Conferinţa Diaspora în Cercetarea Ştiinţifică şi Invăţământul Superior din România, Timisoara, 2016

Principii de medicina personalizata in melanomul cutanat

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Workshop - Perspective în medicina personalizată – de la concept la aplicaţii clinice

Monica Neagu 1,2, Carolina Constantin1

1 Laborator Imunologie, Institutul Național de Patologie “Victor Babeş”, București, Romania

(e-mail: neagu.monica@gmail.com)

2 Facultatea de Biologie, Universitatea București, Romania

Institutul National “Victor Babes” Institutul National “Victor Babes” www.ivb.ro

99-101 Splaiul Independentei, 050096, Bucharest, Romania

Melanomul cutanatMelanomul cutanat

Particularitati

melanomul cutanat are cea mai mare rată a mutațiilor

100 - 120 mutații / megabază

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Istoria Istoria terapieiterapiei •Melphalan

•Dacarbazina

•2001 – imatinib pentru leucemia cronica mieloida !!

• modificarile genetice care stau la baza patogenezei melanomului pot sa

fie tinte terapeutice

• 2002 - mutatiile NRAS si proteina downstream BRAF sunt descoperite

mutatia BRAF in 50% din cazuri, 80 % substitutia valinei cu acidul

glutamic (V600E) “discovery of BRAFV600E has proven to be a turning point for melanoma treatment”

• Sorafenib – insucces

• Vemurafenib – 2011 FDA

•2015 combinatie dabrafenib (inhibitor de BRAF de a 2-a generatie) cu

trametinib (inhibitor de MEK) – supravietuire crescuta

•Imunoterapie personalizata

EEvolutivolutia a publicatiilorpublicatiilor

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0

100

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1960 1970 1980 1990 2000 2010 2020

Publication count 800

““Immune therapy and melanomaImmune therapy and melanoma””

ImunoterapiaImunoterapia in in melanommelanom Melanom – tumora cu potential imunogenic crescut 1987 – prima publicatie cu TIL

Imunoterapia in melanom a inceput cu 1992 - FDA doze crescute de IL-2

4 Neagu M. The immune system - a hidden treasure for biomarker discovery in cutaneous melanoma. Adv Clin Chem, 2012; 58 : 89-140

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Monica Neagu and Carolina Constantin, New Insights in Cutaneous Melanoma Immune-Therapy — Tackling Immune-Suppression and Specific Anti-Tumoral Response, Melanoma - Current Clinical Management and Future Therapeutics, Prof. Mandi Murph (Ed.), InTech, 2015, DOI: 10.5772/59494.

ImunoterapiaImunoterapia in in melanommelanom

7 noi medicamente aprobate din care 4 (ipilimumab, nivolumab,

pembrolizumab si talimogene laherparepvec) actiune directa pe sistem imun, iar

restul de 3 actiune indirecta.

Inhibitorii de CTLA-4 si PD-1

2004 anti-CTLA-4 “can break peripheral immunologic tolerance” - ipilimumab

aprobat de FDA in 2011, apoi de EU, Oct 2015 adjuvant in

melanomul avansat

PD-1 – nivolumab si pembrolizumab

Talimogene laherparepvec (T-VEC) virus oncolitic format din

herpes simplex virus type 1 care se reproduce in tumora si

sintetizeaza GM-CSF

6 Robert Ancuceanu, Monica Neagu, Immune based therapy for melanoma, Indian Journal of Medical Research, Volume 143 Number 2, 135-144, 2016

TerapiaTerapia personalizatapersonalizata in in melanommelanom

Cancer Genome Atlas Network – genotiparea tumorilor in

BRAF, NRAS si NF1 – orienteaza terapia (Akbani R et al, Cell, 2015)

In 2015 primele incercari medicina personalizata – neo-

antigenele specifice ale tumorilor individualizate – vaccin

specific (Carreno BM et al, Science, 2015)

Vaccinarea a indus pacientilor raspuns T specific fiecarui

set de neo-antigene tumorale

Terapia adoptiva – T de la pacient, modificate genetic

pentru a exprima un TCR specific antigenelor tumorale

specifice si reintroduse la pacient (Urba et al, NEJM, 2011)

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Medicina personalizata inca la inceput !

Melanoma Research FoundationMelanoma Research Foundation

2015 - 30 de institutii (echipe) din Europa, USA si Australia – raport

diagnostic, prognostic, recurenta, terapie, monitorizare eficienta etc

Personalizarea terapiei – dormanta celulelor tumorale

Biomarkeri circulanti, imagistica pentru detectarea celulelor

dormante – metastaze

Orientarea terapiei dupa urmatoarele scenarii:

Pastrarea celulelor in G0 indefinit (ani de administrare a terapiei);

Activarea celulelor dormante si tintirea celulelor tumorale (riscant, aparitia

unor celule inalt agresive);

Tintirea celulelor dormante (multi-terapie fata de antigene specifice

tumorale, fata de caile d ementinere a celulelor dormante, fata de celulele

nisei etc)

8 MRF, The state of melanoma: challenges and opportunities, Pigment Cell Melanoma Res. 5 April 2016, doi: 10.1111/pcmr.12475

BiomarkeriBiomarkeri circulanticirculanti –– orienteazaorienteaza terapiaterapia

Raportul CD4/CD8

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Monica Neagu, The immune system - a hidden treasure for biomarker discovery in cutaneous melanoma, In Gregory S. Makowski, editor: Advances in Clinical Chemistry, Burlington: Academic Press vol 58, 2012 pp. 89-140, ISBN: 978-0-12-394383-5

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BiomarkeriBiomarkeri circulanticirculanti –– orienteazaorienteaza terapiaterapia

Monica Neagu, Carolina Constantin, Sabina Zurac, Immune parameters in prognosis and therapy monitoring of cutaneous melanoma patients - experience, role and limitations, BioMed Research International, special issue Molecular Biomarkers: Tools of Medicine (MBTM) Volume 2013, 15 November 2013 Article ID 107940

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BiomarkeriBiomarkeri circulanticirculanti –– orienteazaorienteaza terapiaterapia IL-8 – vit D

Ene CD, Anghel AE, Neagu M, Nicolae I, 25-OH Vitamin D and Interleukin-8: Emerging Biomarkers in Cutaneous Melanoma Development and Progression. Mediators Inflamm. 2015;2015:904876. doi: 10.1155/2015/904876.

25-OH vitamin D3 (ng mL−1) serum level in melanoma patients for individuals with normal and high serum IL-8 (pg mL−1). Prevalence depicts the subgroups of melanoma patients with high serum IL-8 congregating in the low serum 25-OH vitamin D3 ranges.

HeterogeneitateaHeterogeneitatea tumoralatumorala

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Monica Neagu, Carolina Constantin, Sabina Zurac, Immune parameters in prognosis and therapy monitoring of cutaneous melanoma patients - experience, role and limitations, BioMed Research International, special issue Molecular Biomarkers: Tools of Medicine (MBTM) Volume 2013, 15 November 2013

HeterogenHeterogeneeitateaitatea tumoralatumorala

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Sabina Zurac, Monica Neagu et al, Variations in the expression of TIMP1, TIMP2 and TIMP3 in cutaneous melanoma with regression and their possible function as prognostic predictors, Oncology Lett, 11: 3354-3360, 2016

In In practicpractica a –– medicina demedicina de precipreciziezie

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Modele experimentale noi – tinte imuno, tinte de semnalizare intracelulara corelate cu particularitatile genetice individuale

Mecanistica heterogeneitatii intratumorale -strategii terapeutice individuale.

Biomarkeri pentru stratificarea sub-grupelor de pacienti si individualizarea terapiei

Biomarkeri pentru selectia terapiei la aparitia tumorilor rezistente la terapia de prima linie.

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In loc de In loc de concluziiconcluzii “the road ahead”“the road ahead”

MRF, The state of melanoma: challenges and opportunities, Pigment Cell Melanoma Res. 5 April 2016, doi: 10.1111/pcmr.12475

Research? – what ?

5/11/2016 17

M. Neagu, C. Constantin, C. Tanase, Immune-related biomarkers for diagnosis/prognosis and therapy monitoring of cutaneous melanoma, Expert Rev. Mol. Diagn. 10 (7) (2010) 897–919.

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Carolina Constantin, PhD

Thank you! Thank you! MultumescMultumesc!!

Prof. Sabina Zurac – Spitalul Colentina, Bucuresti

Dr. Amalia Anghel – SkinMed, Bucuresti

Dr. Ilinca Nicolae - Spitalul Victor Babes, Bucuresti

Centrului de Excelenta in Dermato-oncologie – UMF Carol Davila

Dr. Amanda Bulman – Brucker, USA

Dr. Diane McCarthy – Caprion, USA

PN-II-PCCA-2013-4-1407 (acronym MELTAG,

Grant no. 190/2014)