potential predictive markers for immunotherapies. Several years ago (Cochrane et al. Mod Pathol 2001), it was demonstrated that a nodal immune suppression due to tumor influence, mediated in part by melanoma-derived materials, reduced the interdigitating dendritic cells area in nodes proximal to the tumor or partly replaced by tumor (like the sentinel lymph nodes). Moreover, it was recently identified a 12-chemokine gene expression signature which can predict the presence of the tumor-localized ectopic lymph node-like structures (TL-ELNs) in metastatic melanoma samples. The TL-ELNs seems to be associated, in metastatic melanoma, with a better patient outcome (Messina JL, et al. Sci Rep. 2012). The immunoscore and the gene signature represent the new challenge in the field of biomarkers. Several findings support the hypothesis that cancer development is influenced by the host immune system. The evaluation of systemic and local immunological biomarkers could offer useful prognostic information and facilitate clinical decision about the need for systemic treatment (Galon et al. J Transl Medicine 2012).





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  • 1. Paolo A. Ascierto, MDUnit Melanoma, Cancer Immunotherapy and Innovative TherapyIstituto Nazionale Tumori – Fondazione “G. Pascale”, Napoli, ItalyThe Medical Need for anImmune Scoring/Profiling forMelanoma and Other CancerPatients
  • 2. Why is Immune important?
  • 3. Friedman et al. Nature Reviews Cancer 2012; 12, 298-306
  • 4. Tumor peripheryTumorH&E sectionsTumor centerIHC which showsthe tumor (cyan)and the T cellwith the CD3(brown)The basis of the Immunoscore
  • 5. Courtesy of Jerome Galon
  • 6. Concept: An Immunoscore for Several Diseases(Lymphocytic infiltration and survival benefit published fordecades)…Pages 2005, Galon 2006, Hojo 2007, Laghi 2009, Katz 2009, Mlecnik 2009,…• colorectal• gastric• endometrial• cervical• urothelial• melanoma• head & neck• bladder• breast• ovarian• esophageal• renal• prostate• lung• hepatocellular• …Lee 2008,…De Jong 2009,…Piersma 2007,…Sharma 2007,…Gao 2007,…Clark 1989, Tefany 1991, Mackensen 1993, Clemente 1996, Taylor 2007,…Nakano 2001,…Vesalainen 1994, Karja 2005, Richardsen 2008,…Ito 2005, Hiraoka 2006, Dieu-Nosjean 2008, Al-Shibli 2008, Kawai 2008,…Schumacher 2001, Cho 2003,…Zhang 2003, Sato 2005,…Marrogi 1997, Menegaz 2008,…Sharma 2007,…Reichert 2001, Shibuya 2002, Badoual 2006,…
  • 7. What inMelanoma ?
  • 8. Korn E. et al. J Clin. Oncol. 2008; 26:527-34Median survival time6.2 monthsAlive at 1 year25.5%Median PFS1.7 monthsProgression free at 6months14.5%Meta-Analysis of Phase II Cooperative Group Trials in Metastatic Stage IV Melanoma toDetermine Progression-Free and Overall Survival Benchmarks for Future Phase II Trials
  • 9. A wonderful 2011 …IpilimumabApproved FDA on 25 March 2011Approved EMA on 14 Jul 2011PLX4032/VemurafenibApproved FDA on 17 August 2011Approved EMA on 17 Feb 2012
  • 10. Advanced melanoma: differentapproaches according to mutationalstatusBRAFV600E/Kc-KITQ61NRASNRAS wtBRAF wtAscierto P, et al. J Transl Med. 2012 May 2;10(1):83
  • 11. 1 2 3 40.00.10.20.30.40.50.60.70.80.91.0ProportionaliveYearsYearslpi + Gp100lpi + Gp100 (A)(A)lpi Alonelpi Alone (B)(B)Gp100 AloneGp100 Alone (C)(C)Survival RateSurvival Rate Ipi + gp100 N=403Ipi + gp100 N=403 Ipi + pbo N=137Ipi + pbo N=137 gp100 + pbo N=136gp100 + pbo N=1361 year1 year 44%44% 46%46% 25%25%2 year2 year 22%22% 24%24% 14%14%Kaplan-Meier Analysis of SurvivalKaplan-Meier Analysis of SurvivalComparison HRComparison HR pp--valuevalueArms A vs. C 0.68 0.0004Arms A vs. C 0.68 0.0004Arms B vs. C 0.66 0.0026Arms B vs. C 0.66 0.0026Hodi S et al.Hodi S et al. NEJM 2010;363(8):711-23NEJM 2010;363(8):711-23
  • 12. PFS: Impact of Both Ipilimumab Regimens vs gp100PFS: Impact of Both Ipilimumab Regimens vs gp100Comparison Hazard Ratio (C.I.) p-valueArms A vs C 0.81 (0.66–1.00) 0.0464Arms B vs C 0.64 (0.50–0.83) 0.0007Arms A vs B 1.25 (1.01–1.53) 0.0371Hodi S et al. NEJM 2010;363(8):711-23
  • 13. Ipilimumab Improves Best Objective Response RateIpilimumab Improves Best Objective Response Rate(BORR(BORR)‡‡: Disease control rate: percentage of patients with CR, PR, or SD: Disease control rate: percentage of patients with CR, PR, or SDHodi S et al.Hodi S et al. NEJM 2010;363(8):711-23NEJM 2010;363(8):711-23Arm AArm AIpi + gp100Ipi + gp100N=403N=403Arm BArm BIpi + pboIpi + pboN=137N=137Arm CArm Cgp100 + pbogp100 + pboN=136N=136BORR, %BORR, % 5.75.7 10.910.9 1.51.5P-value: A vs CP-value: A vs C 0.04330.0433P-value: B vs CP-value: B vs C 0.00120.0012DCRDCR‡‡, %, % 20.120.1 28.528.5 11.011.0P-value: A vs CP-value: A vs C 0.01790.0179P-value: B vs CP-value: B vs C 0.00020.0002
  • 14. TumourLNMay Immunoscore concept have a role inmelanoma ?MetastaticLymphnodeNon-MetastaticLymphnodeAscierto et al. CCR 2013
  • 15. Which is the role ofT-Reg cells?
  • 16. Mohos A. et al. J Trans Med 2013; 11:43.All pts All ptsSLN+ SLN+SLN- SLN-Density of immune cell types and Kaplan-Meier curves of PFSand OS for melanoma patients according to FOXP3+ celldensity
  • 17. An old concept in melanomaClemente CG et al. Cancer 1996 ;77:1303-10
  • 18. Tumor Infiltrating LymphocytesClemente CG et al. Cancer 1996 ;77:1303-10BriskNon-BriskAbsent
  • 19. Tumor Infiltrating LymphocytesClemente CG et al. Cancer 1996 ;77:1303-10Overall Survival Thickness
  • 20. Cochran AJ et al. Mod Pathol 2001;14(6):604–608
  • 21. The relative area of a sentinel node andnonsentinel node occupied by the paracortex.Cochran AJ et al. Mod Pathol 2001;14(6):604–608(Antibody to CD43)nonsentinel node sentinel node
  • 22. Dendritic cell populations in the sentinel nodeand nonsentinel nodeCochran AJ et al. Mod Pathol 2001;14(6):604–608nonsentinel node sentinel node
  • 23. Association of Breslow thickness, sentinel node(SN) tumor burden, interdigitating dendritic cellarea and density with metastases in thenonsentinel node (NSN)Cochran AJ et al. Mod Pathol 2004; 17, 747–755
  • 24. Association of Breslow thickness, sentinel nodetumor burden, IDC area and density with survivalCochran AJ et al. Mod Pathol 2004; 17, 747–755
  • 25. Time to melanoma recurrence and Survivalcurves related to different amounts of tumor inthe sentinel node and differing densities of IDCCochran AJ et al. Mod Pathol 2004; 17, 747–755IDC density < 65 IDC/mm2IDC density > 65 IDC/mm2IDC density < 65 IDC/mm2IDC density > 65 IDC/mm2
  • 26. Erdag G et al. Cancer Res 2012; 72(5); 1070–80Different Immunotypes in melanomaImmunotype A Immunotype B Immunotype C
  • 27. Erdag G et al. Cancer Res 2012; 72(5); 1070–80Immunotype frequency, prognosis, and cellularcomposition
  • 28. Erdag G et al. Cancer Res 2012; 72(5); 1070–80Patient survival and associations with immune celldensity
  • 29. Friedman et al. Nature Reviews Cancer 2012; 12, 298-306
  • 30. Messina JL et al. Sci Rep 2012; 2 :765Ectopic lymph node-like structures in melanomaexamined by immunohistochemistry
  • 31. Messina JL et al. Sci Rep 2012; 2 :765Presence of ectopic lymph node-like structuresin melanomaThe 12-chemokine GES canaccurately identify the presence ofunique, TL-ELNs in metastaticmelanoma, which also appear to beassociated with better patientoutcome
  • 32. Messina JL et al. Sci Rep 2012; 2 :765Preliminar Clinical Findings in Melanoma… We plan to evaluate the capacityof the 12-chemokine GES to predictthe likelihood of patients achievinga response of prolonged duration toimmune checkpoint inhibitoryantibodies (e.g., anti-PD-1 and anti-CTLA-4) and/or cytokines (e.g.,high-dose IL-2) …
  • 33. Hamid O et al. J Transl Med 2011; 9 :204Dosing and testing schedule CA184-004 trial
  • 34. Hamid O et al. J Transl Med 2011; 9 :204Association of clinical activity with tumor biomarkers… Baseline expression ofimmune-related tumorbiomarkers and a post-treatment increase in TILs maybe positively associated withipilimumab clinical activity …
  • 35. CD8/Cd68 in BreastWhat will the Macrophage story be?Specific Macrophage markers are needed.
  • 36. Gabrilovich et al. Nature Reviews Immunology 12, 253-268 (April 2012)
  • 37. The presence of the mannose receptor(CD206) suggests that these cells areactivated M2CD124 is interleukin-4 receptor.This is another marker for M2CD206 and CD124 are markers for Macrophages M2
  • 38. Predina J et al. PNAS 2013; 110:E415-24Macrophages express higher levels of CD206and CD124 in recurrent tumors than in primarytumors.
  • 39. KinaseinhibitorsiBRAFiMEKic-KitiPI3KiAKTimTORImmunomodulatingantibodiesipilimumabAnti-PD1Anti-CD137Anti-CD40OX40Anti TGF βL19IL2Immunomodulatingsmall molecule1 MTChemothepateuticsagentsDTICTMZFTMCDDPPaclitaxelNAB-paclitaxelAntimelanoma as of December, 2010Antimelanoma as of December, 2010More than 10 Drug ClassesMore than 10 Drug ClassesVaccinationMAGE A3PRAMENY-ISO1IL2 + gp100Adoptive CelltherapiesPARPinhibitorsABT-888HDACPro-apoptoticDrugsAnti-angiogenicAgentsPlasmid /Oncolytic VirusAllovectin-B7Onco-VexGSI
  • 40. Melero … Asciertol. Clin Cancer Res 2013Clinical development of immunostimulatory monoclonalantibodies and opportunities for combination.
  • 41. Immunoscore in Melanoma
  • 42. Immunoscore ImmunoprofilingPrognostic/Predictive(?) Prognostic/Predictive(?)Number ofimmune markers2-4 1 – SeveralImmunoscoremarkersCD3/CD8Immune gene signaturesMultiplex assaysCD137, Galectin1, LAG-3, OX40,PD-L1, TIM3, etc.Immunoscore-likemarkersCD3/CD8/CD20/FoxP3CD3/CD8/CD45ROCD4/CD8/CD68CD3/CD8/CD20,CD3/GZMBCD8/FoxP3CD8/IL17(others)Possibleapplication• Staging in colorectal cancer(already tested)• Staging in Melanoma, Breastcancer, Ovarian cancer, NSCLC,Prostate cancer, Pancreaticcancer, Head & Neck cancer (to bedefined).• Prognostic assay• Predictive assay• Personalized immune-treatmentImmunoscore vs ImmunoprofilingAscierto et al JTM 2013 in press

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