Terapias anti CTLA-4

Curso Básico de Inmunología e Inmunoterapia y cáncer

Alfonso Berrocal

Hospital General Valencia

Mecanismo de acción

Teoría Tres señales: Co-estimulación

Interacción B7/CD28

• CD28 se expresa constitutivamente en linfocitos CD4 y CD8 naive

• Su función es coestimulatoria tras ligarse a B7 1 y 2

• CTLA-4 se induce tras la estimulación y frena respuesta inmune

• La expresión de B7 1 y 2 es regulada por el estado de activación de la APC

Mecanismo de acción anti CTLA-4

Célula T

TCR CTLA4

APC

MHC

CD28

B7

Inhibición Célula T

Célula T

TCR CD28

CTLA4

APC

MHC B7

Activación Célula T

Célula T

TCR

CTLA4

APC

MHC B7

Potenciación Célula T

IPILIMUMAB bloquea CTLA-4

Ipilimumab y T-regs

OX40 e Ipilimumab y T-regs

Tipos inmunoglobulinas

Tremelimumab IgG2 sin ADCC

Eficacia en la clinica

Perspectiva histórica de Ipilimumab

1991

1990 1995 2000 2005 2010

UC Berkeley team hypothesizes that blocking CTLA-4 could potentiate

immune system to fight cancer

1996

BMS Seattle team identifies CTLA-4

as target for impacting immune

system

First phase 1 trial for ipilimumab in prostate cancer

2000

Medarex develops first fully human

monoclonal antibody to block

CTLA-4

1999

BMS acquires Medarex gaining

full rights to ipilimumab

2009

BMS and Medarex enter agreement to co-develop & co-

commercialize ipilimumab

2004

Ipilimumab approved for

metastatic melanoma

2011

First phase 3 data presented in ipilimumab in

metastatic melanoma

2010

Eficacia en Melanoma

Median OS, months 95% CI HR P value

Survival rate (%)

1-year 2-year

Ipilimumab + gp100 10.0 8.5–11.5 0.68 <0.001 43.6 21.6

Ipilimumab 10.1 8.0–13.8 0.66 0.003 45.6 23.5

gp100 6.4 5.5–8.7 25.3 13.7

Pro

po

rtio

n o

f p

atie

nts

aliv

e (

%)

Years

0

20

40

60

80

100

0 1 2 3 4

• Ipilimumab was the first therapy for unresectable or metastatic melanoma to improve overall survival in a phase 3 trial1

Hodi FS, et al. N Engl J Med 2010;363:711–723

Primary Analysis of Pooled OS Data: 1861 Patients

Patients at Risk

Ipilimumab 1861 839 370 254 192 170 120 26 15 5 0

Pro

po

rtio

n A

live

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Months

0 12 24 36 48 60 72 84 96 108 120

Median OS, months (95% CI): 11.4 (10.7–12.1)

3-year OS rate, % (95% CI): 22 (20–24)

Ipilimumab

CENSORED

Schadendorf D, et al. Eur J Cancer 2013;49(suppl 2): abstract 24LBA

Analisis subgrupos SG (N=1861)

Naive 604 301 106 74 64 60 18 1 0 0 0

Pretratados 1257 538 264 180 128 110 102 25 15 5 0

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 12 24 36 48 60 72 84 96 108 120

Treatment-naive

CENSORED

Previously Treated

CENSORED

Meses

Pro

po

rció

n v

ivo

s

Pacientes en Riesgo 3 mg/kg 965 429 127 73 41 29 28 12 8 4 0 10 mg/kg 706 316 191 145 118 111 64 2 0 0 0 Otros 190 94 52 36 33 30 28 12 7 1 0

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 12 24 36 48 60 72 84 96 108 120

10 mg/kg

CENSORED

Other

CENSORED

3 mg/kg

CENSORED

Pro

po

rció

n v

ivo

s

Meses

Mediana, meses (95% CI)

Tasa SG 3 años,%

(95% CI)

Naive 13.5 (11.9, 15.4) 26 (21, 30)

Pretratados 10.7 (9.6, 11.4) 20 (18, 23)

Mediana, meses (95% CI)

Tasa SG 3 años, % (95% CI)

3 mg/kg 11.4 (10.3, 12.5) 21 (17, 24)

10 mg/kg 11.1 (9.9, 13.0) 24 (21, 28)

Other 12.4 (10.4, 15.1) 20 (14, 26)

• Por tratamiento previo • Por dosis

Schadendorf D, et al. Eur J Cancer 2013;49(suppl 2): abstract 24LBA

Los datos de LTS son consistentes con diferentes dosis y regímenes de tratamiento

Total N > 240 Phase I/II studies (Pre-chemo, TXT eligible, TXT failure)

Phase III: Single-dose XRT ± ipilimumab (n = 800) Survival

Phase II: Paclitaxel/carboplatin ± ipilimumab NSCLC (n = 210) irPFS SCLC (n = 210) irPFS

Phase III: ipilimumab vs placebo (n = 600) Survival

Phase III: Paclitaxel/carboplatin ± ipilimumab NSCLC (n = 920) Survival

Phase III: Etoposide/platinum ± ipilimumab SCLC (n = 1100) Survival

Phase II Gastric Ca

Phase II Ovarian Ca Study 201

Study 162 (n = 114) irPFS

Other development programs

NSCLC/SCLC

Prostate

7 Phase I/II Studies

Study 043 (post-tax)

Study 041

Study 095 (chemo-naïve)

Study 104

Study 156

Ipilimumab en otros tumores

Pancreas, Glioma, Hodgkin, Head and Neck, Cervix, Lymphoma, Breast, Renal, Sarcoma, GIST, Merckel….

Other

Próstata 043 (Post TAX) Ipi

(n=399) Pbo

(n=400)

Median OS, mo (95% CI) 11.2 (9.6–12.6) 10.0 (8.4–11.2)

HR (95% CI) 0.84 (0.72–0.98)

Stratified log-ranka P=0.03

1-yr OS rate 47% 41%

2-yr OS rate 25% 17%

3-yr OS rateb 12% 6%

Supervivencia NSCLC

Lynch T, et al. J Clin Oncol 2012;30(17):2046-54

Características especiales de respuesta y toxicidad

Ipilimumab response patterns

150

125

100

75

50

25

0

-25

-50

-75

-100

-125

19,373

17,242

15,111

12,980

10,849

8,718

6,587

4,456

2,325

194

-1,937

SPD

(mm

2)

Week after initial dose

50

25

0

–25

–50

–75

–100

–125

Ch

ange

fro

m b

ase

line

SP

D (

%)

Week after initial dose

1,272

1,124

975

827

678

530

382

233

85

-64

-212

SPD

(mm

2)

Ch

ange

fro

m b

ase

line

SP

D (

%)

-9 -3 3 9 15 21 27 33 39 45 51

Week after initial dose

Ch

ange

fro

m b

ase

line

SP

D (

%)

SPD

(mm

2)

2,894

2,556

2,218

1,881

1,543

1,206

868

530

193

-145

-482

50

25

0

-25

-50

-75

-100

-125

Total tumor volume

Index lesion

New lesions

Ipilimumab

SPD = Sum of the Product of the perpendicular Diameters (a measure of tumor volume)

-9 -3 3 9 15 21 27 33 39 45 51

-9 -3 3 9 15 21 27 33 39 45 51

Stable disease with slow

reduction in tumor volume

Response after an initial increase in tumor volume

Response in basal lesions

Ch

ange

fro

m b

ase

line

SP

D (

%)

SPD

(mm

2)

2,810

2,482

2,154

1,826

1,498

1,171

843

515

187

-140

-468

50

25

0

-25

-50

-75

-100

-125

-9 -3 3 9 15 21 27 33 39 45 51

9 months

Week after initial dose

PD

PR

CR

5.2 months 6 months

9.4 Months

Response after new lessions

aparition

Wolchok J, et al. Clin Cancer Res 2009;15:7412–7420

Criterios de respuesta inmune irRC

* **

Adapted from Wolchok et al. 2009

Adapted from Hodi et al. 2010

Toxicidades inmunes

Toxicity kinetics

Weber JS, et al. J Clin Oncol 2012;30:2691–2697 YERVOY SmPC, available at http://www.ema.europa.eu

CTLA-4 y PD-1 Diferente acción sobre el sistema inmune

Toxicity management

Symptomatic treatment Mild

Persistent mild or moderate

Severe , clinical deterioration or

persistent moderate

Oral steroid 1 mg/kg Delay next Ipilimumab dose

High dose IV steroid 2 mg/kg with an slow reduction (1 month) if improvement

Immunosuppressive therapy if no response in 7 days

End Ipilimumab

Weber JS, et al. J Clin Oncol 2012;30:2691–2697 YERVOY SmPC, available at http://www.ema.europa.eu

Predicción de respuesta

Cifra de linfocitos

Ku GY et al. Cancer 2010; 116:1767-1775.

Neo-antigenos y Checkpoint therapy

Neoantigenos y CTLA-4

Carga mutacional y beneficio Ipilimumab

Supervivencia por numero mutaciones

Supervivencia por firma genética de neo-epitopos

Conclusiones anti CTLA-4

• Primer tratamiento sobre punto de control inmunológico

• Mecanismo de acción innovador

• Eficacia clínica demostrada de forma consistente en melanoma

• Patrón especifico de respuesta y toxicidad

• Dificultad predicción de la respuesta