"DELS BIOLÒGICS A LES TERÀPIES CEL.LULARS IMMUNOMEDIADES EN EL
TRACTAMENT DE MALALTS AMB CÀNCER"
Cristina Cruz
Unitat de Fases I
Servei d'Oncologia
Hospital Vall d'Hebron
Biològ cs en càncer
biològics
1
La teràpia basada en biològics utilitza:
organismes vius,
Substàncies procedents d’organismes vius, o
versions sintètiques d’aquestes substàncies
biològics: 4ª modalitat de tractament del
càncer
2
Cirurgia
Radioteràpia
Quimioteràpia
Biològics
Alguns tipus de
teràpia biològica
ataquen
directament la
cèl.lula cancerosa
...
p.e. oncovirus
immunoteràpia
3
… Altres tipus de teràpia biològica exploten la capacitat
natural del sistema immune per atacar la cèl.lula
cancerosa
Vacunes
Cèl.lules
Bacteris
Citoquines: IL, IFN
Pèptids
Anticossos
immunoteràpia
4
Immune
checkpoints:
ANTI -CTLA-4
ANTI -PD-1 /
-PDL-1
Limfòcit T citotòxic
i complement Bloqueig dirigit de
receptors
immunomoduladors
5
Immune checkpoints:
CTLA-4 ( Cytotoxic T-lymphocyte–
associated antigen 4 )
6
PD- 1 (Programmed Death-1)
Ipilimumab
- anticòs monoclonal - Ig G1humana – anti-CTLA-4
(actua a fases inicials d’activació de la cèl.lula T)
- melanoma -> regressió (RR 10-15%)
- dosi ?
- freqüents efectes adversos (AE) relacionats amb la
immunitat
7
60% de pacients – algun AE immunològic (15% G2-3)
Pell > diarrea >>> endocrinopatia> hepatitis
4 patrons de resposta al tractament amb
Ipilimumab Response in
baseline lesions
Response in total tumor burden in the presence of new lesions
Response after initial increase in total tumor burden Slow, steady decline
in total tumor burden
3 months
PD
PR
CR
1.4 years
9 months
6 months 8 months 5 months
Ch
an
ge f
rom
baseli
ne (
%)
Relative day from randomization date
153
135
117
99
82
64
46
28
10
–8
–26
SP
D (m
m2)
977
863
749
635
521
407
293
179
65
–49
–163
SP
D (m
m2)
Ch
an
ge f
rom
baseli
ne (
%)
3737
3301
2865
2429
1993
1557
1121
685
249
–187
–623
SP
D (m
m2)
748
664
580
496
411
327
243
159
75
–9
–94
100
75
50
25
0
–25
–50
–75
–100
–125
2067
1826
1585
1344
1102
861
620
379
138
–103
–345
SP
D (m
m2)
SP
D (m
m2)
Ch
an
ge f
rom
baseli
ne (
%)
Relative day from randomization date Relative day from randomization date
Relative day from randomization date Relative day from randomization date Relative day from randomization date
Ch
an
ge f
rom
baselin
e (
%)
50
25
0
–25
–50
–75
–100
–125
Ch
an
ge f
rom
baselin
e (
%)
Ch
an
ge f
rom
baselin
e (
%)
SP
D (m
m2)
50
25
0
–25
–50
–75
–100
–125
50
25
0
–25
–50
–75
–100
–125
50
25
0
–25
–50
–75
–100
–125
50
25
0
–25
–50
–75
–100
–125
8528
7533
6538
5543
4548
3553
2558
1563
569
–426
–1421
9
Wk 20: Regression
Wk 36: Still Regressing
Screening
Wk 12: Progression
Pseudoprogressió
J.D. Wolchok, et al.“Guidelines for the evaluation of immune therapy activity in solid tumors:
immune-related response criteria.” Clin Cancer Res 2009;15(23):7412–20
The Immune-related Response Criteria (irRC) s
10
RECIST 1.1 irRC Target/index lesions
Up to 5 total (2/organ), unidimensional
up to 15 total (5/organ), bidimensional
New lesions Always represent PD Incorporated into TB if ≥5 x 5 mm
Non-target/index lesions
Contribute to define CR, PR, SD and PD
Contribute to define irCR
CR Disappearance of all known lesion(s); confirmed at 4 wk+
Disappearance of all known lesion(s); confirmed at 4 wk+
PR At least 30% decrease in SLD; confirmed at 4 wk+
At least 50% decrease in TB; confirmed at 4 wk+
SD Neither PR nor PD criteria met
Neither PR nor PD criteria met
PD 20% increase in SLD compared with nadir and/or unequivocal progression of non-target lesions and /or appearance of new lesions
At least 25% increase in TB compared with nadir in two consecutive observations at least 4 wk apart
RECIST 1.1 vs irRC
11
PD- 1 (Programmed Death-1)
12
PD- 1 (Programmed Death-1)
- T-cell coinhibitory receptor
- 2 known ligands: PD-L1 (B7-H1) & PD-L2 (B7-DC)
Via PD-1 / PDL-1
13
14
Anti PD-L1
15
ASCO 2013, estudi fase I MPDL3280A
Tumor Typea
Estimated PD-L1 Prevalence (non-
trial samples),b ≈ %
NSCLC (SCC) 50%
NSCLC (adeno) 45%
Colon 45%
Melanoma 40%
Head and neck SCC 25%
Renal 20%
Anti-PD-1 (BMS-936558, MDX-
1106)
Design 3+3 dose escalation (MEL, RCC, NSCLC, prostate, CRC)
Objectives Safety, MTD, PK, efficacy, biomarkers
Schedule IV infusion every 2w. Doses 0.1, 1.0, 3.0, or 10.0 mg/kg
Patients n=296 (CRC, CRPC, NSCLC-122 pt-, MEL-104-, RCC -34pt)
DLTS No DLTs (10mg/Kg).
Common AE Fatigue, rash, diarrhea, pruritus, decreased appetite, and nausea (similar across the dose levels tested). (irAE: pneumonitis, colitis, hepatitis, hypophysitis, thyroiditis, vitiligo)
MTD NO MTD.
PK Linear
PD PD-1–receptor occupancy by the antibody on circulating CD3+ T cells by FACS
16
Nivolumab
Frequent (>5%)
Special Interest (>3%)
17
Nivolumab:
AEs
Nivolumab:
Eficàcia
20
Biomarcador: PD-L1
Anti-PD-L1 antibody (BMS-
936559)
Design 3+3 dose escalation Advanced NSCLC, MEL, RCC, CRC, Gastric, Pancreatic, Ovarian, Breast
Objectives Safety, MTD, PK, efficacy, biomarkers
Schedule IV infusion every 2 w of each 6-week treatment cycle. 0.3 -1 – 3 - 10.0 mg /kg
Patients n=207
DLTS No DLTs (10mg/Kg).
Common AE Fatigue, infusion reactions, diarrhea, arthralgia, rash, nausea, pruritus and headache (similar across the dose levels tested). (irAE: rash, hypothyroidism, hepatitis; sarcoidosis (1), endophtalmitis (1), DM (1), myasthenia gravis (1))
MTD NO MTD.
PK half life: 15d; dose-dependent serum levels
PD/Biomarker
s
PD-L1 occupancy on CD3+ PBMC: >65% in 4 groups
Efficacy OR in NSCLC, MEL, RCC, ovarian (at all doses of 1mg/kg or higher). 21
22
BMS-936559:
AEs
23
24
Anti-PD-1 antibody
(MK-3475- Lambrolizumab)
Anti-PD-L1 antibody
(MPDL3280A)
PD-L1 Statusa
(n = 53)
RECIST 1.1
ORRb PD Ratec
IHC 3
(n = 6)
83%
(5/6)
17%
(1/6)
IHC 2 and 3
(n = 13)
46%
(6/13)
23%
(3/13)
IHC 1/2/3
(n = 26)
31%
(8/26)
38%
(10/26)
All patients
(IHC 0/1/2/3 and
7 patients with
diagnostic
unknown;
n = 53)
23%
(12/53)
40%
(21/53)
PD-L1 (Melanoma)
a Patient experiencing ongoing benefit per investigator. Patients first dosed at 1-20 mg/kg by Oct 1, 2012; data cutoff Apr 30, 2013.
Phase Ia: Duration of
Treatment in Responders - NSCLC
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 75 78 81 84
Time in Study (Weeks)
1 mg/kg IV q3wk
20 mg/kg IV q3wk
10 mg/kg IV q3wk
15 mg/kg IV q3wk
15 mg/kg IV q3wk
15 mg/kg IV q3wk
20 mg/kg IV q3wk
20 mg/kg IV q3wk
20 mg/kg IV q3wk
20 mg/kg IV q3wk
15 mg/kg IV q3wk
20 mg/kg IV q3wk
Figure 1. Duration of treatment and response for NSCLC patients with response
dosed by 1 October 2012 in Study PCD4989g
On study, on treatment
Treatment discontinued
First response
First PD
On study, post treatment
Ongoing response
NSCLC = Non-small cell lung cancer
On treatment = Last Dose + 3 weeks
Duration of Treatment and Response
Time (Weeks)
Histology IHC
Nonsquamous IHC 0
Squamous IHC 3
Nonsquamous IHC 0
Nonsquamous IHC 1
Nonsquamous IHC 0
Squamous IHC 2
Nonsquamous IHC 3
Squamous IHC 3
Nonsquamous IHC 3
Nonsquamous IHC 0
Nonsquamous IHC 3
Nonsquamous IHC 1
a
25
Anti-PD-L1 antibody
(MPDL3280A)
26
Futur desenvolupament de la
immunoteràpia…
Combinació amb altres fàrmacs:
Ipilimumab + Nivolumab
29
ASCO 2013
Totes les combinacions són segures?
30
Preguntes per un immunòleg…
Lawrence MS, et al. Nature. 2013.
Somatic mutation frequencies observed in exomes from 3083 tumor-normal pairs
- immunogenicitat?
- immunocompetència?
- coexistència de mecanismes inhibidors?
-PD1 / PDL1?
31
Walter John Urba MD, PhD