Embed Size (px)
DESCRIPTION
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).
Citation preview
Paolo A. Ascierto, MD Unit Melanoma, Cancer Immunotherapy and Innovative TherapyIstituto Nazionale Tumori – Fondazione “G. Pascale”, Napoli, Italy
The Medical Need for an Immune Scoring/Profiling for Melanoma and Other Cancer
Patients
The Medical Need for an Immune Scoring/Profiling for Melanoma and Other Cancer
Patients
Why is Immune important?
Friedman et al. Nature Reviews Cancer 2012; 12, 298-306
Tumor periphery
Tumor
H&E sections
Tumor center
IHC which shows the tumor (cyan) and the T cell with the CD3 (brown)
The basis of the ImmunoscoreThe basis of the Immunoscore
Courtesy of Jerome Galon
Concept: An Immunoscore for Several Diseases(Lymphocytic infiltration and survival benefit published for decades)…
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,…
What in Melanoma ?
Korn E. et al. J Clin. Oncol. 2008; 26:527-34Korn E. et al. J Clin. Oncol. 2008; 26:527-34
Median survival time 6.2 months
Alive at 1 year 25.5%
Median PFS1.7 months
Progression free at 6 months 14.5%
Median survival time 6.2 months
Alive at 1 year 25.5%
Median PFS1.7 months
Progression free at 6 months 14.5%
Meta-Analysis of Phase II Cooperative Group Trials in Metastatic Stage IV Melanoma to Determine Progression-Free and Overall Survival Benchmarks for Future Phase II Trials
A wonderful 2011 …
Ipilimumab
Approved FDA on 25 March 2011Approved EMA on 14 Jul 2011
PLX4032/Vemurafenib
Approved FDA on 17 August 2011Approved EMA on 17 Feb 2012
Advanced melanoma: different approaches according to mutational
status BRAFV600E/K
c-KITQ61NRAS
NRAS wtBRAF wt
Ascierto P, et al. J Transl Med. 2012 May 2;10(1):83
1 2 3 4
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Pro
port
ion
aliv
eP
ropo
rtio
n al
ive
YearsYears
lpi + 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=136
1 year 1 year 44%44% 46%46% 25%25%
2 year2 year 22%22% 24%24% 14%14%
Kaplan-Meier Analysis of SurvivalKaplan-Meier Analysis of Survival
Comparison HR Comparison HR pp--value value Arms A vs. C 0.68 0.0004Arms A vs. C 0.68 0.0004 Arms B vs. C 0.66 0.0026Arms B vs. C 0.66 0.0026
Hodi S et al. Hodi S et al. NEJM 2010;363(8):711-23NEJM 2010;363(8):711-23
PFS: Impact of Both Ipilimumab Regimens vs gp100PFS: Impact of Both Ipilimumab Regimens vs gp100
Comparison Hazard Ratio (C.I.) p-value Arms 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) 0.0371
Hodi S et al. NEJM 2010;363(8):711-23
Ipilimumab Improves Best Objective Response Rate Ipilimumab 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 SD
Hodi S et al. Hodi S et al. NEJM 2010;363(8):711-23NEJM 2010;363(8):711-23
Arm AArm AIpi + gp100Ipi + gp100
N=403N=403
Arm BArm BIpi + pboIpi + pboN=137N=137
Arm CArm Cgp100 + pbogp100 + pbo
N=136N=136
BORR, %BORR, % 5.7 5.7 10.910.9 1.51.5
P-value: A vs CP-value: A vs C 0.04330.0433
P-value: B vs CP-value: B vs C 0.00120.0012
DCRDCR‡‡, % , % 20.1 20.1 28.5 28.5 11.0 11.0
P-value: A vs CP-value: A vs C 0.01790.0179
P-value: B vs CP-value: B vs C 0.00020.0002
Tumour
LN
May Immunoscore concept have a role in melanoma ?May Immunoscore concept have a role in melanoma ?
Metastatic Lymphnode
Non-Metastatic Lymphnode
Ascierto et al. CCR 2013
Which is the role of T-Reg cells?
Mohos A. et al. J Trans Med 2013; 11:43.
All pts All pts
SLN+ SLN+
SLN- SLN-
Density of immune cell types and Kaplan-Meier curves of PFS and OS for melanoma patients according to FOXP3+ cell density
Density of immune cell types and Kaplan-Meier curves of PFS and OS for melanoma patients according to FOXP3+ cell density
An old concept in melanomaAn old concept in melanoma
Clemente CG et al. Cancer 1996 ;77:1303-10
Tumor Infiltrating LymphocytesTumor Infiltrating Lymphocytes
Clemente CG et al. Cancer 1996 ;77:1303-10
Brisk
Non-Brisk
Absent
Tumor Infiltrating LymphocytesTumor Infiltrating Lymphocytes
Clemente CG et al. Cancer 1996 ;77:1303-10
Overall Survival Thickness
Cochran AJ et al. Mod Pathol 2001;14(6):604–608
The relative area of a sentinel node and nonsentinel node occupied by the paracortex.
The relative area of a sentinel node and nonsentinel node occupied by the paracortex.
Cochran AJ et al. Mod Pathol 2001;14(6):604–608
(Antibody to CD43) nonsentinel node sentinel node
Dendritic cell populations in the sentinel node and nonsentinel nodeDendritic cell populations in the sentinel node and nonsentinel node
Cochran AJ et al. Mod Pathol 2001;14(6):604–608
nonsentinel node sentinel node
Association of Breslow thickness, sentinel node (SN) tumor burden, interdigitating dendritic cell area and density with metastases in the nonsentinel node (NSN)
Association of Breslow thickness, sentinel node (SN) tumor burden, interdigitating dendritic cell area and density with metastases in the nonsentinel node (NSN)
Cochran AJ et al. Mod Pathol 2004; 17, 747–755
Association of Breslow thickness, sentinel node tumor burden, IDC area and density with survival
Association of Breslow thickness, sentinel node tumor burden, IDC area and density with survival
Cochran AJ et al. Mod Pathol 2004; 17, 747–755
Time to melanoma recurrence and Survival curves related to different amounts of tumor in the sentinel node and differing densities of IDC
Time to melanoma recurrence and Survival curves related to different amounts of tumor in the sentinel node and differing densities of IDC
Cochran AJ et al. Mod Pathol 2004; 17, 747–755
IDC density < 65 IDC/mm2
IDC density > 65 IDC/mm2
IDC density < 65 IDC/mm2
IDC density > 65 IDC/mm2
Erdag G et al. Cancer Res 2012; 72(5); 1070–80
Different Immunotypes in melanomaDifferent Immunotypes in melanomaImmunotype A Immunotype B Immunotype C
Erdag G et al. Cancer Res 2012; 72(5); 1070–80
Immunotype frequency, prognosis, and cellularcomposition
Immunotype frequency, prognosis, and cellularcomposition
Erdag G et al. Cancer Res 2012; 72(5); 1070–80
Patient survival and associations with immune celldensity
Patient survival and associations with immune celldensity
Friedman et al. Nature Reviews Cancer 2012; 12, 298-306
Messina JL et al. Sci Rep 2012; 2 :765
Ectopic lymph node-like structures in melanoma examined by immunohistochemistry
Ectopic lymph node-like structures in melanoma examined by immunohistochemistry
Messina JL et al. Sci Rep 2012; 2 :765
Presence of ectopic lymph node-like structures in melanomaPresence of ectopic lymph node-like structures in melanoma
The 12-chemokine GES can accurately identify the presence of unique, TL-ELNs in metastatic melanoma, which also appear to be associated with better patient outcome
Messina JL et al. Sci Rep 2012; 2 :765
Preliminar Clinical Findings in MelanomaPreliminar Clinical Findings in Melanoma
… We plan to evaluate the capacity of the 12-chemokine GES to predict the likelihood of patients achieving a response of prolonged duration to immune checkpoint inhibitory antibodies (e.g., anti-PD-1 and anti-CTLA-4) and/or cytokines (e.g., high-dose IL-2) …
Hamid O et al. J Transl Med 2011; 9 :204
Dosing and testing schedule CA184-004 trialDosing and testing schedule CA184-004 trial
Hamid O et al. J Transl Med 2011; 9 :204
Association of clinical activity with tumor biomarkersAssociation of clinical activity with tumor biomarkers
… Baseline expression of immune-related tumor biomarkers and a post-treatment increase in TILs may be positively associated with ipilimumab clinical activity …
CD8/Cd68 in Breast
What will the Macrophage story be?Specific Macrophage markers are needed.
Gabrilovich et al. Nature Reviews Immunology 12, 253-268 (April 2012)
The presence of the mannose receptor (CD206) suggests that these cells are activated M2
CD124 is interleukin-4 receptor. This is another marker for M2
CD206 and CD124 are markers for Macrophages M2 CD206 and CD124 are markers for Macrophages M2
Predina J et al. PNAS 2013; 110:E415-24
Macrophages express higher levels of CD206 and CD124 in recurrent tumors than in primary tumors.
Macrophages express higher levels of CD206 and CD124 in recurrent tumors than in primary tumors.
Kinase inhibitors
iBRAF
iMEK
ic-Kit
iPI3K
iAKT
imTOR
Immunomodulating antibodies
ipilimumab
Anti-PD1
Anti-CD137
Anti-CD40
OX40
Anti TGF
L19IL2
Immunomodulating small molecule
1 MT
Chemothepateutics agents
DTIC
TMZ
FTM
CDDP
Paclitaxel
NAB-paclitaxel
Antimelanoma as of December, Antimelanoma as of December, 20102010
More than 10 Drug ClassesMore than 10 Drug ClassesVaccination
MAGE A3
PRAME
NY-ISO1
IL2 + gp100
Adoptive Cell therapies
PARPinhibitors
ABT-888HDAC
Pro-apoptoticDrugs
Anti-angiogenicAgents
Plasmid /Oncolytic Virus
Allovectin-B7
Onco-VexGSI
Melero … Asciertol. Clin Cancer Res 2013
Clinical development of immunostimulatory monoclonal antibodies and opportunities for combination.
Immunoscore in MelanomaImmunoscore in Melanoma
Immunoscore ImmunoprofilingPrognostic/Predictive(?) Prognostic/Predictive(?)
Number of immune markers
2-4 1 – Several
Immunoscore markers
CD3/CD8
Immune gene signaturesMultiplex assays
CD137, Galectin1, LAG-3, OX40, PD-L1, TIM3, etc.
Immunoscore-like markers
CD3/CD8/CD20/FoxP3CD3/CD8/CD45RO
CD4/CD8/CD68CD3/CD8/CD20,
CD3/GZMBCD8/FoxP3CD8/IL17(others)
Possible application
Staging in colorectal cancer (already tested)
Staging in Melanoma, Breast cancer, Ovarian cancer, NSCLC,
Prostate cancer, Pancreatic cancer, Head & Neck cancer (to be
defined).
Prognostic assay Predictive assay
Personalized immune-treatment
Immunoscore vs ImmunoprofilingImmunoscore vs Immunoprofiling
Ascierto et al JTM 2013 in press
