Inmunidad y cáncer de pulmón JULIAN SANZ

Transcripción

1 Inmunidad y cáncer de pulmón JULIAN SANZ

2 Esquema Conceptos básicos de inmunidad. Métodos para valorar la inmunidad intratumoral Importancia de la inmunidad en diferentes estadios y situaciones del cáncer de pulmón. Nuestra experiencia Biopsia liquida?

3 II.- Conceptos de inmunidad: -First theories: W Coley and P Elrich -Immunosurvilliance Burnet and Thomas s -Immunosenescence William Coley, 1880s, New York surgeon, Coley toxins Frank Macfarlane Burnet ( ). -Immunoediting: Schreiber, Old and Smyth s 1.- Elimination, 2.- Equilibrium, 3.- Escape.

4 A.- Sin inflamación intratumoral Menor antigenicidad vs inmunotolerancia Peor pronóstico B.- Con inflamación intratumoral Mejor pronóstico

5 Innate immunity CD117 Adaptive immunity CD1a CD56+, CD3- CD56+, CD3+ Chemical microenvironment

6 Role of Lymphocytes

7 T cells CD4+ CD25- Foxp3- CD4+ CD25+ Foxp3+ 7

8 Linfocito T: Balance de checkpoints activadores o inactivadores Mellman I et al, Bature 2011; 480:481-9.

9 Ongoing therapies to avoid cancer avoiding immunity 1) Block immune checkpoints (inmunotolerancia): AntiPDL1 Anti CTLA-4 2) Accelerating immunity with Agonist Ab: GITR, Anti-OX40, anticd40, 3) Peptide-based vaccines Ej: A10VAC 4) MDSC suppressor 5) Adoptive Immunity.

10 Agent FDA Approved Target(s) FDA-approved indication(s) Erlotinib (Tarceva) EGFR (HER1/ERBB1) Non-small cell lung cancer Pancreatic cancer Afatinib (Gilotrif) EGFR, HER2 NSCLC(EGFR exon 19 del,l858r) Gefitinib (Iressa) EGFR (HER1/ERBB1) NSCLC( EGFR exon 19 del or L858Rmut) Bevacizumab (Avastin) VEGF ligand Cervical cancer Colorectal cancer Fallopian tube cancer Glioblastoma Non-small cell lung cancer Ovarian cancer Peritoneal cancer Renal cell carcinoma Ipilimumab (Yervoy) CTLA-4 Melanoma Ceritinib (Zykadia) ALK Non-small cell lung cancer (ALK +) Crizotinib (Xalkori) ALK, ROS1, MET Non-small cell lung cancer (ALK +) Nivolumab (Opdivo) PD-1 Melanoma Non-small cell lung cancer Ramucirumab (Cyramza) VEGFR2 Colorectal cancer Gastric cancer or Gastroesophageal junction (GEJ) adenocarcinoma Non-small cell lung cancer Pembrolizumab (Keytruda) PD-1 Melanoma Non-small cell lung cancer (PD-L1+)

11 II.- La respuesta inmune intratumoral es variable. Métodos para clasificarla.

12 Biomarker Platform Function Additional Features B7H3 IHC B7H4 IHC CD3 IHC Regulatory T cells CD4 IHC Helper T cells CD8 IHC Cytotoxic T cells. QIA. Interface measurement. CD79b IHC B cell CD163 IHC Tumor Associated Macrophages QIA on immune and tumor cells. Interface measurement. C-MYC IHC Pathologist scoring. DC-LAMP IHC FOXP3/CD3 IF Immune Suppression Granzyme B IF Cytolytic Mediator HLA-DR ICOS (CD278) IHC IHC * + Costim Molecule. Candidate biomarker for CTLA4 therapies IDO IHC Tumor Immune Escape IRF-1 IHC QIA. Interface measurement. Ki67/CD4 IHC Proliferating Helper T cells Ki67/CD8 IF Proliferating Cytotoxic T cells LAG-3 IHC Checkpoint receptor QIA. Interface measurement. MHC-1 IHC OX40 (CD134) IHC Immune Suppression PD-L1 (E1L3N) IHC Checkpoint Receptor QIA on immune and tumor cells. Available for patient selection. PD-L1 (SP142) IHC Checkpoint Receptor QIA on immune and tumor cells. Available for patient selection. PD-L2 IHC Perforin IHC Cytolytic Mediator STING IHC From Yuan et al; Journal for Immunotherapy of cancer 2016; Histogenex 4 (3) TIM-3 IHC Checkpoint Receptor Pathologist scoring *Exoma, multiplex PCR, Immunosequencing or B and T deep sequencing, neoepitopes +Prognostic and predictive immune gene signatures. Bedognetti, et al; Current opinions in Oncology, Nov 2015

13 Inmunohistoquímica PDL1 PDL1 en CPNM: Sobreexpresión: 13-70% Problemas: Heterogeneidad : intratumoral, 1io/mts, tratamiento, Ac distintos: Punto de corte. Cel Tumoral +/- inmune Localización (membrana/intracelular/estroma) Distribución Ej: Para tratamiento con Keytruda, Ac DAKO/Agilent en cels tumorales >1%

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15 III.- Importancia de la inmunidad en diferentes estadios y situaciones del cáncer de pulmón.

16 Estadios iniciales: No tratados Neoadyuvancia Adyuvancia Estadios avanzados: 1ª línea Otras líneas Combinaciones HCSC

17 IV.- Nuestra experiencia.

18 Lung Parameter cancer Patient s % Association RFS 95% CI HR Chronic Inflammation Absent/weak Moderate/ (>10%) strong (>20%) ( ) Acute Inflammation Absent The leading cause of death in developed countries (1.5 million deaths worlwide per year). Present ( ) Combination of radiological imaging, TIL clinical, histopathological Absent 76 and 90.5 molecular data for personalyzed treatment. Present ( ) Targeted therapies have shown a dramatic impact on patients outcome, since Limited amount of tissue available in most cases. CD20 IHC Weak/absent (0.05)** **1.99 ( ) Moderate ( cells/mm2) Strong CD79 Weak/absent (0.08)** **1.47( ) Moderate Strong CD3 Weak/absent **1.06 ( ) Moderate (0.875)** Strong mm CD57 Weak/absent ( ) Moderate/Strong CD8 Weak absent ( ) Moderate/strong 42 50

19 A 50-gene immune expression profile classifies early-stage NSCLC (n=246) into low and high recurrence risk Firma génica HCSC 50 genes : distinta situación de partida External Validation (n=162) Low risk expression profile Disease-free survival High risk expression profile Cluster High risk (112) Cluster Low risk (50) Development series (n=84) Years Sanz-Ortega J et al, CTO Hazard Ratio: 3.359, Log-Rank: P=0.001

20 More validations: Director's Challenge Consortium for the Molecular Classification of Lung Adenocarcinoma dataset, Shedden et al, Nature Genetics (n=439)

21 Firma 50 genes: Inmunidad B sobre-expresada en Low-risk B-cell-specific transcrtiptional co-activator (POU2) TNFR, 17 SLAM7F (CD139), proliferation, autocrine cytokine CXCL13, a B-cell-attracting chemokine, IRF4, B-cell development CD38: proliferation and survival of B cells CD27 memory cells Pim-2 anti-apoptotic B and plasma cells: Maduration Recruiting Memory cells Proliferation Anti-apoptosis

22 Is there any immune gene overexpressed in high-risk? -----x regulates B cell interactions with other cell types in tumor microenvironment (Aassheim, Blood 2000) It inhibits B cell transmigration from vascular endothelium (Zapata, Blood 2011).

23 One third of NSCLC have an intratumoral lymphocyte infiltrate, B-cell mediated associated with better prognosis.

24 Biopsia Líquida - Célula tumoral circulante - ADN circulantes Estudio biomarcadores Cuándo? Material insuficiente/no válido o no hay. Correlación con primario A la progresión A la resistencia Cómo: NGS, PCR, FISH en CTC

25 Case report: Breast cancer: PIK3CA: Primary, rib and skin: w.t, Liver and cfdna: mut. Romero A et al:trasl Res Dic 2015.

26 Conclusiones Hay que conocer las bases de la relación sistema inmune y cáncer. Al diagnóstico la respuesta inmune es variable. NO disponemos de inmunoscores adecuados, y estandarizados, aunque empieza a haber muchas opciones disponibles: IHQ, firmas, NGS (incluyendo immunosequencing),. PDL1 x IHQ es el marcador directo para anti-pd1/pdl1 Nuestra experiencia (y algunos otros autores) la activación de respuesta B es clave para distinguir que los linfocitos T tengan un papel activo..