nuove frontiere: la ricerca immunologica
TRANSCRIPT
XXVI CORSO DI FORMAZIONEPER VOLONTARI ALL’ASSISTENZA
DEL MALATO ONCOLOGICO
Nuove frontiere: la ricerca
immunologica
Vanna Chiarion Sileni
AR
SEL
psoriasis
Progressive vitiligo
Risposte
immunitarie
efficaci
Alterazioni strutturali e
funzionali deil’immunità
linfonodale
Accumulo di cellule
disfunzionali e
immunosoppressorie
negli organi linfoidi e
nel midollo
Soppressione
dell’immunità
anti-tumorale
a livello sistemico
Stadio I
Malattia primitiva iniziale
Prognosi favorevole
Malattia non-clinicamente
evidente
Limitata
risposta immunitaria
e iniziale
immunosoppressione
Stadio I-II
Malattia primitiva iniziale
Prognosi Sfavorevole
Stadio III
Malattia nei linfonodi
drenanti
Stadio IV
Malattia metastatica
a organi distanti
Stadio IV
Malattia metastatica
avanzata
L’immunità anti-tumore è un fenomeno iniziale, che viene progressivamente
alterato durante il decorso della malattia
Tumour antigens released bytumour cells
Tumour antigens presented to T cells T cells are
activated and
proliferate
T cells recognise tumour antigens
T cells kill tumour cells
The T-cell Anti-Tumour Response
Andersen MH, et al. J Invest Dermatol 2006;126:32–41; Pardoll DM. Nat Rev Cancer 2012;11:252–64; Mellman I, et al. Nature 2011;480:480–9; Heemskerk B, et al. EMBO J 2013;32:194–203; Boudreau JE, et al.
Mol Ther 2011;19:841–53; Janeway CA, et al. Immunobiology: The Immune System in Health and Disease. 6th ed. New York, NY: Garland Science; 2004
1
4
2
3
5
Tumour cell
APC
Inactive T cell
Activated T cell
Activated T cell
Tumour cell
Tumour
cell
APC = antigen-presenting cell
Immune escape mechanisms are complex and frequently overlapping
Tumour cells
CD8+
T cell
A. Ineffective presentation of
tumour antigens to the
immune system
TregMDSC
B. Recruitment of
immunosuppressive cells
(Tregs, MDSCs, others)
CD8+
T cell
CD4+
T cell
TGF-β
IL-10
TGF-β
ARG1
iNOS
C. Secretion of
immunosuppressive
factors
VEGF
APC
TGF-β
IDO
IL-10
D. T cell checkpoint
PD-1
PD-L1
PD-1
PD-L1
CTLA-4TCR
MHC
Tumours Use Various Mechanisms to Escape the Immune System
Vesely MD, et al. Ann Rev Immunol 2011;29:235–
Cancer is a chronic immunologic disease
• Cancer is recognized by immuno system
(TAA, CTL)
• Tumors have multiple mechanisms to evade the immuno system
- Expression of molecules that inhibit
immune responses
Slide 35
Presented By Axel Hauschild at 2014 ASCO Annual Meeting
HR= 0.66 p= 0.003
MS 10 mos vs 6.4
Median FU 21 vs 27.8 vs 6.4
Subset Ipilimumab OS Analyses by Prior Therapy (N=1 861)*
Presented By Axel Hauschild at 2014 ASCO Annual Meeting
Response Characteristics in Patients with Melanoma Receiving Nivolumab
� Longest follow-up of any PD- 1 pathway inhibitor; MEL pt enrollment: November 2008 through January 2012
� Responses ongoing in 19/34 (56%) responders at time of analysis
� 52% (11/21) of responding pts who discontinued therapy for reasons other than PD responded for ≥24 weeks
� 64% (7/11) remained in response from 24-56 weeks
� 44% (15/34) of responding patients showed a response at first tumor assessment (8 weeks)
Median DOR 22.9 months
Presented by: F. Stephen Hodi, MD
OS at the Second Interim Analysis
Presented By Lynn Schuchter at 2015 ASCO Annual Meeting
PEMBRO: 1-year 74%
IPI: 1-year 58 %
Keynote-006
Rapid Eradication of a Bulky Melanoma Mass with One Dose of Immunotherapy
Nov 2013 baseline
Feb 2014
IPI vs NIVO vs IPI+NIVO ( M , 80-y, NRAS mut )
Jan 2015
OCT 2013 baseline
Jan 2014
IPI vs NIVO vs IPI+NIVO (M,62-y, wt)
Baseline Jul 2013
Sep 2013
262 BMS 066 Male 67-y old, pT4bN3M1b NRAS mut (c .182A>T=p.Q61L del)
Courtesy by V.Chiarion Sileni
MA.Postow et al NEJM 2015
IPI+Nivo vs IPI
ORR= 61% 11%
CR= 22% 0%
PD= 16% 47%
MA.Postow et al NEJM 2015
Per
cent
Aliv
e
0 1 2 3 4Years
Overall survival aftercheckpoint blockade
100
ipilimumab
PD-1 pathway blockade
nivolumab+
ipilimumab
James Patrick Allison ASCO 2012
Mobilizing the Immune System to Treat Cancer: Immune Checkpoint Strategies
Maximising clinical benefit: <br />building on immunological approaches
Presented By Axel Hauschild at 2014 ASCO Annual Meeting
Tumor Immunotherapy is an established reality in the
treatment of melanoma
Grazie