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

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%)

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