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Combining radiotherapy and immunotherapy in
breast cancer: clinical translation
Silvia Formenti, M.D.
NYU School of Medicine
New York, NY
• The irradiated tumor as an immunogenic hub :
contribution of the immune system to clinical response
to standard treatment, at any stage of the disease
• Enhancing the immune response of the host :
preliminary results of RT with anti-CTLA4, anti-PD1, TLR
agonists, anti TGF-beta, etc.
How do standard anti-cancer
treatments interfere with this
landscape ?
Dunn et al, Nature Immunology 2002
Koebel et al, Nature 2007
N+ Breast Cancer: Impact on BC mortality
Chemo vs no Chemo
Figure 2
RT vs no RT
Post-mastectomy
Post-BCT
Effect of radiotherapy (RT) after breast-conserving surgery (BCS) on 10-year risk of any (locoregional or distant) first recurr
on 15-year risk of breast cancer death in women with pathologically verified nodal status
Vertical lines indicate 1 SE above or below the 5, 10, and 15 year percentages. Further details are in webappendix pp 6–7.
EBCTG Lancet 2006, 2011, 2012
pN0=pathologically node-negative. pN+=pathologically node-positive. RR=rate ratio. Rate ratios in this figure include all av
IN SITU VACCINATION HYPOTHESIS
RT
TUMOR
CD4
T cell
IL-12
CD8
T cell
IJROBP, 2005
IJROBP, 2012
IMMUNOGENIC CELL DEATH: CRT, HMGB1 and ATP
!
CRT
!
TLR4
!
TUMOR
!
DC
D
C
P2XR7
CD4
T cell
IL-12
Tumor cell lysis
CD8
T cell
CTL activation
IL-2
gIFN
Obeid et al., Nat Med 2007, 13:54-61; Cell Death Differ 2007, 14:1848
Apetoh et al., Nat Med 2007, 13:1050; Ghiringhelli et al., Nat Med 2009, 15:1170
Abscopal effect*
Effect of ionizing radiation on malignancy
outside
theabscopal
radiationeffects
field of
Why are
radiation rarely observed
in theand
clinic?
Latin ab (away from)
scopus (target)
*Mole
RJ. Whole body irradiation - radiology or medicine? Br J Radiol 1953; 26:234
Demaria S, Ng B, Devitt ML, Babb JS, Kawashima N, Liebes L, Formenti SC.
Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune
mediated. Int J Radiat Oncol Biol Phys. 2004. 1;58(3):862-70
IMMUNOSUPPRESSION DOMINATES IN ESTABLISHED TUMORS
A need to combine
radiotherapy with
immunotherapy
Vesely MD, 2011, Annu.Rev.Immunol 29:235-71
Hypothesis:
Ionizing radiation can stimulate anti-tumor immunity –by generating an in situ
vaccine - and combination with IRM may uncover this effect
Day: 0
20
RT
2 Gy
67NR
5x104 or 105
Flt3-L (0.5mg/kg)
each sides,
primary R and secondary L
R
“primary”
RT
L
“secondary”
X
BALB/C mice injected at two separate sites with the syngeneic mammary carcinoma 67NR cell line
IRRADIATE RIGHT SIDE ONLY AND ASSESS RESPONSE IN BOTH
RT+Flt3-L : systemic anti-cancer effects
Irradiated
non-irradiated
IJROBP 2004
NYU 02-58: A “proof of principle” clinical trial
Aimed at detecting a response outside the radiation field after GM-CSF
administration (as DC growth factor) in patients with metastatic cancer
DAY
1
8
15
22
29
36
42
49-56
Week 4, 5
Week 1, 2
Chemo-RT
Chemo-RT
Week 2, 3
Week 5, 6
GM-CSF
Within 2 weeks from study entry:
Baseline measurements
CT and PET
GM-CSF
End of Week 3
Assess clinical response
Response assessed by an independent review panel of 4 MD
Week 7-8
Assess clinical response
and CT/PET response
Treatment Fields & Abscopal Lesion
Abscopal Response
Baseline
Cycle 1
5 yr F/U
4/4/2007
7/12/2007
7/28/2012
Abscopal effect and survival, 37 patients (NYU 02-58)
A.
Responders are patients already more immunocompetent
• The irradiated tumor as an immunogenic hub :
contribution of the immune system to clinical response
to standard treatment, at any stage of the disease
• Enhancing the immune response of the host :
preliminary results of RT with anti-CTLA4, anti-PD-1, TLR
agonists, anti TGF-beta, etc.
4T1 syngeneic murine mouse mammary cancer model
Lung
metastases
Primary
tumor
Endpoints:
• Tumor control
• Survival
RT sensitizes a poorly immunogenic tumor
to anti-CTLA-4 treatment
Demaria et al., Clin. Cancer Res. 11:728-34, 2005
Inhibition of spontaneous metastasis by RT to the primary
tumor + CTLA-4 blockade requires CD8+ T cells
Characterization of T cell-tumor cell interactions
by intravital two-photon laser scanning microscopy
Blood vessels
T cells
collagen
Injection of
4T1 tumor cells
day 0
RT
RT
13
14
2-p intravital imaging
15
16
‘Short term’
18
22
‘Long term’
Only RT + anti-CTLA-4 treatment
leads to tumor eradication
Blood vessels
T cells
Tumor cells
Only RT + anti-CTLA-4 leads to increased T
cell-tumor cell interactions
Radiation up-regulates ICAM-1 and
Rae1 on 4T1 cancer cells in vivo
TUMOR CELLS
CD8 T CELLS
NONE
RT+9H10
NKG2D
TUMOR
SPLEEN
TDLN
CD69
Blocking NKG2D abolishes immune-mediated tumor
inhibition by combination of RT+anti-CTLA-4
2012
Patient with Metastatic NSCLC
Progressing after 3 lines of chemo
and chest RT: Multiple lung, bone
and liver metastasis
RT to one liver met
6 Gy X 5 ( TD 30 GY)
Ipilimumab, 3 mg/Kg, after first RT
q3 weeks, X 4 cycles
Metastatic NSCLC:
Response to RT+ipilimumab
Cancer Immunology Research, 2014, in press
Same patient: clinical and radiological CR at one year
Pre-clinical to clinical testing of
of RT and IRM
•
Flt3L (Demaria et al., Int J Radiat Oncol Biol Phys, 2004)
•
anti-CTLA-4 (Demaria et al., Clin Cancer Res 2005;
Matsumura et al., J Immunol 2008; Pilones et al., Clin
Cancer Res 2009; Dewan et al., Clin Cancer Res 2009;
Ruocco et al., J Clin Invest 2012)
•
NYU 02-58 Proof of
principle abscopal trial
•
open trial S12-02746
melanoma
•
trial in NSCLC pending
IRB
•
GVAX (Newcomb et al., Clin Cancer Res 2006)
anti-CD137 (Newcomb et al., Rad Res 2010)
•
TLR7-agonist (Dewan et al. Clin Cancer Res 2012)
•
open trial NCT01421017
•
anti-TGFb (Bouquet et al Clin Cancer Res 2012)
•
open trial NCT01401062
Radiation and Immunity Research Incubator
RT
/Immunotherap
ycombinations
IN VITRO
ICD Assay
(NIH) S10 RR027619-01
IN VIVO
Preclinical Research
Irradiator
Funding: $469,716
models
Clinical
protocol
Summary
• Radiation-induced immunogenic cell death as a
component of the in field response that can translate in
immunization against the primary tumor and its metastasis
• Mechanism of RT synergy with anti-CTLA4
• Successful combination of RT with anti CTLA-4 in different
pre-clinical and clinical tumor types
• Other combinations (TLR agonists, anti-TGFbeta, etc.)
• Optimal dose/fractionation is likely to be “model/system
specific”
Combining radiotherapy and cancer immunotherapy: a paradigm shift?
A novel application for an established cancer tx modality
JNCI, 2012
RT and Immunity Team
MH Barcellos-Hoff Ph.D.
Ilenia Pellicciotta Ph.D
Encouse Golden M.D.,Ph.D.
Derek Frances
Keith DeWyngaert, Ph.D.
Our patients
Sandra Demaria, M.D.
Maria Fenton-Kerimian, N.P.