Overview of Modern Oncologic Therapies

December 8, 2014

Steven T. Rosen, M.D.Provost and Chief Scientific Officer

Director, Comprehensive Cancer Center and Beckman Research InstituteIrell & Manella Cancer Center Director’s Distinguished Chair

City of Hope

1913 2014

Biologic Response Modifiers

• Monoclonal Antibodies• Recombinant Toxins• Vaccines• Adoptive Immunotherapy• Immunomodulatory Drugs• Interferons and Cytokines• Hormonal Agents• Signal Transduction Modifiers• Transcriptional Regulators• Anti-sense Compounds• Angiogenesis Inhibitors• Proteasome Inhibitors• Metabolism Inhibitors• DNA Repair Inhibitors• Apoptosis Inducers• RNA Based Analogs• Oncolytic Viruses

Target Antigens

NH2 COOH

FabVARIABLE REGION

ANTIGEN BINDING SITE

FcCONSTANT REGION

EFFECTOR FUNCTIONS

Immune based

Naked mAbs

Engineered mAbs

NK Cells

T Cell

C1q Compliment

Growth factors

Radioactivity

Biotoxin

Chemokine, etc..

Prodrug

Signaling mechanism based

Immune based

Selective Drug Delivery

Immune based

Bispecific

Enhance Selectivity

Poison

Antibodies in Medicine

Monoclonal Antibodies - Naked

Year Generic/Trade Names Route Indications Mechanism of Action

1997Rituximab/Rituxan IV B-cell NHL - CD20+ADCC, CDC, Apoptosis

1998Trastuzumab/Herceptin IV Breast Cancer-HER2+ Signal Inhibition

2001Alemtuzumab/Campath IV, SC CLL - CD52+ ADCC, CDC, DC

2004Cetuximab/Erbitux IV H&N/Colon Cancer -EGFR+ Signal Inhibition

2004Bevacizumab/Avastin IVColon Cancer, Adenocarcinoma Lung, RCC-VEGF Angiogenesis Inhibitor

2006Panitumumab/Vectibix IV Colon Cancer -EGFR+ Signal Inhibition

2009Ofatumumab/Arzerra IV CLL - CD20+ ADCC, CDC, DC

2012Pertuzumab/Perjeta IV Breast cancer - HER2+ Signal Inhibition

2013Obinutuzumab/Gazyva IV CLL - CD20+ ADCC, CDC, DC

2014Ramucirumab/Cyramza IV Gastric Cancer - targets VEGFR2 Angiogenesis Inhibitor

2014Siltuximab/Sylvant IVCastleman's Disease - anti-interleukin-6 Signal Inhibition

Monoclonal Antibodies - Conjugated

Year Generic/Trade Names Route IndicationsMechanism of Action

2002Ibritumomab tiuxetan/Zevalin IV B-cell NHL-CD20+ Yttrium 90

2003Tositumomab/Bexxar IV B-cell NHL-CD20+ Iodine 131

2011Brentuximab Vedotin/Adcetris IVHodgkins and ALCL -CD30+ Auristatin E

2013Ado-trastuzumab Emtansine/Kadcyla IV Breast cancer - HER2+ Mertansine

Biologic Response Modifiers

• Monoclonal Antibodies• Recombinant Toxins• Vaccines• Adoptive Immunotherapy• Immunomodulatory Drugs• Interferons and Cytokines• Hormonal Agents• Signal Transduction Modifiers• Transcriptional Regulators• Anti-sense Compounds• Angiogenesis Inhibitors• Proteasome Inhibitors• Metabolism Inhibitors• DNA Repair Inhibitors• Apoptosis Inducers• RNA Based Analogs• Oncolytic Viruses

Recombinant Toxins

Year Generic/Trade Names Route Indications Mechanism of Action

1999Denileukin diftitox/Ontak IV CTCL - CD25+ Diphtheria Toxin

Mechanism of Action

Biologic Response Modifiers

• Monoclonal Antibodies• Recombinant Toxins• Vaccines• Adoptive Immunotherapy• Immunomodulatory Drugs• Interferons and Cytokines• Hormonal Agents• Signal Transduction Modifiers• Transcriptional Regulators• Anti-sense Compounds• Angiogenesis Inhibitors• Proteasome Inhibitors• Metabolism Inhibitors• DNA Repair Inhibitors• Apoptosis Inducers• RNA Based Analogs• Oncolytic Viruses

Adapted from: Berzofsky et al, J Clin Invest. 2004;113(11):1515–1525

StabilizedmRNA

Lactobacilus

D

IrradiatedTumor Cells

Dendritic Cells Adjuvant Oral

Active Cancer Vaccination Strategies

Vaccine Therapy

Year Generic/Trade Names Route Indications Mechanism of Action

1998BCG/TheraCys Intravesical Bladder Cancer Inflammation

2010Sipuleucel-T/Provenge IV Prostatic CancerProstate Acid Phosphatase exposed dendritic cells

Provenge

Biologic Response Modifiers

• Monoclonal Antibodies• Recombinant Toxins• Vaccines• Adoptive Immunotherapy• Immunomodulatory Drugs• Interferons and Cytokines• Hormonal Agents• Signal Transduction Modifiers• Transcriptional Regulators• Anti-sense Compounds• Angiogenesis Inhibitors• Proteasome Inhibitors• Metabolism Inhibitors• DNA Repair Inhibitors• Apoptosis Inducers• RNA Based Analogs• Oncolytic Viruses

Allogeneic Bone Marrow Transplant

CAR T-Cell Lymphoma

Biologic Response Modifiers

• Monoclonal Antibodies• Recombinant Toxins• Vaccines• Adoptive Immunotherapy• Immunomodulatory Drugs• Interferons and Cytokines• Hormonal Agents• Signal Transduction Modifiers• Transcriptional Regulators• Anti-sense Compounds• Angiogenesis Inhibitors• Proteasome Inhibitors• Metabolism Inhibitors• DNA Repair Inhibitors• Apoptosis Inducers• RNA Based Analogs• Oncolytic Viruses

Immunomodulatory Drugs

Year Generic/Trade Names Route Indications Mechanism of Action

1998Thalidomide/Thalomid O Myeloma Immune modulation

2005Lenalidomide/Revlimid O Myeloma, CLL Immune modulation

2011Ipilimumab/Yervoy IV MelanomaTarget CTLA - 4 Receptor, Blocks CTL Inhibition

2013Pomalidomide/Pomalyst O Myeloma Immune modulation

2014Blinatumomab/BITE IV ALL Anti-CD19, Anti-CD3

2014Pembrolizumab/Keytruda IV MelanomaTarget PD-1 Receptor, Blocks CTL Inhibition

Thalidomide/Lenalidomide/Pomalidomide

T/L/P

T/L/P

T/L/P T/L/P

T/L/P

T/L/P

CTLA - 4 Receptor (Immune Checkpoint Inhibitor)

Blinatumomab

Topp MS, et al. J Clin Oncol 2011Topps MS, et al. Blood 2012

• Bispecific (CD19 and CD3) T-cell engaging Ab; continuous IV

• Ph 2: MRD+ B-ALL, n = 21• 16 pts of 20 evaluable pts

became MRD neg after 1 cycle (80% ORR)

• RFS probability 78% at median followup of 405 days

• After median followup of 33 months, RFS of the 20 evaluable pts was 61% 65% in 9 pts who went to allo 67% in 6 pts with PH neg

MRD responders with no further treatment

Biologic Response Modifiers

• Monoclonal Antibodies• Recombinant Toxins• Vaccines• Adoptive Immunotherapy• Immunomodulatory Drugs• Interferons and Cytokines• Hormonal Agents• Signal Transduction Modifiers• Transcriptional Regulators• Anti-sense Compounds• Angiogenesis Inhibitors• Proteasome Inhibitors• Metabolism Inhibitors• DNA Repair Inhibitors• Apoptosis Inducers• RNA Based Analogs• Oncolytic Viruses

Interferons-Cytokines

Year Generic/Trade Names Route Indications Mechanism of Action

1992Aldesleukin/Proleukin IVMelanoma and Renal Cell Cancer - target IL2 Receptor Immune modulation

1997Interferon Alfa-2b/Intron A DC, SC

Follicular non-Hodgkin's Lymphoma, Hairy Cell Leukemia, CML, CTCL, Melanoma, Kaposi's Sarcoma - target Interferon Receptor Immune modulation

1999Interferon Alfa-2a/Roferon A DC, SC

Hairy Cell Leukemia, Philadelphia chromosome, Cutaneous T-cell lymphoma, Follicular non-Hodgkin's lymphoma, Renal cell carcinoma Immune modulation

IFNa

Jak kinases

Stat-pathway

gene transcription

p38 Map kinase pathway

IRS-proteins

PI-3K

p70S6K 4E-BP1-P

mRNA translation

Crk-pathway

Rap1

growth inhibitory/antitumor effects

mTOR

Biologic Response Modifiers

• Monoclonal Antibodies• Recombinant Toxins• Vaccines• Adoptive Immunotherapy• Immunomodulatory Drugs• Interferons and Cytokines• Hormonal Agents• Signal Transduction Modifiers• Transcriptional Regulators• Anti-sense Compounds• Angiogenesis Inhibitors• Proteasome Inhibitors• Metabolism Inhibitors• DNA Repair Inhibitors• Apoptosis Inducers• RNA Based Analogs• Oncolytic Viruses

Biologic Response Modifiers

Hormonal Therapies

Year Generic/Trade Names Route Indications Mechanism of Action

1977Tamoxifen Citrate/Nolvadex O Breast Cancer Anti-estrogen

1996Goserelin/Zoladex IM Prostate Cancer LHRH Agonist

1996Anastrozole/Arimidex O Breast Cancer Aromatase Inhibitor

1996Nilutamide/Nilandron O Prostate Cancer Anti-androgen

1998Letrozole/Demara O Breast Cancer Aromatase Inhibitor

1999Targretin/Bexarotene O CTCL Rexinoid

1999Exemestane/Aromasin O Breast Cancer Aromatase Inhibitor

2000Triptorelin/Trelstar IM Prostate Cancer LHRH Agonist

Hormonal Therapies

Year Generic/Trade Names Route Indications Mechanism of Action

2001Flutamide/Eulexin O Prostate Cancer Anti-androgen

2002Fulvestrant/Faslodex IM Breast Cancer Anti-estrogen

2007Raloxifene Hydrochloride/Evista O Breast Cancer Anti-estrogen

2008Degarelix/Firmagon IM Prostate Cancer LHRH Antagonist

2009Leuprolide/Lupron IV Prostate Cancer LHRH Agonist

2009Bicalutamide/Casodex O Prostate Cancer Anti-androgen

2011Abiraterone Acetate/Zytiga O Prostate Cancer CYP17A1 Inhibitor

2012Enzalutamide/Xtandi O Prostate Cancer Inhibits Androgen Receptor

Biologic Response Modifiers

• Monoclonal Antibodies• Recombinant Toxins• Vaccines• Adoptive Immunotherapy• Immunomodulatory Drugs• Interferons and Cytokines• Hormonal Agents• Signal Transduction Modifiers• Transcriptional Regulators• Anti-sense Compounds• Angiogenesis Inhibitors• Proteasome Inhibitors• Metabolism Inhibitors• DNA Repair Inhibitors• Apoptosis Inducers• RNA Based Analogs• Oncolytic Viruses

Cancer Targets

Signal Transduction Inhibitors

Year Generic/Trade Names Route Indications Mechanism of Action

2001Imatinib / Gleevec O CML, GIST Bcr-Abl, C-Kit

2003Gefitinib/Iressa O NSCLC EGFR

2004Trametinib/Mekinist O

Metastatic melanoma with BRAF V600E or V600K mutations BRAF

2005Erlotinib/Tarceva O NSCLC, Pancreatic Cancer EGFR, JAK2

2005Sorafenib/Nexavar O RCC, HCCVEGFR, PDGFR, BRAF, C-Kit

2005Dasatinib/Sprycel O CML Bcr-Abl, STC, C-Kit

2006Sunitinib/Sutent O RCC, GISTPDGFR, VEGFR, C-Kit, RET, CS-1R, Fit3

2007Lapatinib /Tykerb O HER2 (ErbB2) HER2

2007Temsirolimus/Torisel IV RCC mTORC1

2007Nilotinib/Tasigna O CML, (Ph+ CML) Bcr-Abl

2009Everolimus/Afinitor/Zortress O RCC, SEGA, PNET mTORC1

Signal Transduction Inhibitors

Year Generic/Trade Names Route Indications Mechanism of Action

2009Pazopanib/Votrient O RCC, Soft Tissue Sarcoma PDGFR, C-Kit

2011Vandetanib/Caprelsa OSymptomatic or progressive medullary thyroid cancer

VEGFR, EGFR, RET, BRK

2011Vemurafenib/Zelboraf O

Treatment of unresectable or metastatic melanoma with the BRAFV600E mutation as detected by an FDA-approved test. BRF

2011Crizotinib/Xalkori O ALK+NSCLC ALK, HGFR, C-MET

2011Ruxolitinib/Jakafi O Myelofibrosis JAK

2012Axitinib/Inlyta O RCCVEGFR, PDGFR, C-Kit

2012Vismodegib/Erivedge OMetastatic basal cell carcinoma, or with locally advanced basal cell carcinoma SMOR

2012Ziv-aflibercept/Zaltrap IV mCRC VEGF

2012Bosutinib/Bosulif OPh+ chronic myelogenous leukemia (CML) Bcr-Abl

Signal Transduction Inhibitors

Year Generic/Trade Names Route Indications Mechanism of Action

2012Regorafenib/Stivarga OMetastatic colorectal cancer (CRC)/GIST RET, VEGFR, PDGFR

2012Cabozantinib/Cometriq O MTC C-MeT, VEGFR

2012Ponatinib/Iclusig O CML

Bcr-Abl, BEGFR, PDGFR, FGDR, EPH, SRC, C-KiT, RET, TIE2, FLT3

2013Dabrafenib/Tafinlar O

Metastatic melanoma with BRAF V600E mutation/ Metastatic melanoma with BRAF V600E or V600K BRAF

2013Afatinib/Gilotrif O NSCLC ErbB

2013Ibrutinib/Imbruvica O MCL, CLL BTK

2014Ceritinib/Zykadia O ALK+NSCLC ALK

2014Zydelig/Idelalisib O Follicular Lymphoma, CLL PI3 Kinase Inhibitor

Biologic Response Modifiers

• Monoclonal Antibodies• Recombinant Toxins• Vaccines• Adoptive Immunotherapy• Immunomodulatory Drugs• Interferons and Cytokines• Hormonal Agents• Signal Transduction Modifiers• Transcriptional Regulators• Anti-sense Compounds• Angiogenesis Inhibitors• Proteasome Inhibitors• Metabolism Inhibitors• DNA Repair Inhibitors• Apoptosis Inducers• RNA Based Analogs• Oncolytic Viruses

DNA Methylation in Eukaryotes

Promoter with CpG island Exon I Exon II Exon III

X

Azacitidine: MDS, AMLDecitabine: MDS, AML

(hypo-acetylated histones)

Pol2 mRNA

Activated Chromatin(hyper-acetylated histones)

Histoneacetylation

HAT

Ac-

Ac-

Ac-

Ac-

Ac-

Ac-

Ac-

Ac-

TranscriptionalFactors

Corehistones

Repressed Chromatin

Histonedeacetylation

HDACs

Cofactors

Reversible Histone Acetylation Regulates Gene Expression

Yoo CB and Jones PA. Nat Rev Drug Discov. 2006;5:37.

Repressed Chromatin

Year Generic/Trade Names Route Indications Mechanism of Action

2006Decitabine/Dacogen IV MDS DNA Methylation Inhibitor

2006Vorinostat/Zolina O CTCL HDAC Inhibitor

2009Romidepsin/Istodax IV CTCL HDAC Inhibitor

2012Omacetaxine Mepesuccinate/Synribo SC CML Protein translation

2014Belinostat/Beleodaq O PTCL HDAC Inhibitor

Transcription/Translation Regulation

Biologic Response Modifiers

• Monoclonal Antibodies• Recombinant Toxins• Vaccines• Adoptive Immunotherapy• Immunomodulatory Drugs• Interferons and Cytokines• Hormonal Agents• Signal Transduction Modifiers• Transcriptional Regulators• Anti-sense Compounds• Angiogenesis Inhibitors• Proteasome Inhibitors• Metabolism Inhibitors• DNA Repair Inhibitors• Apoptosis Inducers• RNA Based Analogs• Oncolytic Viruses

Antisense Oligonucleotide Activity

Biologic Response Modifiers

• Monoclonal Antibodies• Recombinant Toxins• Vaccines• Adoptive Immunotherapy• Immunomodulatory Drugs• Interferons and Cytokines• Hormonal Agents• Signal Transduction Modifiers• Transcriptional Regulators• Anti-sense Compounds• Angiogenesis Inhibitors• Proteasome Inhibitors• Metabolism Inhibitors• DNA Repair Inhibitors• Apoptosis Inducers• RNA Based Analogs• Oncolytic Viruses

Angiogenesis Inhibitors

Year Generic/Trade Names Route Indications Mechanism of Action

2004Bevacizumab/Avastin IV

Colon Cancer, Adenocarcinoma Lung, RCC-VEGF, Metastatic cervical cancer Angiogenesis Inhibitor

2005Sorafenib/Nexavar O RCC, HCCVEGFR, PDGFR, BRAF, C-Kit

2006Sunitinib/Sutent O RCC, GISTPDGFR, VEGFR, C-Kit, RET, CS-1R, Fit3

2011Vandetanib/Caprelsa OSymptomatic or progressive medullary thyroid cancer VEGFR, EGFR, RET, BRK

2012Axitinib/Inlyta O RCCVEGFR, PDGFR, C-Kit

2012Ziv-aflibercept/Zaltrap IV mCRC VEGF

2012Regorafenib/Stivarga OMetastatic colorectal cancer (CRC)/GIST RET, VEGFR, PDGFR

2012Cabozantinib/Cometriq O MTC C-MeT, VEGFR

2014Ramucirumab/Cyramza IVGastric Cancer - targets VEGFR2 Angiogenesis Inhibitor

Biologic Response Modifiers

• Monoclonal Antibodies• Recombinant Toxins• Vaccines• Adoptive Immunotherapy• Immunomodulatory Drugs• Interferons and Cytokines• Hormonal Agents• Signal Transduction Modifiers• Transcriptional Regulators• Anti-sense Compounds• Angiogenesis Inhibitors• Proteasome Inhibitors• Metabolism Inhibitors• DNA Repair Inhibitors• Apoptosis Inducers• RNA Based Analogs• Oncolytic Viruses

The 26S proteasome and its function

• Present in all cells• Ubiquitin-proteasome

pathway– Essential role in

regulating intracellular concentration of specific proteins

– Control of protein homeostasis in the cell

• Ubiquitin “tags” proteins for degradation by the proteasome

NEJM

Proteasome Inhibitors

Year Generic/Trade Names Route Indications Mechanism of Action

2003Bortezomib/Velcade IV/SC Myeloma/MCL Proteasome Inhibitor

2012Carfilzomib/Kyprolis IV Myeloma Proteasome Inhibitor

Biologic Response Modifiers

• Monoclonal Antibodies• Recombinant Toxins• Vaccines• Adoptive Immunotherapy• Immunomodulatory Drugs• Interferons and Cytokines• Hormonal Agents• Signal Transduction Modifiers• Transcriptional Regulators• Anti-sense Compounds• Angiogenesis Inhibitors• Proteasome Inhibitors• Metabolism Inhibitors• DNA Repair Inhibitors• Apoptosis Inducers• RNA Based Analogs• Oncolytic Viruses

http://www.uams.edu/radiology/info/clinical/pet/images.asp

Adapted from: Deberardinis RJ, Sayed N, Ditsworth D, Thompson CB. “Brick by brick: metabolism and tumor cell growth.” Curr. Opin. Genet. Dev. 2008, Feb; 18(1):54-61.

Tumor Cell Metabolism

Gly

coly

sis

Biologic Response Modifiers

• Monoclonal Antibodies• Recombinant Toxins• Vaccines• Adoptive Immunotherapy• Immunomodulatory Drugs• Interferons and Cytokines• Hormonal Agents• Signal Transduction Modifiers• Transcriptional Regulators• Anti-sense Compounds• Angiogenesis Inhibitors• Proteasome Inhibitors• Metabolism Inhibitors• DNA Repair Inhibitors• Apoptosis Inducers• RNA Based Analogs• Oncolytic Viruses

DNA Damage

Biologic Response Modifiers

• Monoclonal Antibodies• Recombinant Toxins• Vaccines• Adoptive Immunotherapy• Immunomodulatory Drugs• Interferons and Cytokines• Hormonal Agents• Signal Transduction Modifiers• Transcriptional Regulators• Anti-sense Compounds• Angiogenesis Inhibitors• Proteasome Inhibitors• Metabolism Inhibitors• DNA Repair Inhibitors• Apoptosis Inducers• RNA Based Analogs• Oncolytic Viruses

Apoptosis Induction

Biologic Response Modifiers

• Monoclonal Antibodies• Recombinant Toxins• Vaccines• Adoptive Immunotherapy• Immunomodulatory Drugs• Interferons and Cytokines• Hormonal Agents• Signal Transduction Modifiers• Transcriptional Regulators• Anti-sense Compounds• Angiogenesis Inhibitors• Proteasome Inhibitors• Metabolism Inhibitors• DNA Repair Inhibitors• Apoptosis Inducers• RNA Based Analogs• Oncolytic Viruses

RNA-Directed Nucleoside Analogues

N

NN

N

NH2

O

OHOH

HO

NH2

8-Amino-adenosine 8-Chloro-adenosine

N

NN

N

NH2

O

OHOH

HO

Cl

Metabolism of 8-Cl-Adenosine

8-Cl-Adenosine

Ado Kinase

8-Cl-AMP

8-Cl-ADP

8-Cl-ATP (Cytotoxic Metabolite)

8-Cl-Inosine

AdoDeaminase

ATP Synthase

Generation of the cytotoxic metabolite requires activity of adenosine kinase and ATP synthase.

Intracellular Accumulation of 8-Cl-ATP

                      

                     

0 2 4 6 8 10 12

0

100

200

300

400

500

0

25

50

75

100

Hours

8-Cl

-ATP

, µM

ATP, % of control

Conclusion: By 6 hours of incubation, myeloma cells accumulate high levels (300 mM) of the 8-Cl-ATP while endogenous ATP falls leading to reduced energy sources

                       0 2 4 6 8 10 12

0

25

50

75

100

Hours

% o

f con

trol

RNA

DNA

Conclusion: 8-Cl-Ado inhibits RNA but not DNA synthesis which may be a more effective way to kill slow growing cancer cells such as myeloma or CLL.

RNA

DNA

Inhibition of RNA Synthesis

Drug Sensitivity Score of 8-chloro-adenosine in AML Patient Samples

Biologic Response Modifiers

• Monoclonal Antibodies• Recombinant Toxins• Vaccines• Adoptive Immunotherapy• Immunomodulatory Drugs• Interferons and Cytokines• Hormonal Agents• Signal Transduction Modifiers• Transcriptional Regulators• Anti-sense Compounds• Angiogenesis Inhibitors• Proteasome Inhibitors• Metabolism Inhibitors• DNA Repair Inhibitors• Apoptosis Inducers• RNA Based Analogs• Oncolytic Viruses

Oncolytic Viruses

Virus

Measles Killing Cancer

Supportive Care

Year Generic/Trade Names Route Indications Mechanism of Action

1991Neupogen/Filgrastim SC Neutropenia G CSF

1991Leukine/Sargramostim SC Neutropenia GM CSF

1997Neumega/Oprelvekin SC Thrombocytopenia ILII

2002Neulasta/ Pegfilgrastim SC Neutropenia PEG-G-CSF

2002Elitek/ Rasburicase IV Hyperuricemia urate oxidase

2004Kepivance/Palifermin IV Oral mucositis Keratinocyte Growth Factor

2008Romiplostim/Nplate SC Thrombocytopenia Thrombopoietin

2008Eltrombopag/ Promacta O Thrombocytopenia c-Mpl Receptor Agonist

2008Plerixafor/Mozobil SC Enhance stem cell mobilization Blocks CXCR4

2010Denosumab/Prolia/Xgeva SC Osteoporosis Inhibits RANKL

Personalized Medicine Cancer Diagnostic Market is Rapidly Evolving

Questions?