Transcript immunotherapy

IMMUNOTHERAPY
Vanesa Gregorc MD
IRCCS San Raffaele, Milano
LUNG CANCER AS AN IMMUNOLOGICMEDIATED DISEASE AND TARGET FOR
IMMUNOTHERAPY
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Although many immunotherapies are being
investigated in NSCLC, currently
none have been FDA approved, as
vaccines and other immune-modulators have
yet to demonstrate considerable
improvements inOS in phase III clinical
trials
NOVEL ASPECTS
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Immune-related response criteria
Endpoints
The immune-related toxicities
All differ considerably
from conventional
cytotoxic agents and
targeted therapies
RESPONSE EVALUATION FOR
IMMUNOTHERAPY
•Permissive not restrictive
•RECIST/mWHO modified by
immunological criteria
•First radiological examination
the most critical (pseudoprogressions)
•irResponders with new lesions
also but decrease in baseline
lesions
•PD should be confirmed after 4 w
Wolchok JD, et al Clin Cancer Res
2009; 15:7412-7420.
NSCLC IMMUNOTHERAPY
IMMUNOMODULATORS
ANTI PD1-PDL1
ANTI CTLA4
VACCINES
MAGE A3
MUC1
BELAGEN-PUMATUCEL L
Tumor/T cells
Mechanism of action
IMMUNOMODULATORS
PROGRAMMED DEATH-1 IMMUNE
CHECKPONT (PD-1)
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PD-1 (cell receptor) is overexpressed on NSCLCinfiltrating T cells and these are functionally
exhausted cells
Ligands: PDL-1 and PDL-2 (tumor cell /APC)
Higher tumoral PDL-1 expression correlates with
decreased OS
RATIONALE
Blocking the PD-1 or PDL-1 pathway would
restore/promote the function of chronically
exhausted tumor-specific T cells and decrease
tumor-induced immune suppression
Zhang Y et al. Cell Mol Immunol. 2010;7:389- 395.
OF T CELL
OF TUMOR CELL
CLINICAL DEVELOPMENT OF INHIBITORS OF PD-1
IMMUNE CHECKPOINT
Inhibitors of PD-1 – Phase I trial
CT-O11
CT-O11
(0.26.0mg/kg
N=17
0.2-6.0 mg/kg IV
1YEAR SURVIVAL=42%, 2 YEAR SURVIVAL 24%
Lambrolizumab in NSCLC
Garon E. et al Abstract
MO18.02 IALS 2013
INHIBITORS OF PDL1- phase I
trial
Inhibitors of PD-L1-Activity in
NSCLC
PD L1 Expression
Pd-L1 Is broadly expressed in NSCLC
UPDATE
UPDATE
EGFR STATUS AND IMMUNOTHERAPY
EGFR wild type has higher PD-L1
expression vs EGFRm
MO18.01 EGFR status and MPDL3280A Activity in NSCLC Horn et al.
IPILIMUMAB
Co-stimulation via CD28: CTLA-4 blocks co-stimulation: Ipilimumab blocks CTLA-4:
T-cell activation
No T-cell activation
T-cell activation
T cell
T cell
T cell
CTLA4
CTLA4
TCR
CD28
APC
CD28
CD28
B7
MHC
TCR
TCR
MHC
APC
B7
MHC
ipilimumab
B7
APC
Adapted from Lebbé et al. ESMO 2008
APC, antigen-presenting cell; CTLA-4, cytotoxic T-lymphocyte antigen-4; MHC, major histocompatibility complex; TCR, T-cell receptor.
Adapted from DoomC. 2012 PILC
RANDOMIZED PHASE II STUDY OF
IPILIMUMAB AND CT IN ADVANCED NSCLC
[TITLE]
Lynch TJ, et al. phase II study. J Clin Oncol. 2012;30:2046-2054.
Adapted by J. Brahmer, 2013 ASCO Annual Meeting
RESULTS
RANDOMIZED PHASE II STUDY OF
IPILIMUMAB AND CT IN ADVANCED NSCLC
[TITLE]
Lynch TJ, et al. phase II study. J Clin Oncol. 2012;30:2046-2054.
Adapted by J. Brahmer, 2013 ASCO Annual Meeting
OUTCOME BY HISTOLOGY
OS IN SQUAMOUS
ONGOING PHASE III OF IPILIMUMAB IN
SQUAMOUS CELL LUNG CANCER
Carbo –
paclitaxel placebo
R
Carbo AUC 6
Paclitaxel 175 mg/mq
Ipilimumab 10 mg/kg q3w
Carbo –
paclitaxel ipilimumab
Double blind
Primary endpoint: OS
Secondary: OS in patients who receive one dose of ipi/placebo, PFS, RR
Adapted by J. Brahmer, 2013 ASCO Annual Meeting
LUNG CANCER VACCINATION. NSCLC
ONGOING PH 3 TRIALS
setting
Phase III
Early stage
Post surgery
MAGE-A3
MAGRIT Target 2270
recruited
Loc.adv. Stage
L-BLP25
START target 1300
Reported ASCO 2013
Post chemorad
>
8000
Advanced
In combo with chemo
Belagenpumatucel-L
STOP target 700
Reported ESMO2013
rEGF target 1000
ongoing
TG4010
TIME target 1000
ongoing
1E10 Target 1082
ongoing
L-BLP25
MUC1 is a mucinous glycoprotein that is overexpressed and aberrantly
glycosylated in many human malignancies. BLP25 is a synthetic, liposomal
cancer vaccine that targets the extracellular tandem repeat sequences of
Butts ASCO2013
the MUC1 tumour-associated antigen.
START TRIAL – STUDY DESIGN stage IIIA/B
post CT/RT (DC)
[TITLE]
START TRIAL – PRIMARY ENDPOINT OS
START TRIAL – SECONDARY ENDPOUINT
TIME TO PROGRESSION
START TRIAL – OS SUBGROUP ANALYSES BY
RANDOMIZATION DATA
STOP TRIAL
stage III/IV in DC after 1° line
belagenpumatucel-L
Primary endpoint: OS
Other endpoints: PFS, RR, QoL, CNS metastases, safety
Belagenpumatucel-L(Lucanix®) uses genetically modified whole tumour cells to
stimulate the patient's own immune system to attack the tumour. It is comprised
of 4 transforming growth factor (TGF)-ß2 antisense gene-modified,
Giaccone et al.ESMO 2013
irradiated, allogeneic NSCLC cell lines.
STOP TRIAL did not meet predefined
end point-OS
BUT: Significantly prolonged overall survival in
patients who began belagenpumatucel-L within
12 weeks of the completion of front-line
chemotherapy or RT in Sq and Non-Sq
conclusions
Immunotherapy has promising anti-tumor activity
in NSCLC and an unique set of side effects
consistent with the immune mechanism of action
Patient selection (biomarker) might be the key to
further development as a single agent and in
combination with other therapies
Phase III trials are ongoing in order to make
immunotherapy a reality for the treatment of
NSCLC