Moderne terapie nel trattamento del mesotelioma pleurico

Rossana Berardi

Clinica di Oncologia Medica Università Politecnica delle Marche

Ospedali Riuniti di Ancona

Incidenza dei tumori in Italia

Sopravvivenza a 5 anni in Italia

Amianto (IARC)

“Raro” tumore della pleura

Maschi:femmine = 3:1

Periodo di latenza: 20-40 anni dall’esposizione ambientale

Età: sesta-ottava decade

Agente patogenetico: asbesto (70-80% dei casi)

Tsao AS, et al. J Clin Oncol. 2009;27:2081-2090.

Mesotelioma: epidemiologia

Esposizione all’asbesto e rischio

individuale

Mutazione

BAP1?

Strategia terapeutica multimodale

Mutazione

BAP1? Radioterapia

chemioterapia

Chemioterapia

Mutazione

BAP1?

Limitata risposta obiettiva (<20%)

Migliori risultati con terapie di combinazione a più farmaci (cisplatino, pemetrexed)

Nuovi farmaci?

Ieri:

…tanti pazienti, una sola terapia…

Oggi:

… a ciascuno la sua

terapia!

BOMBE INTELLIGENTI

TERAPIE MIRATE

TERAPIE A BERSAGLIO

• Azione selettiva

• Minore tossicita’ sistemica

• Elevate risposte in subset

selezionati di pazienti

• Somministrazione orale

(piccole molecole, non anticorpi monoclonali)

TERAPIE A BERSAGLIO BIOMOLECOLARE

Entra in scena l’IMMUNOTERAPIA

nuova

…se il sistema immunitario è tanto potente,

perchè le persone sviluppano il cancro?

Cancers look like “self”

– Cancers are shaped by the host microenvironment

Is there a way to effectively and safely break tolerance to “self”?

Tumors actively defeat the host immune response

Cancer immunotherapy

Shankaran V, et al. Nature. 2001;410:1107-1111.

In other words, competent immune systems force the tumors to figure

out how to survive in hostile environments

Immunocompetent Mice Reject Tumors Originating in Immunodeficient Mice

“Antigen-specific”

Specific priming of immune system

antigen-specific antibodies & cytotoxic T cells

“Non antigen-specific”

Enhancement of innate/adaptive immune system

altered action of e.g. dendritic cells.

Cancer immunotherapy

Cancer immunotherapy: any interaction

with the immune system to treat cancer

Cancer-vaccination therapy

Immunomodulation therapy

Res

po

nse

Time (months) 0 6 12

IMMUNOTHERAPY

Chemotherapy and Targeted Therapies

Chemotherapy/Targeted Agents and

Immunotherapy Differ in Action and Outcome

Nishino M et al. Journal for ImmunoTherapy of Cancer 2014, 2:17.; Ribas A, et al. Clin Cancer Res 2009;15:7116–7118;

Wolchok JD et al. Clin Cancer Res. 2009;15(23):7412-20.

Tumour

immunotherapy

Immunotherapy-Hot topic

Ma…ma… che

c’è???

Target Therapy? ….Variabilita` Biologica!!

______________________________________________

Immunotherapy in Mesothelioma:

combinatorial approach

• Mesothelioma: lack of potent anti-tumor

T-cells and strong immunosuppressive tumor

microenvironment

• Induction of potent anti-tumor response by:

– Induction of tumor-specific T-cells : DC-immunotherapy

– Reduction of local immune suppression: CD40-agonist

• Hypothesis: combinatorial approach has a synergistic

effect on treatment outcome

Conclusions and future plans

CD40-agonist (in combination with DC-therapy):

• Enhanced mesothelioma survival

• Skewed monocytes to a pro-inflammatory, M1-like phenotype

• Increased CD8+ (and CD4+) T-cell proliferation and KLRG1+ CD8+ cells

Future plans:

Interim sacrifice of mice to investigate intra-tumoral leukocyte

populations

Validation of Ki67 and KLRG1 positive CD8 T-cells as potential

biomarkers for therapeutic success

Implementation of combinatorial approach in clinical trial

Ancona University Hospital

La prevenzione e la cura cominciano

dall’informazione

LA NUOVA ME: PINK DAY IN PINK ROOM

r.berardi@univpm.it