Combining radiation therapy with immunotherapy: clinical translation

Silvia C Formenti, M.D.

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

Dunn et al, Nature Immunology 2002Koebel et al, Nature 2007

How do standard anti-cancer treatments interfere with

this landscape ?

TUMOR

CD8T cell

CD4 T cell

IL-12

IN SITU VACCINATION HYPOTHESIS

RT

IJROBP, 2005 IJROBP, 2012

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

Encouse Golden

Oncoimmunology, 2014

In vitro assay for RT-induced ICD

HMGB1

ATP

CRT

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

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?

IMMUNOSUPPRESSION DOMINATES IN ESTABLISHED TUMORS

Vesely MD, 2011, Annu.Rev.Immunol 29:235-71

A need to combine radiotherapy with immunotherapy

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:

\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

RT+Flt3-L : systemic anti-cancer effects

Irradiated non-irradiated

Int J Radiation Oncology Biol Phys 2004

Abscopal Effect is abrogated in nude mice

Int J Radiation Oncology Biol Phys 2004

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

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

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

TLR agonists and RT+/-Cytoxan

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)

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:

Blockade of CTLA-4 is required for anti-tumor T cell priming by radiation in vivo

Demaria et al., Clin Cancer Res 2005

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

Metastatic NSCLC: Response to RT+ipilimumab

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

Clinical and radiological CR at one year: currently NED at 25 m

2012

12 ongoing trials testing testing combinations of RT and Ipilimumab:

At NYU:NCT01689974

799 patients randomized

Site: bone mets

Dose : 8 Gy, single fraction

Time: RT within 2 days fromIPI, then anytime during IPI

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

Difference in progression free survival

Is PFS good enough of an endpoint?At 6 months 30.7% versus 18.1%

MANY QUESTIONS REMAIN:

- Optimal site to irradiate in metastatic disease- Patient selection- Sequencing of radiotherapy/immunotherapy- RT dose and fractionation- Best combinations

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)

Fresolimumab+RT TRIAL, in metastatic breast cancer

MTA from DOD

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

Accrued 22 patients:11 per armComparison of OS and PFS based on

fresolimumab dose ( arm A=10mg, arm B=1 mg)

PD-1 blockade improves therapeutic efficacy of RT+TGFbeta neutralization

Vanpouille-Box et al., In preparation

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

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

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

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.