Optimization of fractionation with immunotherapy

Silvia Formenti, M.D.

Weill Cornell Medical College

New York Presbyterian Hospital

New York, NY

This presentation is the intellectual property of the presenter. Contact formenti@med.cornell.edu for permission to reprint/distribute

Grant/Research support from: Bristol Myers Squibb, Varian, Eli-Lilly,

Janssen, Regeneron, Eisai, Merck

Honoraria from: Bayer, Bristol Myers Squibb, Varian, ViewRay, Elekta,

Janssen, Regeneron, GlaxoSmithKline, Eisai, Astra Zeneca, MedImmune,

Merck US, EMD Serono, Sanofi

I will discuss the following off label use and/or investigational use in my presentation:

Ipilimumab (BMS)

Disclosures

Cancer: A Tumor/Host Interaction

Normal cell

Tumor cells

Immune cell

Elimination

Protection

Immune

rejection

Equilibrium Escape

a

Cancer

ProgressionResult of escape:less immunogenic tumor in a more

tumor-immune-tolerant host

How do standard anti-cancer treatments interfere with

this landscape ?

This presentation is the intellectual property of the presenter. Contact formenti@med.cornell.edu for permission to reprint/distribute.

Radiotherapy to convert the tumor into an in situ vaccine

IJROBP, 2004, 2005 IJROBP, 2012

Out of field,distant sites

ABSCOPAL EFFECTS ARE RARE

IMMUNOSUPPRESSION DOMINATES IN

ESTABLISHED TUMORS

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

Clinical Cancer Res 2005

1 2 3 4 5 6 7 8 90

50

100

150

250

500

750

1000

IFNδ

(pg/m

L)

Strain

RT

α-CD1d

BALB/c WT NKT-/-

-

--

+

- - - - +

+

+

- +

++ -

-

-

-

+

- - -

- +

++

α-CTLA4

AH-1-A5

pMCMV

***

***

**

*

**g

AH1

Tumor irradiation + CTLA-4 blockade

Primary tumor

Lung metastases

Anti-CTLA-4

mAb 9H10

4T1 mouse model of metastatic breast cancer

Experimental Endpoints: - Primary Tumor growth

- Lung metastasis - Immune response evaluation

Jim Allison

• Synergy of focal radiotherapy and immune checkpoint blockade

• Mechanisms of radiation-induced immunogenicity

- adjuvanticity

- antigenicity

• Dose/fractionation dependence

Fuertes et al., J Exp Med 2011

Diamond et al., J Exp Med 2011

Radiation-induces IFN-I

CTLs

3

1

2

BATF3-DCs (DC1)

4

5

6

TDLN

IFN-I

n-fo

ld c

ompa

red

to 0

Gy

c

0Gy

3x8G

y20G

y

0Gy

3x8G

y20G

y

Tnfsf10

Hsh2dIfih1Ccl7

Ccl2Gbp3Il18bpZbp1Bst2C2Ifi204Zbp1H28

Zbp1

CfbOas3Irf7Trim30aOas1aOas1a

Dhx58Ccl5Ifih1

Mx2

Mx1Ddx58Ddx58Il1rl1

Rsad2Ifit1

Ifnb1S100a9

4.0

1.0

0.25

Claire Vanpouille-Box

Single dose 30 GY with anti CTLA-4 precludes the abscopal effect

0Gy 0Gy

+

a-CTLA-4

30Gy 3x8Gy 30Gy

+

a-CTLA-4

3x8Gy

+

a-CTLA-4

Irra

dia

ted

sit

eA

bs

co

pa

l s

ite

0200

600

1000

1400

0200

600

1000

1400

14 22 30

14 22 30

Tu

mo

r volu

me (m

m3)

Tu

mo

r volu

me (m

m3)

14 22 30 14 22 30 14 22 30 14 22 30 14 22 30

6/70/7

14 22 30

0/7 0/7

14 22 30 14 22 30 14 22 30 14 22 30

p* p*

p# #

p**p*

p*

RT

a-CTLA-4

12 13 14

14 17 20

Vanpouille-Box et al., Nature Communications, 2017

Claire Vanpouille-Box

Cytoplasmic dsDNA accumulation

depends on RT dose per fractionTSA

shNS

DAPI

dsDNA

RFP

Merge

0Gy 8Gy 20Gy

c

Nature Communications, 2017Cai X, ET AL Molecular Cell. 2014;

Teunis B H GeijtenbeekNature Immunology 11, 979–980 (2010)

Host DNase TREX1 hides HIV from DNA sensors

Single high-dose RT induces TREX1 up-regulation

Nature Communications, 2017

The window of radiation immunogenicity

is determined by dsDNA vs TREX1

MDA-MB-231

4175-TR

Human TNBC

Is dose/fraction clinically relevant?

38

40

36

10

33

16

27

32

43

22 5 9

30

17 1

23

37

44 3 4-100

-50

0

50

100

150

200

250

Mean

tu

mo

r vo

lum

e c

han

ge (

%)

CR

PR

SD

PD

RECIST

38

40

36

10

33

16

27

32

43

22 5 9

30

17 1

23

37

44 3 4-100

-50

0

50

100

150

200

250

Best

tum

or

vo

lum

e c

han

ge (

%)

b c

0 10 20 30 40 500

50

100

Months

Overa

ll s

urv

ival (%

)

d

Median: 7.36 mo95% CI: 4.4-12.62

0 5 10 15 200

50

100

Months

Pro

gre

ssio

n f

ree s

urv

ival (%

)e

0 10 20 30 40 500

50

100

Months

Overa

ll s

urv

ival (%

) PD

CR/PR/SD

p<0.001

f

Median: 3.81 mo95% CI: 3.06-5.49

a

6 Gy 9.5 Gy

Blood sampling PET/CT imaging

Radiation therapy

Days 1 2 3 4 5 22 43 64 88 FUBaseline

Ipilimumab

Blood sampling

PET/CT imaging

g

0 5 10 15 200

50

100

Months

Pro

gre

ssio

n f

ree s

urv

ival (%

)

PD

CR/PR/SD

p<0.001

Abscopal response to RT+Ipilimumab

38

40

36

10

33

16

27

32

43

22 5 9

30

17 1

23

37

44 3 4-100

-50

0

50

100

150

200

250

Mean

tu

mo

r vo

lum

e c

han

ge (

%)

CR

PR

SD

PD

RECIST

38

40

36

10

33

16

27

32

43

22 5 9

30

17 1

23

37

44 3 4-100

-50

0

50

100

150

200

250

Best

tum

or

vo

lum

e c

han

ge (

%)

b c

0 10 20 30 40 500

50

100

Months

Overa

ll s

urv

ival (%

)

d

Median: 7.36 mo95% CI: 4.4-12.62

0 5 10 15 200

50

100

Months

Pro

gre

ssio

n f

ree s

urv

ival (%

)

e

0 10 20 30 40 500

50

100

Months

Overa

ll s

urv

ival (%

) PD

CR/PR/SD

p<0.001

f

Median: 3.81 mo95% CI: 3.06-5.49

a

6 Gy 9.5 Gy

Blood sampling PET/CT imaging

Radiation therapy

Days 1 2 3 4 5 22 43 64 88 FUBaseline

Ipilimumab

Blood sampling

PET/CT imaging

g

0 5 10 15 200

50

100

Months

Pro

gre

ssio

n f

ree s

urv

ival (%

)

PD

CR/PR/SD

p<0.001

Response : 18% (RECIST v1.1)

CR = 2PR = 5SD = 5

PD = 28

Total pts = 39

Radiation “repositioned” Ipilimumab in metastatic

NSCLC: 18% ORR

Nature Medicine, Nov 2018

*

CR/P

R (n

=7)

SD (n

=5)

PD (n

=8)

NE (n

=15)

0

2

4

6

20

30

IFN

b (

pg

/ml)

*

**

***

*

*

Day 22Baseline

CD8 T cells present in the post-treatment blood of pt #4

recognize an immunogenic mutation in KPNA2

(karyopherin A2)

Nature Medicine 2018

p15 not detected in pre-tx tumorp16 detected in pre-tx tumor

HLA-A*24:02

HLA-C*12:03 Tumor cell Mutated peptide

Mutated protein

MHC-I

Mutated peptide (neoantigen) presented on MHC-I complex

Mutated DNA

Mutated KPNA2 in patient 4

Example of a radiation-induced neo-antigen: an epitope from a mutated gene known to be up-regulated by radiation in human cancer cells in vitro and in vivo

=Radiation converts the tumor into an in situ vaccine

Lhuillier et al., Genome Medicine, 2019

Production of

endogenous

adjuvants

Viral mimicry and in situ vaccination by focal RT

Exposure of

neoantigensNature Medicine 2018

45 Gy in 3 fractions for peripheral lung, liver, and abdominal/pelvic; 50 Gy in 5 fractions for central lung and mediastinal/cervical;30 Gy in 3 fractions for osseous and spinal/ paraspinal”

13% ORR

~ Pembrolizumab alone

● Phase II study ● 92 pts w/ metastatic NSCLC

● Pembro +/- RT (8Gy x 3)

● 12-week ORR: 18% vs 36%

● Median PFS: 1.9 vs 6.6 mo

● Median OS: 7.6 vs 15.9 mo

Doubling of ORR (36 VS 18)and median OS (16 m VS 8m )

by adding RT, 8 GyX3, to pembro

Most effect in PDL1 negative

Significantly better intracranial PFS for patients receiving multi-fraction SRS (9 Gy X3)

compared to single-fraction SRS(70% versus 46% at 6 months, p = 0.01)

• Radiation induces viral mimicry with cytosolic DNA accumulation leading to

cGAS/STING pathway activation and IFNb production, with a dose/fraction effect

• Radiation increases tumor immunogenicity by enhancing the expression of

immunogenic mutations

• There is a dose/fraction dependency for the combination of RT with ICB to covert

the tumor into an in situ vaccine

Conclusions

Silvia C. FormentiEncouse Golden Josephine Kang

Andrew BrandmeierJohn Ng

Himanshu NagarEric Ko

J. Keith Dewyngaert

Sandra DemariaClaire Vanpouille-Box

Julie DiamondErik Wennerberg

Claire LhuillierNils RudqvistSheila Spada

Maud CharpentierSamantha Van Nest

Yasmeen SarfrazMaria Rodriguez-Ruiz

Lorenzo GalluzziTakahiro Yamazaki

Aitziber BuqueAi Sato

Marissa Friedman Jonathan J.

Preclinical CoreKarsten PilonesCamille DaviaudJeffrey Kraynak

Clinical CoreMaria Fenton

Sharanya ChandrasekharPragya Yadav

NYUAbraham Chachoua

Benjamin CooperKent FriedmanAdriana Heguy

Robert SchneiderBeatrix M. Ueberheide

Jessica R. Chapman

WCM Biostatistics & EpidemiologyXi Kathy Zhou

FUNDINGNational Cancer Institute R01 CA201246 & R01 R01CA198533The Chemotherapy Foundation BCRFNYU Vittorio Defendi Fellowship in Pathobiology

NIH, NCI Radiation Branch Molykutty J. Aryankalayil

Norman Coleman

Mount SinaiSacha GnjaticNaoko Imai