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Combining radiation therapy with immunotherapy: clinical translation
Silvia C Formenti, M.D.
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Disclosures
Principal Investigator:
NIH 1 S10 RR027619-01 Preclinical Research Irradiator
NCI R01CA161891-01Immunomodulation of breast cancer via TLR7 agonist IMQ and RT
DOD BC100481 / W81XWH-11-1-0530Multi-Team Award (MTA)Radiation-Induced Vaccination to Breast Cancer
13-A0-00-001870-01Breast Cancer Research Foundation Targeting key inhibitory pathways to improve radiation-induced vaccination in breast cancer
Consultant/Speaker:Bristol Myers Squibb, Varian, Jensen, Elekta, Regeneron
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Dunn et al, Nature Immunology 2002Koebel et al, Nature 2007
How do standard anti-cancer treatments interfere with
this landscape ?
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TUMOR
CD8T cell
CD4 T cell
IL-12
IN SITU VACCINATION HYPOTHESIS
RT
IJROBP, 2005 IJROBP, 2012
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Immunogenic cell death induced by treatment is defined by 3 molecular signals
TUMOR DC
CTL activationCD8T cell IL-2
γIFN
DC
CD4 T cell
IL-12
CRT TLR4!! !
!
P2RX7
HMGB-1
ATP
CRT, the “eat me” signal calreticulin translocates to cell surface (Obeid et al., Nat Med 2007, 13:54-61; Cell Death Differ 2007, 14:1848)
HMGB-1, a damage associated molecular pattern (DAMP) binds to TLR4 to promote cross-presentation of tumor-derived antigens (Apetoh et al., Nat Med 2007, 13:1050)
ATP released by dying cells binds to P2RX7 purigergic receptor leading to inflammasome activation and IL-1β production (Ghiringhelli et al., Nat Med 2009, 15:1170)
IL-1β
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Encouse Golden
Oncoimmunology, 2014
In vitro assay for RT-induced ICD
HMGB1
ATP
CRT
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Pro-immunogenic effects of ionizing radiation
Chen and Mellman, Immunity, 2013
1. Apetoh, Nature Med 2007Golden, Oncoimmunology 2014
2. Chakravarty, Can Res 1998Nikitina, Int J Can 2001Liao, JI 2004 Gulley, Clin Can Res, 2005
3. Lugade, JI 2005Demaria, Clin Can Res 2005Reits, JEM 2006Brody, JCO 2010Burnette, Can Research 2011
4. Matsumura JI, 2008Klug, Cancer Cell 2013
5. Lugade, JI 2005
6. Chakraborty, JI 2003Chakraborty, Can Res 2004Newcomb, Clin Can Res 2006
7. Demaria, IJROBP 2004Ruocco, JCI 2012
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Abscopal EffectEffect of ionizing radiation on cancer
outside the radiation field Latin ab (position away from) and scopus (mark or target)
*Mole RJ. Whole body irradiation - radiology or medicine? Br J Radiol 1953; 26:234
Abscopalresponse
IJROBP 2004; Lancet Oncology 2009
Why are abscopal effects so rare?
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IMMUNOSUPPRESSION DOMINATES IN ESTABLISHED TUMORS
Vesely MD, 2011, Annu.Rev.Immunol 29:235-71
A need to combine radiotherapy with immunotherapy
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NYU experience in combining immunotherapy strategies with radiation
FLT-3L/GM-CSF TLR agonists
Anti-CTLA4 Anti-PD-1 Anti-TGFβ
Priming phase :
Effector phase:
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\BALB/C mice injected at two separate sites with the syngeneic mammary carcinoma 67NR cell line
R“primary”
L“secondary”
XRT
20 Flt3-L (0.5mg/kg)RT
2 Gy
067NR5x104 or 105each sides,
primary R and secondary L
Day:
Hypothesis: Ionizing radiation can stimulate anti-tumor immunity –by generating an in situ
vaccine - and combination with immunotherapy may uncover this effect
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RT+Flt3-L : systemic anti-cancer effects
Irradiated non-irradiated
Int J Radiation Oncology Biol Phys 2004
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Abscopal Effect is abrogated in nude mice
Int J Radiation Oncology Biol Phys 2004
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NYU 0258Abscopal trial RT+GM-CSF in metastatic solid tumors
GM-CSFGM-CSF
DAY1 8 15 22 29 36 42 49-56
Within 2 weeks from study entry: Baseline measurementsCT and PET
RTWeek 4, 5
RTWeek 1, 2
Week 2, 3 Week 5, 6
End of Week 3Assess clinical response
Week 7-8Assess clinical response and CT/PET response
GM-CSF125 µg/m2
RT 3.5GyX10
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Abscopal effect 10/37 (27%)Abscopal effect and survival, 37 patients (NYU 02-58)
A.
Abscopal responders likely to be patients already more immunocompetent
ASTRO 2012
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Study Design: TimelineImiquimod (IMQ) is a synthetic TLR-7 agonist
IMQ topical cream FDA approved for treatment of superficial basal cell carcinoma, actinic keratosis, and external genital warts
Clin Can Res, 2012
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TLR agonists and RT+/-Cytoxan
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NCI-R01 Immunomodulation of breast cancer via TLR7 agonist IMQ and RT, 2011-15
TLR7 agonist Imiquimod: Abscopal response
Response at a distant site of disease
10/2012 01/2013 03/2013
Baseline vs post-tx photo of control area (NO) ImiquimodBaseline vs post-tx photo of RT + Imiquimod)
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NYU experience in combining immunotherapy strategies with radiation
FLT-3L/GM-CSF TLR agonists
Anti-CTLA4 Anti-PD-1 Anti-TGFβ
Priming phase :
Effector phase:
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Blockade of CTLA-4 is required for anti-tumor T cell priming by radiation in vivo
Demaria et al., Clin Cancer Res 2005
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Progressing after 3 lines of chemoand chest RT: Multiple lung, bone and liver metastasis
RT to one liver met6 Gy X 5 ( TD 30 GY)Ipilimumab, 3 mg/Kg, after first RTq3 weeks, X 4 cycles
Patient with Metastatic NSCLC
Golden et al Cancer Immunology Research, 2014
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Metastatic NSCLC: Response to RT+ipilimumab
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2010 2013
H&E
TIA-1
CD8
20132010R
atio
CD
8/Fo
xP3
cells
/HP
F
CD8
cells
/HP
F Fox-P3
Cancer Imm. Research, 2014
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Clinical and radiological CR at one year: currently NED at 25 m
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2012
12 ongoing trials testing testing combinations of RT and Ipilimumab:
At NYU:NCT01689974
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799 patients randomized
Site: bone mets
Dose : 8 Gy, single fraction
Time: RT within 2 days fromIPI, then anytime during IPI
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Study failed to meet its main endpoint
Study powered to detect a 4 month difference in median overallsurvival (15.8 versus 12 months)
Curves split after 6 months Lancet Oncology 2014
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Difference in progression free survival
Is PFS good enough of an endpoint?At 6 months 30.7% versus 18.1%
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MANY QUESTIONS REMAIN:
- Optimal site to irradiate in metastatic disease- Patient selection- Sequencing of radiotherapy/immunotherapy- RT dose and fractionation- Best combinations
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Tum
or v
olum
e (m
m3 )
Days post inoculation
***
**
Lung
s m
etas
tase
s
***
******
Inhibition of tumor lung metastases is seen only when radiation to the primary tumor is given with anti-TGFβ mAb
4T1: spontaneous systemic micro-metastases
“primary”tumor
Lungs micro-metastases
RT
(submitted for publication)
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Fresolimumab+RT TRIAL, in metastatic breast cancer
MTA from DOD
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Patient #2
11/10/11 before tx 12/19/11 a month after first TX 2/27/12 Last PET/CT11/18/11 First Fresolimumab+RT to liver 2/8/12 Second Freso+RT to breast skin Response reported as irSD, 28%
reduction, no new lesions,
Fresolimumab and radiation (7.5 GyX3) to one lesion
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Accrued 22 patients:11 per armComparison of OS and PFS based on
fresolimumab dose ( arm A=10mg, arm B=1 mg)
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PD-1 blockade improves therapeutic efficacy of RT+TGFbeta neutralization
Vanpouille-Box et al., In preparation
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RT combination with: Trial/ tumor site accrual
Flt3L (Demaria et al., Int J Radiat Oncol Biol Phys, 2004)
Proof of principle abscopal trial (met disease all sites)NYU 02-58
37/37
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)
Ipilimumab –RT randomized Met melanomaS12-02746
Ipilimumab -RTMet NSCLC trialS14-00208
12/48
18/29
TLR7-agonist (Dewan et al. Clin Cancer Res 2012)
Imiquimod-RT trialNCT01421017
14/29
anti-TGFβ (Bouquet et al Clin Cancer Res 2012)2
Fresolimumab-RT Randomized NCT01421017
24/24
Clinical translation
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NYU Radiation and Immunity Research Incubator
RT/ITcombinations
IN VITROICD Assay
IN VIVO models
Clinical protocol
(NIH) S10 RR027619-01
Preclinical Research IrradiatorFunding: $469,716
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Summary
Preclinical and clinical evidence suggests that local radiotherapy cancontribute to the efficacy of cancer immunotherapy, by rendering theirradiated tumor more immunogenic
Radiotherapy can be harnessed as an adjuvant to immunotherapy as it mayconvert non-responding patients to responders to the same immunotherapy
Dose/fractionation and sequencing of radiotherapy need to be explored incombination with each immunotherapy strategies, in prospective PHASE I-IIclinical trials
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Our patients
Encouse Golden M.D.,Ph.D. Mike Dustin Ph.D.
Claire Vanpouille-Box Ph.D. Karsten Pilones Ph D.
MH Barcellos-Hoff Ph.D.
Keith DeWyngaert, Ph.D. Maria Fenton-Kerimian, N.P.
NYU RT and Immunity Team
Sandra Demaria M.D.