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Immunterapi ved kreft
hva er status ?
Steinar Aamdal,
Professor
Avdeling for Kreftbehandling
Oslo Universitetssykehus
Evidence for the role of immune
system in tumor rejection
• Spontaneous regression
• Regression of metastases after removal of primary tumor
• Infiltration of tumors by lymphocytes and macrophages
• Lymphocyte proliferation in draining lymph nodes
• Higher incidence of cancer after immunosuppression/-immunodeficiency (AIDS, neonates, aged, transplant patients)
Evidence for the role of immune
system in tumor rejection
• Spontaneous regression
• Regression of metastases after removal of primary tumor
• Infiltration of tumors by lymphocytes and macrophages
• Lymphocyte proliferation in draining lymph nodes
• Higher incidence of cancer after immunosuppression/-immunodeficiency (AIDS, neonates, aged, transplant patients)
Prognostica tumour infiltrating lymphocytes
are identified in many tumour types
• Example: presence of intratumoural T cells correlates with improved
clinical outcome in advanced ovarian carcinoma1
• Also seen in NSCLC,2 CRC,3 breast,4,5 melanoma,6,7 renal,8,9 prostate,10
head and neck,11 cervical12
T cells infiltrating
tumour cells
No intratumoural
T cells: T cells
restricted to tissue
surrounding tumour
No intratumoural T cells (n=72)
Median OS = 18 months
Intratumoural T cells (n=102)
Median OS = 50.3 months
Month
0 132 12 24 36 48 60 72 84 96 108 120
0
100
75
50
25
Ove
rall
su
rviv
al
(%)
P<0.001
aCorrelation with improved overall or progression-free survival, disease stage, or therapy outcome;
type of lymphocyte dictates where there is a correlation with improved or worsened outcome
Figures adapted from Zhang L, et al. N Engl J Med 2003;348(3):203–213, Copyright ©2003 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
1. Zhang L, et al. N Engl J Med 2003;348(3):203–213; 2. Hiraoka K, et al. Br J Cancer 2006;94(2):275–280; 3. Galon J, et al. Science 2006;313(5795):1960–1964; 4. Mahmoud SM, et al.
J Clin Oncol 2011;29(15):1949–1955; 5. Loi S, et al. J Clin Oncol 2013;31(7):860–867; 6. Piras F, et al. Cancer 2005;104(6):1246–1254; 7. Azimi F, et al. J Clin Oncol 2012;30(21):2678–2683
8. Siddiqui SA, et al. Clin Cancer Res 2007;13(7):2075–2081; 9. Donskov F, et al. Br J Cancer 2002;87(2):194–201; 10. Flammiger A, et al. APMIS 2012;120(11):901–908
11. Badoual C, et al. Clin Cancer Res 2006;12(2):465–472; 12. Piersma SJ, et al. Cancer Res 2007;67(1):354–361
The immune system matters
First cancer immunotherapy Colye`s toxins
• William Coley, surgeon in 1888 observed remission of
sarcoma in a patient after infection with Streptococcus pyogenes
• Coley`s toxins: Mixture (Parke Davies)of killed S.pyogens and Serratia, used until 1953.Finally tested out in a clinical trial 1000 cancer patients – inconsistent results and sometimes dangerous - Coley ridiculed as a quack
• But !
• Contained lipopolysaccarides stimulating: interferon production, NK cells, macrophages, and contained CpG stimulating Toll-Like Receptors (TLR) 9 inducing TH1 immune response. Coley Pharmaceutical acquired by Pfizer (2010) - develop drugs targeting TLR`s
IFN-α as adjuvant therapy for
melanoma
History of cancer immunotherapy: key
milestones
Immune component to spontaneous
regressions in melanoma
Adoptive T cell immunotherapy
IL-2 approved for RCC and melanoma (FDA 98)
First immunotherapy approved for
prostate cancer (Provenge-
sipuleucel-T, FDA 2011, EMA Sept
2013)
First checkpoint inhibitor (ipilimumab)
approved for advanced melanoma
(March 2011 FDA, July 2011 EMA, Norway
March 2013) Figure adapted with permission from Kirkwood JM. Ca J Clin 2012;62:309–35, Copyright ©2012 American Cancer Society; George S, et al. JNCCN 2011;9:1011–
18; Garbe C, et al. The Oncologist 2011;16:2–24; Rosenberg SA. Sci Transl Med 2012;4:127ps8; Cheeve, et al. Clin Cancer Res 2011;17:3520–26; Kantoff PW, et
al. N Engl J Med 2010;363; Mansh M. Yale J Biol Med 2011;84:381–89; Hodi FS, et al. N Engl J Med 2010;363:711–23
1970s 1980s 1990s 2000s 2011
First tumour- associated antigen cloned (MAGE-1)
BCG approved for bladder cancer
Discovery of checkpoint inhibitor !
Discovery of the dendritic cell
Tumour specific mAbs
Enthusiasm Phase Skeptisism Phase Renaissance Phase
First cancer vaccine approved by EMA Sept. 2013 Sipuleucel-T, Provenge, in prostate cancer
COMPLETE COURSE OF
THERAPY:
3 CYCLES
WEEKS 0, 2, and 4
Day 1 Leukapheresis
Day 1-2 Sipuleucel-T is
manufactured
Day 2 Patient is infused
Apheresis Center
1.5 – 2.0 ml mononuclear cells
Dendreon Doctor’s Office
•# cells infused was the maximum # of cells that could be prepared from the leukapheresis product. Median # of nucleated cells per infusion = 3.65 x 109 and median # of CD54+ bright cells per infusion = 7.45 x 108. Patients premedicated 30 minutes before each infusion with Tylenol (650 mg) and Benadryl (50 mg). Sipuleucel-T or placebo administered IV over 30 minutes, and patients observed 30 minutes
Active immunotherapy using sipuleucel-T in patients
with metastatic castrate-resistant prostate cancer
• In a phase 3 trial, sipuleucel-T prolonged overall survival compared with
placebo (median overall survival was 25.8 months with sipulecel-T versus 21.7
months with placebo)
• Adverse events more frequently reported in the sipuleucel-T group than in the
placebo group included chills, fever, and headache
Years since randomisation
Pro
babili
ty o
f su
rviv
al (%
)
0 1 2 3 4 5 6
100
80
60
40
20
0
Sipuleucel-T (n=341)
Placebo (n=171)
Adapted from Kantoff PW, et al. N Engl J Med 2010;363:411–422
Hazard ratio 0.78 (0.61–0.98) P=0.03
Cellular immune response to tumour derived
antigens
T-celle Priming and Activation
T-cell Primiing
T-cell activation
T-cell inactivation
Anti-CTLA-41, Ipilimumab, mechanism of action Immune checkpoint inhibitor
CTLA-4: Cytotoxic T-Lymphocyte-Antigen-4
Immune Checkpoint Inhibitors
Immunotherapy using ipilimumab in patients
with advanced melanoma
• Ipilimumab was the first therapy for unresectable or metastatic melanoma
ever to improve overall survival in a phase 3 trial1
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
1. Adapted from Hodi FS, et al. N Engl J Med 2010;363:711–723; 2. Data on file; Bristol-Myers-Squibb Company, Princeton, NJ
Pro
po
rtio
n o
f p
atie
nts
aliv
e (
%)
Years
0
20
40
60
80
100
0 1 2 3 4
• In clinical trials, most adverse events associated with ipilimumab were immune related and were managed using ipilimumab-specific treatment algorithms2
• The most frequently reported immune-related adverse events associated with ipilimumab monotherapy (≥10%, all grades) in a phase 3 trial were: diarrhea (28%), pruritus (24%), and rash (19%)1
Active immunotherapy using ipilimumab in
patients with advanced melanoma
• Ipilimumab was the first therapy in advanced melanoma ever to improve
overall survival in a phase 3 trial1
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
1. Adapted from Hodi FS, et al. N Engl J Med 2010;363:711–723; 2. Data on file; Bristol-Myers-Squibb Company, Princeton, NJ
Pro
po
rtio
n o
f p
atie
nts
aliv
e (
%)
Years
0
20
40
60
80
100
0 1 2 3 4
• In clinical trials, most adverse events associated with ipilimumab were immune related and were managed using ipilimumab-specific treatment algorithms2
• The most frequently reported immune-related adverse events associated with ipilimumab monotherapy (≥10%, all grades) in a phase 3 trial were: diarrhea (28%), pruritus (24%), and rash (19%)1
«tail of the curve»
403 137 136
Need special attention
Evolution of ipilimumab response: initial PD with durable CR
Screening
Week 12 Initial increase in
total tumour burden (mWHO PD)
Week 16 Responding
Week 188 Durable & ongoing response
without signs of IRAEs
Courtesy of K. Harmankaya, Vienna
Week 96 ongoing response
Dr. Kaan Harmankaya – Deptment of Dermatology, Medical University of Vienna, Austria
Initial PD with durable late response CRCorresponding CT-Scans - Ipilimumab 10mg/kg
Baseline Week 12 Week 16
Week 188 total
Week 176 (-025)
NO irAEs
Dr. Kaan Harmankaya – Deptment of Dermatology, Medical University of Vienna, Austria
Initial PD with durable late response CRCorresponding CT-Scans - Ipilimumab 10mg/kg
Baseline Week 12 Week 16
Week 188 total
Week 176 (-025)
NO irAEs
[TITLE]
Presented By Padmanee Sharma, MD, PhD at 2013 ASCO Annual Meeting
Long term ipilimumab results ?
[TITLE]
Presented By Jedd D. Wolchok, MD, PhD at 2013 ASCO Annual Meeting
IINF
NF
INFγ
[TITLE]
Presented By Mario Sznol, MD at 2013 ASCO Annual Meeting
n=17
n=53 1-year survival
82%
95% CI (69.0–94.4)
100
90
70
40
20
0
80
60
50
30
10
0 3 6 9 12 15 18 21 24 27 30 33 36
Pro
po
rtio
n o
f p
atie
nts
aliv
e (
%)
Months
Censored
Targeting distinct and potentially complementary immune evasion
pathways: anti-PD-1 plus anti-CTLA-4
• Clinical activity nivolumaba plus ipilimumab on a concurrent or
sequenced regimen: phase 1 trial in patients with advanced melanoma1
aInvestigational compound; bData from separate, non-comparative trials; use cross-trial comparisons with caution in the absence data from a
randomised, comparative trial 1. Adapted from Wolchok J, et al. Presented at ASCO 2013: oral presentation 9012; 2. Hodi FS, et al. N Engl J Med 2010;363:711–723
3. Sznol M, et al. Presented at ASCO 2013: oral presentation CRA9006
Died/treated
1 mg/kg nivolumab
+ 3 mg/kg ipilimumab 2/17
All concurrent regimen 9/53
• 53% of patients had grade 3/4 AEs on the concurrent regimen; most were manageable using standard protocols1
• With ~13 months of follow-up, 90% of patients continue to respond1
• Historical 1-year survival rates with ipilimumab or nivolumab monotherapy in patients with advanced melanoma are 45.6% (phase 3)2 and 62% (phase 1), respectively3b
Regulating the T cell immune response1,2a
• T cell responses are regulated
through a complex balance of
inhibitory (‘checkpoint’) and
activating signals
• Tumours can dysregulate
checkpoint and activating
pathways, and consequently
the immune response
• Targeting checkpoint and
activating pathways is an
evolving approach to cancer
therapy, designed to promote an
immune response
PD-1
CTLA-4
Inhibitory
receptors
Activating
receptors
TIM-3
LAG-3
Antagonistic
(blocking)
antibodies
Agonistic
antibodies
T cell stimulation
CD28
OX40
CD137
aThe image shows only a selection of the receptors/pathways involved
LAG-3 = lymphocyte-activation gene 3
1. Adapted from Mellman I, et al. Nature 2011:480;481–489; 2. Pardoll DM. Nat Rev Cancer 2012;12:252–264
Pan-tumour potential for immunotherapies
• Therapiesa are being studied for the potential for activity in many different
types of cancer, irrespective of mutated genes or tumour histology
aSelected therapies and tumour types are shown: additional agents are, for example in phase 1 studies in patients with solid tumours
www.clinicaltrials.gov. accessed 19 August 2013
Pembrolizumab (anti-PD-1)
Rationale for combining immunotherapy with other
therapeutic modalities
Multiple mechanisms of potential synergy between the different treatment modalities
CD8 T cell Adhesion molecules
(CAM-1) and death
receptors (FAS)
Peptide pools
Vascular normalisation
T cell initiation
Cytokine release
CD8 T cells
T cell function MDSC
Tregs
Activation of apoptosis
Blockage of cell cycle
TAA
Upregulates MHCI
Adhesion molecules/
death receptors
APM
CD8 T cells
(homeostatic peripheral
expansion)
MDSC
Tregs
M2 macrophages
TAA cross-
presentation
CD8 T cells
Effector immune infiltrate
Release of tumour
antigens (cascade)
Translocation of
calreticulin
Radiation
Chemotherapy Targeted therapies
Dendritic cell
Upregulation of MHCI
Uploading
of antigen
processing
machinery
1. Adapted from Hodge JW. Semin Oncol 2012;39:323–339; 2. Drake CG Ann Oncol 2012;23 Suppl 8:viii41–6; 3. Ménard C, et al. Cancer Immunol
Immunother 2008;57:1579–1587; 4. Hannani D, et al. Cancer J 2011;17:351–358; 5. Ribas A at al. Curr Opin Immunol 2013:25:291–296
Target host
Target
tumor
Immunotherapy Targeted
Therapy
Immunotherapy – targeted therapy
Single agent immunotherapies (ipilimumab) give low but durable response rates
Single agent targeted therapies (vemurafenib, BRAF inhibitors) give high but non-durable responses
Combination ?
In CRC, EGFR
mutations related to
PDL-1 expression
[TITLE]
Presented By Padmanee Sharma, MD, PhD at 2013 ASCO Annual Meeting
[TITLE]
Presented By Padmanee Sharma, MD, PhD at 2013 ASCO Annual Meeting
Other Immunotherapies
• Adaptive T-cell therapy with Tumor Infiltrating Lymphocytes
- TIL and checkpoint inhibitor ?
• Dendritic cell vaccines transfected with tumor mRNA and
checkpoint inhibitor ?
• Peptide vaccines + checkpoint inhibitor ?
• ---
• CAR (Chimeric Antigen Receptor) therapy – retargeting T-
cells
• T-VEC – Herpes simplex derived oncolytic virus, local
injections
Immunotherapy studies Avdeling for kreftbehandling OUS
• Checkpoint inhibitors
– Ipilimumab Phase II (3), melanoma (BMS)
– Ipilimumab + nivolumab versus ipilimumab, Phase III, melanoma (BMS)
– Ipilumumab, Phase III, adjuvant, melanoma (BMS)
– PD1 inhibitor, Nivolumab, Phase III, versus ipilimumab, melanoma (MSD)
– PD1 inhibitor, MK-3475, versus DTIC, Phase III, melanoma (MSD)
– PDI inhibitor, LGX, Phase I, melanoma (Novartis)
– PD1 inhibitor, MK-3475, Phase I, lung cancer (MSD)
– PD1 inhibitor, Nivolumab, Phase II, lymphoma (BMS)
• Dendritic celle vaccines (Section for Cell Therapy), Phase I/II studies
– Malignant melanoma 3 (OUS)
– Prostate cancer (OUS)
– Glioblastoma (OUS)
– (Ovarian carcinoma) (OUS)
• Peptide vaccines (Telomerase - and Ras peptide vaccines)
– Malignant melanoma, Phase I (OUS)
– Lung cancer (2), Phase I and II (OUS)
– Pancreatic cancer, Phase I-II (Targovax)
– Lung cancer, Phase I-II (Ultimovax)
– Prostate cancer Phase I-II (Ultimovax)
• Ipilimumab, National Phase IV, malignant melanoma (HOD)
• Intratumoral injection of LTX -315, solid cancer, Phase I, (Lytix)
• Radio-immunconjugate, Betalutin, lymphoma (Nordic NanoVector)
• Lymvac, intratumoral injection of DC, Rituximab + local radiation, lymphoma(OUS)
PREDICTIVE MARKERS FOR
RESPONSE ?
DRUG COSTS ?
Challenges
[TITLE]
Presented By Padmanee Sharma, MD, PhD at 2013 ASCO Annual Meeting
Immunotherapy Checkpoints
Phase III, randomized, Double-Blind study of Nivolumab or
Nivolumab + Ipilimumab versus Ipilimumab in advanced melanoma
(ongoing)
R Ipilimumab
Ipilimumab + Nivolumab
Nivolumab
Protocol CA209067
Prostate Cancer Vaccine, Provenge
• Provenge (DC and fusion protein PAP + GM-
CSF) in metastatic asymtomatic/minimal
symptomatic androgen independent prostate
cancer- survival benfit of 4.1 months from
median 21.7 to 25.8 months.
• First therapeutic cancer vaccine ever
approved by FDA (2011)
• EMA approval in Sept 2013
[TITLE]
Presented By Padmanee Sharma, MD, PhD at 2013 ASCO Annual Meeting
Immunotherapy Checkpoints