TRATAMENTELE SISTEMICE IN

CANCER: HORMONOTERAPIA ŞI
IMUNOTERAPIA

Prof. Dr. L. Miron

 SUMAR

Agenţii chimioterapici – clasificare

- principii
- mecanisme de acţiune
- efecte secundare
Terapiile biologice:
Terapii moleculare ţintite – clasificare
- mecanisme de acţiune
- indicaţii
- Immunoterapia
- Hormonoterapia
- Terapia genică
 Tratamente “active” in cancer

I. Tratamente loco-regionale:
Chirurgia
Radioterapia
II. Tratamente sistemice:
Chimioterapia citotoxică
Terapiile biologice:
- terapiile moleculare ţintite
- hormonoterapia cancerelor
- imunoterapia în cancer

Terapia genică ?
 II. HORMONOTERAPIA

Hormonoterapia sau manipularea hormonala antitumorală este tratamentul

sistemic al cancerelor hormonodependente prin blocarea surselor hormonale
sau blocarea acţiunii hormonilo la nivel celular.
Actul de naştere al hormonoterapiei

Cancerul mamar – actualităţi şi atitudini în practica clinică

Slide 3
Slide 4
Cancerul mamar – actualităţi şi atitudini în practica clinică
Cancerul mamar – actualităţi şi atitudini în practica clinică
Căile principale de sinteză a estradiol, testosteron
şi DHT
Hormonotherapy:
mecanisms of action
 Clasificarea hormonoterapicelor antineoplazice
I. Hormonoterapia supresivă (ablativă):
 Ablaţia glandelor endocrine- castrarea- ovarectomie cancer mamar), orhiectomie
(cancer de prostată)
II. Hormonoterapia aditivă :
 A. Competitivă:
 a) Modulatorii selectivi ai receptorilor estrogeni (SERM: tamoxifen, toremifen,
raloxifen
 b) Blocanţi puri de receptor: formestan
 c) Antiandrogenii: Flutamid, bicalutamid (Casodex®), nilutamid
 d) Progestive: MEDROXIPROGESTEROL CETAT, MEGESTROL
 e) Estrogens: DIETILSTILBESTROL, ESTRADURIN, CLORTRIANISEN
 f) Androgens: METILTESTOSTERON, FLUOXIMESTERON
 B. Privative:
 a) Inhibitoii funcţiei hipofizare: analogii de RH-LG (Gn-RH): goserlelin
( Zoladex), buserlelin, triptorelin, leuprolid
 b. Inhibitorii de aromatază (IA): aminoglutetimid (generaţia I), anastrazol
(Arimidex), letrozol (nonstreoidieni, generaţia IIIl), exemetan (Aromasnin®, ,
abiraterone (generaţia IV)
 III. Inhibitorie
 Tiroidian hormons
 Somatostatins analogs: octreotid, lanreotid, pasitreotid
 I. Hormonoterapia supresiva (ablativă)

 I. Supresivă (ablativă):

Castrarea ovariana- anexectomia

Castrarea testiculara ( cancerul de prostată)- orhictomia
 I.Hormonoterapia supresivă

GOSERELIN in cancerul mamar

Sir Beatson raporta primul succes
clinic prin ovariectomie

1895 1930… 1967 1980…

Iradierea ovarelor
Elwood Jensen descopera
ca alternativa la ovariectomie
receptorii estrogenici
in cancerul mamar
Sainsbury R. British J. of Surgery 2003; 90: 517- 526
Ekmektzoglou K.A. Eur. J. of Obstetrics & Gynecology 145 (2009) 3 - 8
 B. Hormonoterapia aditivă privativă

B. Privativă:
a) Inhibarea funcţei hipofizare: Gn-RH inhibitors: goserlelin,b
userlelin, triptorelin, leuprolid acetat

b. Inhibitorii de aromataza (AI): AMNOGLUTETIMID (gen I),

ANASTROZOL, LETROZOL (gen III, nonsteroidal), FORMESTAN
(steroidieni, EXEMESTAN)
 Nivele de supresie hormonala in mamar

Gonadotropi Estrogeni
(FSH + LH) Progesteron
Premenopauza
Ovar

Prolactina Tamoxifen
RE +
Glanda hipofiza Corticosteroizi
LHRH
FASLODEX
Pre/post- Corticosuprarenala
(hipotalamus)menopauza
GOSERELIN Androgeni EstrogenI
Hormonul
adenocorticotrop Progesteron
(ACTH)
Conversie periferica
ARIMIDEX
 III> Hormonoterapia aditivă- competitivă

C. Competitivă:
 a) Modulatorii selectivi ai receptorilor estrogeni (SERM:
TAMOXIFEN, TOREMIFEN, RALOXIFEN
 b) Blocanţi puri de receptor: formestan
 c) Antiandrogenii: Flutamid, bicalutamid (Casodex®), nilutamid
 d) Progestive: MEDROXIPROGESTEROL CETAT, MEGESTROL
 e) Estrogens: DIETILSTILBESTROL, ESTRADURIN,
CLORTRIANISEN
 f) Androgens: METILTESTOSTERON, FLUOXIMESTERON
Cancerul mamar – actualităţi şi atitudini în practica clinică
 Optiuni ale hormonoterapiei in cancerul mamar

Mecanism de actiune Optiuni

Blocarea receptorilor estrogenici • Antiestrogeni
Tamoxifen
Toremifene

Ablatie hormonala • Chirurgie

• Iradiere (utilizata rara)
• Analogi LHRH
Goserelin (ZOLADEX)

Supresia sintezei de estrogen • Inhibitori de aromataza

Anastrozol (ARIMIDEX)
Exemestan
Letrozol

Estrogen receptor downregulation • Antagonist pur al receptorilor

estrogenici
Fulvestrant (FASLODEX)

LHRH = luteinizing hormone-releasing hormone.

Hayes DR, Robertson JFR. In: Robertson JFR et al, eds. Endocrine Therapy of Breast Cancer. 2002. Leake R. Endocrine-
Related Cancer. 1997;4:289-296; NCI. Available at: www.cancer.gov/clinicaltrials/results/fulvestrant0802.
Cancerul mamar – actualităţi şi atitudini în practica clinică
 FASLODEX: primul antagonist pur al
receptorilor estrogenici
Spre deosebire de tamoxifen, FASLODEX inhiba complet expresia RE1-3

FASLODEX se leaga, blocheaza si In consecinta, este foarte mica posibilitatea

accelereaza degradarea dezvoltarii rezistentei prin activarea RE pe cai
si pierderea RE alternative (ex mecanismele mediate de factorul
de crestere)
Prin mecanismul de actiune diferit, FASLODEX poate intarzia dezvoltarea rezistentei
si, astfel, sa creasca sansa unui control durabil al bolii

1. Nicholson RI & Johnston SR et al. Breast Cancer Res Treat 2005; 93: S3-S10;
2. Ring A & D Dowsett M. Endocrine-Related Cancer 2004; 11: 643-658;
3. Moy B & Goss PE. Clin Cancer Res 2006; 12: 4790-4793
 Efecte secundare Tamoxifen

Bufeuri
Edeme
Leucoree
Greturi (rare)
Tromboza
Modificari pasagere ale nr. trombocite
Cataracta
Metroragii
Hiperplazie endometru
Risc scazut de neoplazie uterina
ER and m-TOR pathways
PI3K-Akt-mTOR pathway

24
Everolimus- inhibitor de mTOR

25
 mTOR inhibitors
1. Temsirolimus (Torisel)- first mTOR
inhibitor ever registered
2. Everolimus (RAD001, Afinitor)
3. Ridaforolimus- marginal benefit in STS
second line, not approved by FDA

26
 Regulation of the G1/S checkpoint

Presented By Mitchell Dowsett at 2015 ASCO Annual Meeting

Palbociclib

28
Ribociclib (LEE011) is a selective inhibitor of CDK4/6

• Ribociclib is an orally bioavailable and selective

Ribociclib is an inhibitor of CDK4/6
inhibitor of CDK4/61

• Inhibition of CDK4/6 with ribociclib should prevent the

phosphorylation of Rb, resulting in cell cycle arrest in
G1/S phase
Ribociclib

• Ribociclib has demonstrated in vitro and

in vivo antitumor activity:

– Prevents Rb phosphorylation, reactivating Rb, and

causing cell cycle arrest in Rb+ cell lines1,2

– Antitumor activity against a variety of xenograft

tumor models, including PIK3CA-mutant BC, NRAS-
and BRAF-mutant melanoma, and neuroblastoma1,2

AKT, protein kinase B; AR, androgen receptor; BC, breast cancer; CDK, cyclin-dependent kinase; E2F, E2 transcription factor;ER, estrogen receptor; G, gap phase; INK4, inhibitor
of CDK4; M, mitotic phase; MAPK, mitogen-activated protein kinase;mTOR, mammalian target of rapamycin; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells;
PI3K, phosphatidylinositol 3-kinase; PgR, progesterone receptor; Rb, retinoblastoma; Rb(+), Rb (-positive); S, synthesis phase; STAT, signal transducer and activator of
transcription.
1. Kim S, et al. AACR-NCI-EORTC 2013;Abstract B264; 2. Rader J, et al. Clin Cancer Res 2013;19:6173–6182.
 Changing landscape of ER+ metastatic breast cancer

• SOC regimens for metastatic HR+/HER2- BC based on endocrine Tx

Combination
therapies
Tamoxifen
approved1 Fulvestrant Everolimus Ribociclib,
(Selective ER approved4 approved6 abemaciclib
modulator) (Selective ER (mTOR approved9-12
degrader) inhibitor) (CDK
inhibitors)
AIs
approved2,3 Palbociclib7,8
Anastrozole Fulvestrant approved
Exemestan HD5 (CDK
e approved inhibitor)
Letrozole

1970–801990s 2002 2010 2012 2015 2017

AIs, aromatase inhibitors; BC, breast cancer;
ER, oestrogen receptor; HD, high dose’;
SOC, standard of care
Abemaciclib is currently only approved for use in the US.
The EMA CHMP adopted a positive opinion on abemaciclib on 26 July 2018;
marketing authorisation has not yet been granted by the European
Commission (status as per the date of slide preparation: 18 September 2018)
11. FDA. https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm578081.htm; 12. FDA. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm598404.htm.
1 Cohen MH et al. Oncologist 2001;6:4-11; 2. EMA. http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Arimidex_30/WC500109487.pdf;
3. EMA. http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Femara_30/WC500128492.pdf;
4. Robertson JFR, et al. Cancer 2003;98:229e38; 5. Di Leo A, et al. J Clin Oncol 2010;28:4594e600;
6. Baselga, et al. N Engl J Med 2012;366:520–529; 7. FDA. https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm549978.htm;
8. EMA. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/003853/human_med_002034.jsp&mid=WC0b01ac058001d124;
9. FDA. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm546438.htm;
10. EMA. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/004213/human_med_002149.jsp&mid=WC0b01ac058001d124;
 Anatomia prostatei
A – Central zone 1%
B – Fibromuscular zone
C – Transitional zone 15%
D – Peripheral zone 84%
E – Periurethral zone

Seminal Vesicles

Prostate
 HORMONAL THERAPY – a short history

a | Charles Huggins descopera raspunsul cancerului de prostata la terapia androgenica.

b | Andrew Schally descopera structura hormonului eliberator de gonadotropine (LHRH)
si creaza modalitati de sinteza a acestuia.
c | Patrick Walsh dezvolta tehnici pentru prostatectomia radicala retropubiana.
d | Malcolm Bagshaw investigheaza posibilitatea folosirii radioterapiei in cancerul de
prostata.
e | Gerald Murphy evalueaza eficacitatea chimioterapiei la pacientii cu cancer de prostata
hormonorefractar si descopera antigenul specific prostatei (PSA).
S.R.Denmeade and J.T.Isaacs. Nature Reviews-Cancer 2002;Vol.2:389-96
Cancerul de prostată hormonosensibil
Androgeni

ACTH Celula prostatica

Suprarenala
DHT
LHRH
Hipotalamus
Alte celule tinta

Glanda pituitara DHT Receptor

androgenic

Testicul
LH

Testosteron circulant
Control feed back negativ

LHRH - hormonul eliberator de gonadotropine

LH - hormonul luteinizant
DHT - dihidrotestosteron
ACTH - adrenocorticotrop hipofizar
Hormonodependenţa cancerului de prostata
 Sursele de androgeni masurabili in ser

 Androgenii sunt
sintetizaţi din 3 surse:
 Testicul
 Glande suprarenale
 Tumora prostatica

Ryan et al. AACR Conference 2012; Abstract LB-434 (Oral presentation)

Abiraterone acetat (ZYTIGA) inhibă biosinteza de hormoni
androgeni la nivelul celor trei surse3, 11

 Pentru a încetini progresia tumorală întreţinută de androgeni, toate cele trei surse
de androgeni trebuie inhibate – testiculele, glandele suprarenale şi tumora 11
Nivele de hormonoterapie in cancerul de
prostata

GnRH agonists
Goserelin, Triptorelin
Leuprorelin

GnRH antagonists
Degarelix

Estrogens

Prostate
tumour
 Neoplasm de prostata

I. Hipofizar: analogi de LH-RHŞ goserelin, leuprolid

 agonistii de LH-RH: degarelix

II. Suprarenal: abiraterone, inhibitoi suprarenalieni

III. Periferic –antiandrogenii: bicalutamid, ciproteron

enzalutamid
Chimoterapia citotoxica: docetaxel, cabayitaxel
 Clasificarea hormonoterapicelor
antineoplazice
I. ABLATIV: Hormonoterapia supresivă (ablativă):

Orhiectomia bilaterala- castrarea


 II.PRIVATIV (HIPOTALAMO-HIPOFIZAR):Privative:
a) Inhibitoii funcţiei hipofizare: -Analogii de RH-LG (Gn-RH): goserlelin
( Zoladex), buserlelin, triptorelin, leuprolid, histrelin si triptorelin
- Antagonistii: Degarelix
b) SUPRARENAL : inhibitorii steroidogenezei CYP P450:
KETOCONAZOL
ABIRATERONE

III. COMPETITIV:
a) Antiandrogenii: Flutamid, Bbicalutami, Nilutamid (Casodex®), d)
 b) Estrogens: DIETILSTILBESTROL, ESTRADURIN, CLORTRIANISEN
 c) Androgens: METILTESTOSTERON, FLUOXIMESTERON

Cancerul de prostata hormonorezistent
• Novel hormonotherapies
– Abiraterone (Zytiga)
– Enzalutamide
• Bone targeted radioisotopes
– Radium-223
• Novel cytotoxics
– Cabazitaxel
• Repositioning older cytotoxics
– Docetaxel in androgen dependent prostate cancer
• Immunotherapies
– Sipuleucel-T
– Prostvac
– Ipilimumab
 Bicalutamid si Flutamid

♂ Antiandrogeni Indicate in tratamentul carcinomului de prostata avansat, in

combinatie cu terapia cu analogi LHRH sau cu castrarea chirurgicala

♂ Cele mai frecvente reactii adverse:

♂ Bufeuri ♂ Ameteala
♂ Durere abdominala ♂ Edem
♂ Constipatie ♂ Hematurie
♂ Flatulenta ♂ Ginecomastie
♂ Astenie ♂ Sensibilitatea sanilor

Casodex 50 mg- Rezumatul Caracteristicilor Produsului,

I. IMUNOTERAPIA NESPECIFICĂ: Vaccin BCG Baillus Calmette Guerin
-Interferon Alfa (IFNα)
-Interleukina 2 (IL2)
-Imiquimod
Blocaj CTLA4 ( Ipilimummab)

II. IMUNOTERAPIA SPECIFICĂ: Vaccinuri cu:

- Proteine asociate tumori (PAT)
- Peptide asociate tumorilor
- Celule de tumori iradiate

III. IMUNOTEAPIA ADAPTATIVĂ: - Celule dendritice

- Sipuleucel T
- Clonele de celule T
Limfocitele infiltrative tumoral (TIL)

IV. INHIBITORII CHECKPOINT: CTLA-4 (Ipilimummab)

PD-1 si PDL-1
Immunotherapia in cancer

Prof Lucian Miron

Cancer Regional Institute Iasi
Medicine Faculty „ Gr.T. Popa” Iaşi
Dernières nouvelles: immunotherapie

for the last couple of years…

 Rolul sitemului imun

 Imunoterapia utilizează acţiunea mecanismelor naturale de apărare ale

organismului împotriva tumorii şi/sau substanţe implicate în diferenţierea,
proliferarea şi activitatea celulelor imune

 Aceşti agenţi acţionează prin unul sau mai multe din mecanisme:
- stimularea răspunsului antitumoral
- scăderea mecanismelor supresoare
- ameliorarea toleranţei la chimio- sau radioterapie
- modificarea celulelor tumorale pentru creşterea imunogenicităţii
acestora
47
 Paradigm Shift in Cancer Therapy
Historical Paradigm: New Paradigm:
Targeting Tumor Cells Targeting Immune Cells
Lymphocyte

Tumor Cell
 History of Cancer Immunotherapy:
Key Milestones
IFN-α as adjuvant Pembrolizumab and Atezolizumab
Discovery of therapy for melanoma nivolumab approved approved for
dendritic cell for advanced advanced urothelial
melanoma carcinoma
BCG Discovery of
approved checkpoint inhibitors
for bladder
Tumor-specific
cancer Nivoluma Nivoluma
monoclonal First immunotherapy
Abs approved for prostate b b
Adoptive T-cell cancer (sipuleucel-T) approved approved
immunotherapy for RCC for HL

1970s 1980s 1990s 2000s 2011 2014 2015 2016

Immune component IL-2 approved

for RCC and
Nivolumab Atezolizumab
to spontaneous First checkpoint approved for granted
melanoma (US)
regressions in inhibitor (ipilimumab) NSCLC[12,13] Priority Review
melanoma for PD-L1+
First tumor-associated approved for Pembrolizumab NSCLC
antigen cloned (MAGE-1) advanced melanoma approved for
PD-L1+ NSCLC
Sistemul imun recunoaşte şi elimină celulele
canceroase via mecanisme multiple şi complexe1–5

1. Janeway CA, et al. Immunobiology. The Immune System in Health and Disease. 6th ed. New York, NY: Garland Science; 2004
2. Padmanabhan RR, et al. J Leuk Biol 1988;43:509–519; 3. Kim R, et al. Immunology. 2007;121:1–14
4. Vivier E, et al. Science 2011;331:44–49; 5. Dunn GP, et al. Nat Immunol 2002;3:991–998
Immune Surveillance: Identification and Elimination
of Cancer Cells by the Immune System1-5
51

Antibody
production
Priming/
T-cell activation

Priming APC
activation

NK cell trafficking
& tumor killing

Antigen
release

Activated T-cell
migration to tumor
and tumor killing

Tumor cells
APC, antigen-presenting cell; NK, natural killer.
1.Abbas AK et al. Cellular and Molecular Immunology. 7th ed. Philadelphia, PA: Elsevier Saunders;2012.
2.Mellman I et al. Nature. 2011;480:480-489.
3.Boudreau JE et al. Mol Ther. 2011;19(5):841-853.
4.Janeway CA Jr et al. Immunobiology: The Immune System in Health and Disease. 5th ed. New York, NY:
Garland Science; 2001.
5.Pardoll DM. Nat Rev Cancer. 2012;12:252-264.
 T Cell–Mediated Cytotoxicity
T cells1,2
Antigen-presenting Inactive APCs present antigens to naïve T
T cell cells, which can recognize tumor-
cells1,2 associated antigens
Take up antigens from infected
or malignant cells and process them
into shorter peptide segments
Together with a second, positive
co-stimulation signal, T cells
APC Activated become activated…
T cells

Tumor-
associated
antigens
Tumor
cells
…and play a major role in
Apoptotic killing infected or malignant
tumor cell cells when activated

APC, antigen-presenting cell.

1. Mellman I et al. Nature. 2011;480(7378):480-489.
2. Boudreau JE et al. Mol Ther. 2011;19(5):841-853.
5
2
HOW IMMUNOTHERAPY WORKS

Nature. 2011 Dec 21; 480(7378): 480–489

Immunotherapy = T cell kills a cancer cell

Michael Postow , 2015

Steps in immune response
The adaptive anti-tumour response

 Adaptability

 Specificity

 Memory

Dranoff G. Nat Rev Cancer. 2004;4:11–22

 Summary of the Role of the Immune System in Cancer and
Process of „Immunoediting”

• The three E’s of cancer immunoediting describe the immune system’s roles in protecting
against tumor development and promoting tumor growth[1]
Fenotipuri imune în cancer
 The T-cell army: armed and ready

Cancer

T-cell army

On-treatment
CD8 PD-L1
The T-cell army: sometimes no one is at home

Cancer
No T-cell army

CD8 PD-L1

The T-cell army by Jerome Groupman (The New Yorker, 23 April, 2012); Herbst, et al. Nature 2014
 Signature & mutational processes
in human cancer
Alexandrov LB et al . Nature 2013, 500, 415

Prevalence of somatic mutations across cancers

 Mecanismele de supresie imună
generate de micromediul tumoral (TME)

Johanna A. Joyce, and Douglas T. Fearon Science 2015;348:74-80

Inhibitor role of miromedium

• Cancer cells evolves into an immune-mediated

micromedium by:
•   1) regulating T cells,
•   2) myeloid-derived inhibitory cells (MDSCs),
•   3) cytokine inhibitors (TGFbeta)
•   4) receptors for checkpoint inhibitors and
•    5.Indoleamine 2,3-dioxygenase (IDO)
 Immune Evasion in the Tumor
Microenvironment

 The tumor microenvironment, a network of cells and structures that surround a tumor, creates conditions that
may foster tumor growth and immune evasion1,2
 Immune cell activity is regulated by multiple activation and inhibition pathways that modulate the duration and
level of the immune response2
• Tumors may target these pathways to alter the immune system’s response to cancer cells, resulting in tumor
evasion of the immune system3

APC

Active T cell

Tumor-
associated
antigens

Tumor cells

APC, antigen-presenting cell. Inactive T cell

1. Gajewski TF et al. Nat Immunol. 2013;14(10):1014-1022.
2. Pardoll DM. Nat Rev Cancer. 2012;12(4):252-264.
3. Vesely MD et al. Annu Rev Immunol. 2011;29:235-271.
6
5
 Raspunsul imun ideal
 Răspunsul antitumoral ideal este un proces in 4 trepte:

Activarea celulelor T
Proliferarea celulelor T
Infiltratrarea tumorii de celulele T
Distrucţia tumorală

66
 The T cell anti-tumour response1–6

APC = antigen-presenting cell

1.Andersen MH, et al. J Invest Dermatol 2006;126:32–41;
2. Pardoll DM. Nat Rev
Cancer 2012;11:252–264;
3. Mellman I, et al. Nature 2011;480:480–489
4. Heemskerk B, et al. EMBO J 2013;32:194–203; 5. Boudreau JE, et al. Mol Ther
2011;19:841–853; 6. Janeway CA, et al. Immunobiology. The Immune System in Health

and Disease. 6th ed. New York, NY: Garland Science; 2004
 IMMUNOTHERAPY APPROACHES
• Cancer vaccines
• Lots of studies, few successes
• Sipuleucel-T (Provenge®): Protein pre-stimulated immune cells
• TVEC (Talimogene laherparepvec) in melanoma
• Antibodies against proteins enriched in cancer
• Most commonly used approach now
• Immune checkpoint inhibitors
• Drugs to impact the tumor microenvironment
• IDO inhibitors; ?Epigenetic agents, Anti-angiogenesis agents
• Cellular therapy: “genetic” therapy
• Introduce activating genes into CD8+ CTL that later recognize and kill cancer cells
Vaccinuri anti-cancer
 T-Cell Response: Accelerate or Brake?

Coactivation Signals Inhibitory Signals

TCR

CD28 CTLA-4

OX40 PD-1
T cell
Use agonistic GITR TIM-3
Use blocking
mAbs to ↑ mAbs to ↑
activation CD137 BTLA activation
CD27 VISTA

HVEM LAG-3

T-Cell Stimulation T-Cell Inhibition

Adapted from Mellman I, et al. Nature. 2011;480:480-
489.
 The T Cell Tug-of-War

Presented By Georgina Long at 2016 ASCO Annual Meeting

 AT A CHECKPOINT FOR
SARCOMA (CANCER)
IMMUNOTHERAPY

Robert Maki, MD PhD FACP

Professor of Medicine, Hofstra-Northwell Medical School
Northwell Health – Monter Cancer Center &
Cold Spring Harbor Laboratory Long Island, New York, USA

ESMO.ORG

esmo.or
g
Nobel Prize 2018
for their discovery of
cancer therapy by Kyoto’s Univ
inhibition of negative Tasuku Honjo
immune regulation
(“release the brakes”)
 Ipilimumab: Mecanism de acţiune
T-cell T-cell T-cell
activation inhibition potentiation

CTLA4

T cell T cell T cell

CD28 CD28 CTLA4

CTLA4
TCR TCR TCR
B7 IPILIMUMAB
MHC B7 MHC MHC B7 blocks
CTLA-4
APC APC APC

O‘Day S et al. ASCO 2010 plenary session (#4)

Ipilimumab
 Breaking news : long term survival rates ( cure?)

Melanoma (4846 pat) NSCLC (pretreated)

10-year OS 20%

Ipilimumab Nivolumab

Gettinger CMSTO 2014; P 170

Schadendorf D. J Clin Oncol  2015; 33(17):1889-94
PD1 vs. PDL1—Are All PD1/PDL1 inhibitors the Same?
IMMUNE TARGETED THERAPY

Adapted from Hodi FS, et al.

N Engl J Med. 2010
Aug 19;363(8):711-23.

Hodi et al.
Abstract #3008
ASCO 2008
Nivolumab
 Tumor Immunology: Overview

Coactivation Signals Inhibitory Signals

TCR

CD28 CTLA-4

OX40 PD-1
T cell
Use agonistic GITR TIM-3 Use blocking
mAbs to ↑ mAbs to ↑
activation CD137 BTLA activation
CD27 VISTA

HVEM LAG-3

T-Cell Stimulation T-Cell Inhibition

Adapted from Mellman I, et al. Nature. 2011;480:480-489.
 T-Cell Response: Accelerate or Brake?

Coactivation Signals Inhibitory Signals

TCR

CD28 CTLA-4

OX40 PD-1
T cell
Use agonistic GITR TIM-3
Use blocking
mAbs to ↑ mAbs to ↑
activation CD137 BTLA activation
CD27 VISTA

HVEM LAG-3

T-Cell Stimulation T-Cell Inhibition

Adapted from Mellman I, et al. Nature. 2011;480:480-
489.
NIVOLUMAB
 The T-cell army: armed and ready

Cancer

T-cell army

On-treatment
CD8 PD-L1
 Distinct binding interfaces and compound orientations

Presented By Melissa Johnson at 2017 ASCO Annual Meeting

 Agenţi imunoterapici de uz curent

Agenţi imunoterapici mai frecvent utilizati:

• CTLA-4: Ipilimumab (immunoglobulin IgG1 si Tremelimumab (igG2)

• PD-1: Nivolumab and Pembrolizumab (ambele IgG4)
• PDL-1: Atezolizumab, durvalumab and Avelumab (toate IgG1).
 Nivolumab Mechanism of Action

Presented By David Spigel at 2015 ASCO Annual Meeting

 CheckMate 017/057

5-Year Pooled OS: Nivolumab vs Docetaxela

100
Nivolum Docetax
ab el
80
(n = 427) (n = 427)
Median OS,
1-year 11.1 8.1
mo
48.0%
60 (9.2–
OS (%)

34.3% (95% CI) (7.2–9.2)

13.1)
2-year
HR (95% CI) 0.68 (0.59–0.78)
40 26.9% 3-year
4-year 5-year
13.5% 17.1%
14.2% 13.4%
8.2%
20 4.6% 2.6% Nivolumab

Docetaxel
0
0 6 12 18 24 30 36 42 48 54 60 66 72 78
Months
No. at risk
Nivolumab 427 280 205 150 113 84 70 64 55 54 50 30 6 0
Docetaxel 427 264 145 84 57 45 34 26 19 12 9 4 0 0

•5-year OS rate (nivolumab vs docetaxel): 12.3% vs 3.6% (CheckMate 017; SQ); 14.0% vs 2.1% (CheckMate 057; NSQ)
a
Minimum follow-up for OS: 62.6 months (CheckMate 017), 62.7 months (CheckMate 057).
91
Provided by BMS in response to unsolicited requests only
 OS by PD-L1 expression: CheckMate 057
Nivolumab

• PD-L1 expression was predictive of benefit with nivolumab

100 ≥1% PD-L1 expression level 100 <1% PD-L1 expression level
90 90 Median
Median OS (mo)
80 80 OS(mo)
70 Nivo 17.2 70 Nivo 10.4
Doc 9.0 Doc 10.1
60 60
50 50
40 Nivo 40
Nivo
30 30 Doc
Doc
20 20
10 HR (95% CI)=0.59 (0.43, 0.82) 10 HR (95% CI)=0.90 (0.66, 1.24)
0 0
0 3 6 9 12 21 24 27 0 3 6 9 12 15 18 21 24 27
15 18 Time
(months)

PD-L1 Median OS (mo)

expression level HR
Nivolumab Docetaxel

≥5% 18.2 8.1

HR (95% CI) = 0.43 (0.30, 0.63)
<5% 9.7 10.1 HR (95% CI) = 1.01 (0.77, 1.34)

≥10% 19.4 8.0

HR (95% CI) = 0.40 (0.26, 0.59)
<10% 9.9 10.3 HR (95% CI) = 1.00 (0.76, 1.31)

aPD-L1 expression was measured in pretreatment tumor biopsies (DAKO automated IHC assay).2 CI=confidence
interval; Doc=docetaxel; IHC=immunohistochemistry; Nivo=nivolumab;
1. Paz-Ares L, et al. Presented at ASCO 2015, Abstract LBA109. 2. Rizvi NA, et al. Lancet Oncol 2015;16:257–265.
 Ipilimumab and Nivolumab Mechanism of Action

Presented By Scott Antonia at 2016 ASCO Annual Meeting

PEMBROLIZUMAB
 Pembrolizumab

Presented By Amita Patnaik at 2015 ASCO Annual Meeting

Anti-PD1 Therapy
ATEZOLIZUMAB
DURVALUMAB
 The IO Paradigm:
Cancer is an Auto-Dysimmune Disorder

Hirsch L et al, British Journal of Cancer (2018), in press

 FDA Approval Checkpoint Inhibitors

• 2011- Ipilimumab (BMS)- Melanoma

• 2014- Pembrolizumab (Merk)- Melanoma
• 2014-Nivolumab (BMS)- Melanoma
• 2015-Nivolumab (BMS)- Lung
• 2015-Ipilimumab + Nivolumab (BMS)-Melanoma (BRAF wt)
• 2015- Pembrolizumab (Merk)- Lung
• 2015- Ipilimumab (BMS)-Adjuvant Melanoma
• 2015 -Nivolumab (BMS) - Renal cell carcinoma
• 2016 -Nivolumab (BMS)- Hodgkin’s Lymphomas
• 2016- Atelizumab (Genentech/Roche) Bladder
• 2016-Pembrolizumab (Merk) –Head and Neck
• 2016- Ipilimumab+ Nivolumab (BMS) Melanoma (any BRAF status)
• 2016 - Atelizumab (Genentch/Roche) –Non Small Cell Lung Cancer
• 2017-Pembrolizumab – Triple Negative Breast Cancer
Anti- PD-1- toxicitate secundara

• Astenie
• Rash
• Diaree
• Prurit
• Greturi
• Scaderea poftei de mancare
• Anemie
• Pirexie
• Pneumonita
• Renal
• Uveita
• Endocrinopatii
Can the 2 approaches be combined ?

Immunothera
py

Platinum-based
CT
Summary of CheckPoint Blockade
Immune-Mediated Toxicities

 Toxicity appears to be dose related

Common (> 20%) Rare (< 2%)

Rash, pruritus Episcleritis/uveitis
Fevers, chills, lethargy
Pancreatitis
GI: Diarrhea/colitis
Nephritis
Occasional (3% to 20%)
Neuropathies, Guillain-Barré,
Hepatitis/liver enzyme abnormalities myasthenia gravis
Pneumonitis
Lymphadenopathy (sarcoid)
Endocrinopathies: hypophysitis, thyroiditis,
adrenal insufficiency Thrombocytopenia
Vitiligo Toxic epidermal necrolysis, Stevens-
Johnson syndrome

Weber JS, et al. J Clin Oncol. 2012;30:2691-2697

 Slide 5

Presented By Roy Herbst at 2017 ASCO Annual Meeting

 Efecte secundare la inhibitorii checkpoint
a) Efecte generale: astenia, pirexia, frisoane.
b) Efecte dermatologice: rash cutanat (maculopapular, papulopustular, sindrom Sweet, dermatită
foliculară sau foliculară), rash, prurit, vitiligo ( la 34% din pacienţii trataţi cu nivolumab, şi 39% cu
pembrolizumab)
c) Efecte digestive: diareea, colita ( după anti-CTLA-4 la 6-8 săptămâni de la debutul tratamentului)
d) Toxicitate endocrină: hipofizita, hipotiroidism, hipertiroidism, tiroidita şi insuficienţă cortico-
suprarenală.( desctisă în special după anticorpii anti CTLA-4.
e) Toxicitatea hepatică- se manifestă cel mai frecvent prin creşterea asimptomatică a valorilor
transaminazelor AST şi ALT .
f) Toxicitate pulmonară- pneumonita, definită ca inflamaţia parenchimului pulmonar ( clinic
dispnee,tuse, febră şi dureri toracice) survine la <10% din pacienţii care au primit tratament anti-PD-
1/PDL-1 singură sau în combinaţii la pacienţii cu cancere bronho-pulmonare.
• Toxicităţi mai rare sunt:
- Simptome neurologice: mielite transverse, neuropatie enterică, meningită aseptică) mai ales după
ipilimumab.
- Toxicitate oculară: uveita (după combinaţii de anti-PD-1 şi anti-CTLA4, ca şi la ipilimumab singur).
- Toxicitate renală: nefrită interstiţială (monoterapie cu anti PD-1 şi combinaţie de nivolumab şi
ipilimumab), insuficienţa renală acută ( după asociaţia de nivolumab şi cisplatin).
- Toxicitatea pancreatică- creşterea valorilor lipazei după anti-CTLA4 şi anti PD-1/PDL-1.
PD-1 Rashes
Development of vitiligo
Pembrolizumab rash
 Dermatologic IRAEs

Image courtesy of Jeffrey S. Weber, MD, PhD.

 Example of Pruritic Rash

•Treated with oral or topical

diphenhydramine and oral
fexofenadine
•May require topical or oral steroids

Courtesy, Julie R Brahmer, MD, MSc

Ipilimumab-Related Pituitary
Swelling and Dysfunction

6/30/04 Baseline 12/3/04 Headache/fatigue after 5

(4.5 mm) doses
(10.8 mm)

Blansfield et al, 2005.

 Autoimmune colitis

Colonoscopy performed on a 51-year-old man with metastatic

melanoma who developed watery diarrhea after receiving
an immune checkpoint-blocking drug 

Images courtesy of Animesh Jain, MD, Johns Hopkins University School of Medicine
Diarrhea and Colitis
 Kinetics of Appearance of irAEs

Rash, pruritus
Liver toxicity
Diarrhea, colitis
Hypophysitis
Toxicity Grade

0 2 4 6 8 10 12 14
Wks

Weber JS, et al. J Clin Oncol. 2012;30:2691-2697.

Pneumonitis
Naidoo J, et al JCO 2017;35(7):709-718
Toxicitatea financiară
Nature Reviews Cancer 16, 275–287 (2016)
 Slide 6

Presented By Georgina Long at 2016 ASCO Annual Meeting

 Combination: immune + targeted
therapy

Percent alive
Immunotherapy Targeted therapy Combination

Percent alive
Percent alive

0 1 2 3 0 1 2 3 0 1 2 3
Years Years Years

Ribas A, et al. Clin Cancer Res 2012;18(2):336–341

IMMUNOTHERAPIE
 Imunoterapia- Concluzii

 Aceiaşi imunoterapie poate acţiona într-o varietate de cancere cu diferite origini/

mutaţii genetice driver.

 Sistemul imun ţinteşte antigene-ţintă şi nu căi de semnal biologic

 Mutaţiile tumoral-specifice pot realiza o varietate de antigene pe care sistemul

imun le poate recunoaşte

 Dacă un pacient răspunde la imunoterapie, acest răspuns este adesea durabil

 Imunoterapia tratează tumora şi nu pacientul.

 Recent, imunoterapia a devenit al cincilea „pilon” al terapiei cancerului alături de:

chirurgie, radioterapie, chimioterapia citotoxică, terapiile moleculare ţintite.
Entering the immunotherapy era
Opportunities for targeted treatment

Hanahan D and Weinberg RA. Cell 144:646, 2011

 ARMY AGAINST CANCER

Molecular targeted therapy Immunotherapy

Chemotherapy
Siege weaponry
Blow holes in the tumour;
soften defenses, allow entry
Lower the drawbridge CAR-T cells
Enable entry into the tumour;
army and civilians inside increase
Recruit special forces
Turn any T-cell into a cancer killer;
enhance penetration of armed forces
into the tumour
 Actionable genomic aberations, increased knowledge
….and many new therapeutic classes and agents

IGR available drugs/clinical trials

CELL CYCLE/DIVISION INHIBITORS
APOPTOSIS MODULATORS
• Bcl-2 inh • flavopiridol
• Survivin • CDKs inh
• PARP inh • Aurora/Polo Kinases inh
• Apo/TRAIL agonists, • Kinesin/Microtubules inh
•TRAIL-R mAb

SIGNAL TRANSDUCTION
ANTI-ANGIOGENIC INHIBITORS
• Kit - PDGFR inh
• VEGF/VEGFR inh • HER Family inh
• Angiopoietins inh • Ras inh.
• Integrin antagonists •farnesyl transferase inh
• Vascular Disrupting Agents
• RAF/MEK inh
• PKC inh
• Pi3K/AKT/mTOR inh

CELL REPLICATION/
EPIGENETIC REGULATION INHIBITORS
• Anti-telomerase agents
• Telomere interacting agents
• HDAC inh
• HSP90, proteasome inh
ANTI-INVASIVE AGENTS
IMMUNOMODULATORS
• Metaloproteinases-MMP inh.
• anti-CTLA4, anti-PD1/1L mAbs • Chemokines/R modulators
• TLRs agonists • Src inhibitors
• tumor vaccines
Hanahan & Weinberg, Cell 144, March 4, 2011
Drumul lung…
… al terapiilor sistemice în cancer
TRATAMENTUL PALEATIV
 Prin calitatea vieţii în medicină se înţelege bunăstarea fizică,
psihică şi socială precum şi capacitatea pacienţilor în a-şi îndeplini
sarcinile obişnuite în viaţa cotidiană.
 Dimensiunile calităţii vieţii

• Bunăstarea emoţională sau psihică

• Relaţiile interpersonale
• Bunăstarea materială
• Afirmarea personală
enjoy
• Bunăstarea fizică
• Independenţa;
your
• Integrarea socială;
• Asigurarea drepturilor fundamentale ale omului
life