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 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).

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

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

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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