Monoclonal Ab & Tyr Kinase Inhibitors

8/2/2019 Monoclonal Ab & Tyr Kinase Inhibitors

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Monoclonal Antibodies:

Used In Cancer Chemotherapy

USA FDA Approved Antibodies For Treatment Of Cancer:

Classification:

Unconjugated Mabs: Origin Isotype Indication Target

Rituximab: Rituxan Chimeric Human Ig1 NHL CD20

Trastuzumab:Herceptin Humanized Human Ig1 Breast Cancer HER-2

Alemtuzumab: Campath Humanized Human Ig1 CLL, CD-52

NHL,Promyelocytic

Leukemias

Cetuximab: Erbitux Chimeric Human Ig1 Colorectal, EGFR

Head &Neck

Cancer

Bevacizumab: Avastin Humanized Human Ig1 Colorectal & VEGF

Lung Cancer

Panitumumab: Vectibix Human Human Ig2 Colorectal EGFR

Xeno-Mouse Cancer

Immunoconjuates:

Gemtuzumab (Mylotarg) Humanized HumanIg4 AML CD33

(Calicheamicin

Conjugate )

Ibritumomab( Zevalin) Murine Murine Ig G1 NHL CD20

(90Y-Comjugate)

Tositumomab( Bexxar) Murine Murine IgG2A NHL CD20


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Mechanisms: Target Drug

1. Ligand Sequestrating/ VEGF-A Bevacizumab (Avastin)

Inactivation

2. Receptor Binding/ EGFR Cetuximab (Erbitux)

Inactivation

3. Inhibition Of RTR EGFR Erlotinib (Tarceva)

Phosphorylation

4. Inhibition Of CTK bcr-abl Imatinib (Glevec)

Phsophorylation


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1. Alemtuzumab: (Campath)

A. Structure &Mechanism

1. Humanized IgG-1 Antibody

That Binds toCD-52 Antigen

On Malignant B & T Lymphocytes,

NK Cells, Monocytes, Macrophages

& Some Granulocytes

B. Uses:

1. B Cell Chronic Lymphocytic Leukemia

C. Side Effects:

1. Neutropenia

2. Anemia3. Thrombocytopenia

4. Opportunistic Infections Possible

2, Arcitumomab

A. Structure & Mechanism:

1. Murine Anti-Carinco-Embryonic Antigen Antibody

Labelled With 99m-Tecnetium.

B. Use:

1 Imaging Agent For: Metastatic Colorectal Cancer

C. Side Effects:

1. Due to Immunogeneicity Can Only

Be Given Once.


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3. Bevacizumab: ( Avastin)


1. Humanized IgG-1 Antibody

2. Binds to Vascular Endothelial Growth

Factor and Inhibits VEGF From

Binding to Its Receptor Especially on

Endothelial Cells

3. Anti-Angiogenesis Effect

B. Uses:

1. Metastatic Colorectal Cancer

2. Lung Cancer

C. Precautions:1. Do Not Administer Until Patient

Recovers FromSurgery

2. Watch For Hemorrhage

3. Watch For GI Perforations

4. Watch For Wound Healing Problems

4. Capromab Pendetide


1. Murine Monoclonal Antibody

Specific For Prostate Specific antigen

Coupled With 111-Indium.

B. Use:

1. Imunoscintigraphy:

A. Biopsy Confirmed Prostate Cancer &

B. Post Prostatectomy


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5. Cetuximab: (Erbitux): Metastatic Colorectal Cancer


1. Human-Mouse Chimeric Antibody

That Targets the Epidermal Growth Factor Receptor

2. Thus Inhibits Tumor Cell Growth

Through a Variety of Mechanisms:

A. Decrease in Kinase Activity

B. Matrix Metalloproteinase Activity

C. Growth Factor Produciton

D. Increased Apoptosis

B. Metastatic Colorectal Cancers That

Overexpress EGFR.

6. Gemtuzumab: (Mylotarg) + Ozogamicin : CD33Acute Myelogenous

Leukemia


1. Humanized Ig G-4 Antibody

Specific For CD33 , An SialoAdhesion

Protein Found on Leukemic Blast Cells

In 80-90% of Patients With :

Acute Myelogenous Leukemia

B. Uses:

1. CD 33: Acute Myelogenous Leukemia

(Patients >60 Years of Age) (First Relapses)

C. Side Effects:

1. Severe Myelosuppression

2. Significant Hepatotoxicity

3. Various Hypersensitivity Reactions

7. 90Y Ibritumomab: (Zevalin): Non Hodgkin Lymphoma

A. Structure & Mechanism:1. Murine Monoclonal Antibody Labeled With

Yttrium ( 90Y) or (111-In)

B. Uses:

1. Relapsed or Refractory Low Grade

Follicular or B Cell Non-Hodgkinss Lymphoma

2. Used in Conjunction with Rituximab (Rituxan)


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8. Rituximab: (Rituxan) Non-Hodgkin Lymphoma


1. Chimeric Human-Mouse Monoclonal IgG-1 Antibody

That Binds to the CD20 Molecule on Normal

And Malignant B Lymphocytes

B. Mechanisms:

1. Complement Mediated Lysis

2. Antibody Dependent Cellular Cytotoxicity

3. Induction of Apoptosis of Malignant Lympoma Cells

C. Use:

1. Non-Hodgkins Lymphoma

D. Synergism:1. The Drug Appears to Be Synergistic

With Chemotherapy: (eg: Fludarabine,CHOP)

9. Iodine 131 Tositumomab: (Bexxar):

A. Structure & Mechanism

1. Anti-CD20 Monoclonal Antibody

Complexed with 131 Iodine

B. Use:

1. CD20- Positive Follicular Non-Hodgkins Lymphoma

C. Side Effects:

1. Cytopenias

A. Thrombocytopenia

B. Neutropenia

C. Etc.

10. Trastuzumab: (Herceptin): HER-2 Breast Cancer

A. Structure & Mechanism

1. Recombinant DNA Derived, Human

Monoclonal Antibody2. Binds to the HER-2 Domain of the

Epidermal Growth Factor Receptor

(EGFR) and Dowregulates the Receptor

B. Use:

1. Her-2/Neu Positive Metastatic Breast Cancer


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Monoclonal Antibodies:

As Immunosuppressants &

Anti-Inflammatory Agents:

1. Adalimumab: (Humira): Rheumatoid Arthirtis

A. Uses:

1. Rheumatoid Arthritis

2.Juvenile Rheumatoid Arthritis

B. Rare Side Effects: Reported:

1. Sudden Sepsis

2. Tuberculosis

3. Lymphoma

2. Etanercept (Enbrel):

A. Uses:


2. Psoriatic Arthritis

3. Ankylosing Spondylitis

4. Chronic Plaque Psoriasis

B. Side Effects:

1. Monitor For:

A. Serious Infections

B. Malignancies: Eg: Lymphomas

3. Infliximab: Remicade

A. Uses


2. Crohn Disease

3. Ulcerative Colitis

B. Major Side Effects

1. Rare Transfusion Reactions2. Delayed Serum Sickness

C. Rare Side Effects

1. Sudden Sepsis

2. Disseminated Mycobacterial Infections


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4. Abatacept: Orencia

A. Uses:


Not Responsive to Other DMARDS

B. Serious Side Effects:

Monitor For:

1. Serious Infections:

A. Screen For Latent Tuberculosis

2. Use Caution in COPD

3. Possible Malignancies

5. Alafacept: Almevive

A. Mechanism1. Inhibits T Cell Activation

A. Binds to CD2: Cell Surface Antigen

B. Inhibits Normal CD2/LFA-3Interaction

B. Uses:

1. Chronic Plaque Psoriasis

C. Side Effects:

1. Malignancies

2. Infections

6. Efalizumab: (Rapitva)

A. Mechanism:

1. Binds to the CD11a Antigen

2. Inhibits Interaction of LFA-1

On All Lymphocytes With

Intercellular Adhesion Molecule-1

(ICAM-1)

3. Inhibits Adhesion, Activation, and

Migration of Lymphocytes into the Skin

B. Uses:1. Severe Psoriasis

C. Side Effects:

1. Increased Susceptibility to Infections

2. Thrombocytopenia (Rare)

3. Hemolytic Anemia: May Occur

After 4-6 Months of Treament


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7. Basilixiimab: (Simulect)

A. Mechanism:

1. IL-2 Antagonist

B. Uses:

1. Immunosuppressive:

A. Prophylaxis For Organ

Rejection in Renal Transplant Patients

C. Side Effects:

1. Incidence of Lymphoproliferative

Disorders Is Increased

2. Incidence of Opportunistic Infections

Increased

8. Daclizumab: ZenapaxA. Mechanism:

1. Binds to IL-2 Receptor

B. Uses:

1. Part of Immunosuppressive Regimen

Including Cyclosporine & Coriticosteroids

2. Prophylaxis For Organ Rejection

in Renal Transplant Patients

.

9. Omalizumab: (Xolair)

A. Mechanism:

1. Blocks Binding of IgE

to Fc (episilon) Receptor

on Mast Cells and Basophils

B. Uses:

1. Allergic Asthma.

C. Side Effects

1. Anaphylactic Reactions

Have Been Reported

2. Local Injection Site Reactions: 45%3. URI: 23%

4. Sinusitis: 16%

5. Pharyngitis: 11%

6. Viral Infections: 23%

D. Rare Side Effects:

1. Malignant Neoplasm: < 1%


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Other Monoclonal Antibodies:

1. Abciximab: (Reopro)

A. Mechanism:

1. Binds to the Intergrin GPIIB/IIIA

Receptor on Platelets &

Inhibits Fibrinogen

B. Uses:

1. An Adjunct to Heparin in Acute MI

2. Unstable Angina Not Responding to

Conventional Therapy When Percutaneous

Coronary Intervention is Scheduled Within24 Hours

C. Side Effects:

1. Increased Frequency of

Major Bleeding Complications:

Such As:

A. Pulmonary Bleeding

B. GI Bleeding

C. Retroperitoneal Bleeding


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Proteasome Inhibitors:

1. Bortezomib: (Velcade): Proteasome Inhibitor: Multiple Myeloma

A. Combination With Thalidomide + Dexamethasone: 92% Cure

Rate

B. Side Effects:

1. Peripheral Neuropathy

2. Orthostatic Postural Hypotension

3. Exacerbation of CHF

4. Use With Caution If:

A. Dehydration

B. History of Syncope

C. Medication Associated Hypotension

D. Hepatic or Renal Impairment5. Tumor Lysis Syndrome

6. Hematologic Toxicity Reported

A. Severe Thrrombocytopenia

7. CNS Disturbances:

A. Pyrexia: 25%

B. Psychiatric Disturbances: 35%

C. Headache: 25%

D. Etc.

2. Carfilzomib: Phase 1 Trials:

A. Uses

1. Prostate Cancer ( Partial Response)

2.Hematologic Cancers

3. Lactacystin Analog NPI-0052: Phase 1Trials:

A. Uses:

1. Hematologic Tumors

2. Solid Tumors


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Tyrosine Kinase Inhibitors:

1. Dasatinib: (Sprycel): Gleevec Resistant CML

Philadelphia Chromosome Positive ALL

2. Erlotinib: (Tarceva) Non Small Cell Lung Cancer

Pancreatic Cancer with Gemcitabine

A. Side Effects:

1. Edema (37% of Cases)

2. CNS Effects: : Fatigue, Dizziness, Headache,Insomnia

3. Pulmonary Toxicities: Rarely Reported:

A. Interstitial PneumoniaB. Interstitial Lung Disease

C. Pulmonary Fibrosis

D. Obliterative Bronchiolitis

4. Use With Caution in Liver Impairment

5. Uee With Caution in CVS Disease

6. Microangiopathic Hemmolytic Anemia With

Thrombocytopenai Reported With

Erlotinib + Gemcitabine Therapy

3. Gefitinib: (Iressa) (Epidermal Growth Factor):

: Non Small Cell Lung Cancer

A. Side Effects:

1. Rash: (43-54% of Cases)

2. Diarrhea: (48-76% of Cases)

3. Acne: (25-33% of Cases)

4. Pulmonary Toxicity: Rare

A. Interstitial Pneumonia

B. PneumonitisC. Alveolitis


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4. Imitinib: (Gleevec): Blast Phase of CML

A. Side Effects:

1. Nausea & Vomiting

2. Use With Caution in Fluid Retention Staates

A. Cardiovascular Disease

B. Pulmonary Disease

3. Diarrhea

4. Myalgias

5. Nilotinib: (AMN-107): Gleevec Resistant CML( Novartis Pharmaceuticals)

6. Sorafenib: (Nexavar): Advanced Renal Cancer

A. Mechanism:

1. Multikinase Inhibitor:

A. Intracellular raf Kinase Inhibitor

B. VEGF- R Inhibitor

C. c-KIT Receptor Inhibitor

D. FLT-3 Receptor Inhibitor

B Side Effects

1. Reversible Dose Limiting Toxicities Such As:

A. Diarrhea, Fatigue, Hand-Foot Syndrome

2. Hypertension

3. Cardiac Ischemia or MI

4. Serious Bleeding: Monitor PT/ INR

. in Patients on Warfarin (Coumadin)

5. Animal Studies: Teratogenicity & Fetal Loss


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7. Sunitinib: (Sutent) Advanced Renal Cancer and GIST

A. Mechanism:

1. Multi-Targeted RTK Inhibitor

A. VEGFR 1, 2, 3

B. c-KIT

C. PDGF Receptors

D. FMS Like Tyrosine Kinase -3 : (FLT-3)

E. CSF Receptor Type 1

F. Glial Cell Line Derived NeurotrophicFactor Receptor

(RET)

B. Side Effects:1. Monitor LVEF Function & Adjust

Dosage Accordingly or Interrupt Therapy

2. Hypertension: (15-28% of Cases)

3. Hemorrhagic Events Reported:

A. Upper GI Bleeding

B. Pulmonary Hemorrhage

C. Wound Bleeding

D. Rectal Bleeding

E. Epistaxis

F. Gingival Bleeding

4. Adrenal Function Abnormalities Reported:

A. Adrenal Insufficiency: With:

1. Trauma

2. Severe Infection

3. Undergoing Surgery

5. Skin or Hair Depigmentation or Discoloration Possible

6. Animal Studies: Teratogenicity and Fetal Loss


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Immunomodulatory Drugs:

1. Thalidomide + Dexamethasone

A. Use:

1. Multiple Myeloma

B. Toxicities:

1. Venous Thromboembolism

2. Neuropathy

3. Somnolence

4. Constipation

5. Rash

2. Lenalidomide+ Dexamethasone

A. Use:

1. Multiple Myeloma

2. MyelodysplaticSydromes

A. With Deletion Of 5q Cytogenetic Abnormalities

B. Under Investigation

1. RCC

2. Prostate Cancer

3. Hepatocellular Carcinoma

3. Phase II & III Trials:

A. Prostate Cancer

1. Docetaxel/Thalidomide

2. Docetaxel/ Bevacizumab

4. Phase II Trials:

A. Docetaxel/ Prednisone/ Thalidomide/ Bevacizumab

1. Androgen Independent Prostate Cancer


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Anti-Sense Agents

A. Oligonucleotides

1. Classification:

A. Peptide Nucleic Acids

B. Morpholino Oligonucleotides

C. Phosphorothioates

2. Phoshorothioates:

A. Binding Affinity To:

1. Heparin Binding Proteins

A. Basic & Acidic Fibroblast Growth Factor2. PDGF

3. VEGF

B. The Extracelular Matrix:

1. Laminin

2. Fibronectin

C. Mechanism Of Action:

1. Binds To First 6 Codons In Human bcl- mRNA

Eliciting Activity OF RNAase H

2. RNAase H : Cleaves The mRNA Strand Of

The mRNA-Oligonucleotide Complex.

3. Phosphodiesters & Phosphorothioates:

Are The Only Classes Of Oligonucleotides

Thar Elicit RNAase Activity.

3. Clinical Trials With Oblimersen: G3139

1. Chronic Lymphocytic Leukemias

A. In Combination Chemotherapy :

1. Fludarabine + Cyclophosphamide

2. Complications:A. Catheter Related Complications

B. Hematologic:

1. Thrombocytopenia

2. Febrile Neutropenia


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4. Clinical Trials With Oblimersen: G3139:

1. Advanced Melanoma

A. In Combination Chemotherapy:

1. Dacarbazine + Oblimersen

B. Toxicities:

1. Bleeding Problems

2. Catheter Related Events

A. Venous Thrombosis

B. Occlusion

C. Infections

5. Oblimersen :A. Is The First Oligonucleotide To Demonstrate

Proof Of The Principle OF An Anti Sense

Effect in Human Tumors By Down Regulation

Of Target Bcl-2 Protein.

B. The Bcl-2 Protein Is Overexpressed In Several Cancers

& Is Implicated IN Anti-Apototic Pathways.

6. Oblimersen (Genasense)

A. Is Being Studied For Treatment Of Several Cancers

Including Hematologic Cancers & Solid Tumors

With Combination Chemotherapy.

7. Fomivirsen:

A. FDA Approved Drug For:

1. CMV Retinitis In AIDs Patients


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Investigational Anti-Angiogenesis Agents:

Drug Cellular Targets

1. Anti-VEGF Agents

A. VEGF-AS (Anti-Sense Oligonucleotides) VEGF, VEGF-C

VEGF-D

B. VEGF Trap VEGF, PLGF

2. Multi-Targeted Agents That Interfere

With Growth Factor Receptor

Signalling Pathways

A. Axitinib VEGFR-1.

VEFGR-2, PDGFR

B. AZD-2171 VEGFR-1, 2, &3

PDGFR, c-KIT

C. BMS-582664 VEGFR-2, FGFR

D. Motesanib VEGFR-1, 2 , 3

PDGFR, c-KIT

E. OSI-930 VEGFR-2, c-KIT

F. Pazopanib VEFGR-2

G. RPI-4610 (Angiozyme) mRNA For VEGFR-1

H. Tandutinib FLT-3, PDGFR,C-KIT

I. Vatalanib VEGFR-1, 2, 3 , PDGFR

c-KIT

J. Vandetanib VEGFR -1,2, 3

K. XL- 184 VEGFR-2, MET, c-KIT,

FLT- 3, TIE-2

L. XL- 999 VEGFRs, FGFRs,

PDGFR, FLT-3


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3. Agents Target Other Proteins

Or Pathways:

A. AMG-386 Angiopoietins

B. AMG- 479 Insulin Like Growth

Factor -1 Receptor

C. ATN- 161 Alpha-5 Beta- 1

Integrin Receptor

D. CP- 751871 Insulin Growth Factor-1 Receptor

E. Volociximab Alpha-5-Beta-1

Integrin Receptor


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Examples Of Drugs That Posses Anti-Angiogenic Activity

Or Inhibit Angiogenesis As A Secondary Function:

Drug Class

1. Cetuximab EGFR/HER Monoclonal

Panitumumab Antibodies

Trastuzumab

2. Gefitinib EGFR Small MoleculeErlotinib Receptor Tyrosine Kinase

Inhibitors

3. Everolimus mTOR Inhibitors

Temsirolimus

4. Belinostat HDAC Inhibitors

LBH-589

Vorinostat

5. Celocoxib COX-2 Inhibitor

6. Bortezomib Proteasome Inhibitor

7. Zolendronic Acid Bisphosphonates

8. Rosiglitazone PPAR-Gamma Agonists

9. Doxycyline Antibiotics


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Examples Of Endogenous Angiogenesis Inhibitors:

1. Alphastatin

2. Angiostatin

3. Antithrombin III

4. Arrestin

5. Candstatin

6. Endostatin

7. Interfron Alpha Or Beta

8. 2-Methoxy-Estradiol

9. Pigment Epithelial Derived Factor

10. Tetrahydrocortisol

11. Thrombospondin

12. TIMP-2

13.Tumstatin


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Preventive Cancer Vaccines:

1. Hepatitis B Vaccine

2. HPV Vaccine

3. Vaccine In Preparation For H. Pylori


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Histidine Deacetylase Inhibitors

(HDAC Inhibitors)

1. Mechanism:

A. Effects On Non-Histone Proteins

Related To Acetylation

B. Alter The Degree Of Acetylation

On Non-Histone Proteins

& Thereby Repress Or Increase Their Activity

2. First Generation Inhibitors:

A. Small Chain Fatty Acids

1. Sodium Butyrate

A. Phase 1 Studies: Refractory AML2. Arginine Butyrate

3. Sodium Phenylbutyrate

A. Phase 1 Studies: AML

Myelodyspalstic Syndromes

B. Phase 1 Studies: Papillary Thyroid Cancer (Partial Response)

Mesothelioma (Partial Response)

Laryngeal Cancer (Partial Response)

4. Valproic Acid With All-Trans Retinoic Acid

A. AML

B. Myelodysplastic Syndromes

3. Second Generation Inhibitors:

A. Hydroxamic Acids: (Class 1 &2)

1. Vorinostat: (Class 1&2)

1. FDA Approved For:

A. Cutaneous T-Cell Lymphoma

2. Toxicities:

A. Fatigue

B. Nausea/Vomiting/C. Thrombocytopenia

3. Phase 1 Trials:

1. Hodgkins Lymphoma

2. Non-Hodgkins Lymphoma


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B. Cyclic Tetrapeptides:

1. Romidepsin: (Class 1&2)

A. Phase 1 Trials: Renal Carcinoma

B. Phase 2 Trials: Cutaneous T Cell Lymphoma

C. Side Effects:

1. EKG Changes:

A. T Wave Flattening

B. ST-T Wave Depressions

C. No Changes In LV Ejection Fractions

D. No Changes In Serum Cardiac Troponin Levels

C. Benzamides:1. SNDX275 (Class 1)

A. Phase 1 Trials: Relapse & Refractory AML

B Side Effects:

1. Infection

2. Unsteady Gait

3. Somnolence

D. Pharmocodynamic Changes Associated With HDAC Inhibitors:

1. Vorinostat (Class 1 &2)

A. Transient Increase In Acetylation Of Histone 3

In Peripheral Lympocytes

B. Translocation Of Phosphorylation STAT-3 From Nucleus

To Cytoplasm

2. Romidepsin:

A. Induced Histone Acetylation Of H3 &H4 In Peripheral

Blood Tumor Cells

B. p21 Protein Levels Increased Associated With Increased

Histone 4 Levels At The p21 Promoter Region

3. SNDX275:A. Increased Histone H3 & H4 Acetylation

B. Increased p21 & Activation Of Caspase 3


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DNMT Inhibitors + HDAC Inhibitors:

1. First Studies:

A. 5AC + Sodium Phenylbutyrate:

1. Uses: AML

Myelodysplastic Syndrome

2. Similar Study:

A. Decitabine + Valproic Acid +All Trans Retinoic Acid:

1. Uses: AML

Myelodsyplastic Syndrome

3. Ongoing Studies:

A. Combination Of DNMT Inhibitors +Second Generation HDAC Inhibitors:

Including:

1. SNDX-275 (Class 1)

2. Vorinostat (Class 1&2)

3. Belinostat (Class 1&2)

4. MGCD-0103 (Class 1)

DNA Methyltransferase Inihibtors:

1. 5-Azacitidine

A. Uses:

1. Myelodysplastic Syndrome

2. Investigational Uses:

A. Refractory ALL &AML

2. 2-Deoxy 5-Azactyidine


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Aurora Kinase Inhibitors:

1. The Auroras Are Involved In Regulation

Of Multiple Steps In Mitosis Including:

A. Centrosome Duplication

B. Formation Of The Bipolar Mitotic Spindle

C. Chromosomal Alignment on The Mitotic Spindle

D. Fidelity Of Spindle Checkpoint.

2. Aurora Proteins :

A. Belong To A Family Of Serine/Threonine Kinases

That Are Regulators Of Different Steps In Mitosis

3. Mechanism Of The Inhibitors

A. Targets Enzymes Central To Cellular Mitosis.

4. Inhibitors:

A. ZM447439

B. Hesperadin

C. VX- 680

Serine/Threonine Kinase Inhibitors;

1. Enzastaurin:

A. Oral Agent

B. Mechanism:

1. Induces Tumor Cell Apoptosis

2. Inhibitis Proliferation And Angiogenesis

C. Uses:

1. Second Or Third Line TherapyOf Non-Small Lung Cancer

2. Phase 1/2 Clinical Trials With

Temolozomide & RadiationTherapy

For Glioblastoma Multiforme


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Protein Tyrosine Phosphatase Inhibitors:

1. Sodium Stibogluconate:

A. SSG + Interferon Alpha 2b: Clinical Trials:

1. Inhibits The Following Cancers;

A. Melanoma

B. Colorectal Cancer

C. Squamous Cell Carcinoma Of The Head & Neck

D. Peritoneal Mesothelioma

E. Ovarian Cancer

Hedgehog Antagonists

1. Clinical Trials: Phase 2 Trials

A. With Avastin (Bevacizumab)For First Line Therapy For

Metastatic Colorectal Cancer

Gene Therapy:

1. Gene Augmentation Therapy

A. Is Appropriate For Treatment Of Inherited

Disorders Caused By A Loss Of A Functional

Gene Product.

2. Gene Inhibition Therapy:

A. Is Suitable For Treatment Of Infectious Diseases.

Cancer, & Inherited Diseases.

3. It Is Very Important To Ensure That Suicide Genes

Are Very Appropriately Targeted.


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Immunotherapy:

1. Non Antigen Specific Therapies:

A. Interleukin 2 Therapy:

1. 10-20% Tumor Regression:

A. Melanoma

B. Renal Cancer

B. Anti CTLA-4 Blocking Antibodies

In Combination With Anti CD-25

Antibody & Tumor Vaccines:

1. Show Regression In Murine Tumor Systems

C. Peptide Vaccines

D. Whole Cell Vaccines:1. Canvaxin Trials:

A. 3 Inactivated Allogenic Melanoma Cells

With BCG : Overall Survival: 49%

E. Dendrite Vaccines

F. Recombinant Vaccines:

1. Consist Of :

A. Recombinant Viral Constituents Or

Naked DNA.

B. Contained

1. Full Length Gene Products

G. Heat Shock Protein Vaccines (Oncophage)

1. Numerous Trials Have Failed To

Demonstrate Effectiveness

H. Lymphoma Vaccine: Clinical Trials

1. Shows Promise In Lymphoma

I. Her+2 GM-CSF Secreting Breast Tumor Vaccine:

1. Clinical Trials: With Cyclophosphamide

J. CD4+ T Helper Peptides : Clinical Trials:

1. Evaluation For Her2-Neu Breast CancerK. IGN 101 Cancer Vaccine:

1. Clinical Trials: For

A. Epithelial Cancers

1. Acting On Epithelial Cell Adhesion Molecules

.


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L. Passive Immunological Rx:

1. Lymphokine Activated Killer Cells To Syngenic

Mice + Interleukin 2

A. Regression Of Pulmonary Metastases

2. Allogeneic Hematopoietic Stem Cell Transplants:

A. For Leukemias

M. Antibody Based Therapies:

1. Herceptin: Trastuzumab: Her-Neu-2 Breast Cancer

2. Rituxan: Rituximab: B Cell Leukemia

K. Loss Or Down Regulation Of Class 1 HistocompatibilityLeukocyte Antigens

1. Recent Studies :

NK Cells Express Receptors

(NKG2D) Which Bind To Stress Induced Ligands

That Can Be Upgraded In A Variety Of Tumors.


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Oncogenic Infectious Agents

Agent Tumor Type

1. Bacteria

A. H. Pylori Stomach Cancer,

Gastric Lymphoma

2. Viruses:

A. Human Papilloma Cervical Cancer,

Virus Vaginal Cancer,

Anal Cancer

B. Hepatitis B Virus Liver Cancer

C. Hepatitis C Virus Liver Cancer

D. HIV Kaposi Sarcoma,

NHL

E. Human Herpes Type 8 Kaposi Sarcoma

F. Epstein Barr Virus Nasopharyngeal Carcinoma

Lymphomas: Hodgkins and

Non-Hodkgins Lymphomas

G. Human T Cell

Lymphotrophic Virus-1 Adult T Cell Leukemia

3. Parasites:

A. Schistosomiasis Bladder Cancer

B. Liver Flukes Cholangiocarcinoma


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Major References:

1. Lacy et al: Drug Information Handbook 14th Edition: 2006

2. De Vita, Lawrence & Rosenberg; Cancer: Principles Of Oncology: 2008

3. www.asco.org

4. http://en.Wikipedia.org/wiki/AntiSense_Therapy

5. Clinical Cancer Research Vol 10,4245S-4248S, June 15,2004

Herbst & Frankel et al: Proceedings of the First International Conference

Oblimersen Sodium:Genasense bcl-2 Anti Sense Oligonucleotides

6. Monday Dec 10, 2007 News-Medical.Net

Complete Response With Oblimersen Combination Improves Survival

In CLL Patients7. Maxon & Weaver MD: CancerConsultants.com

Anti -Sense Therapy:Overview

8. http://www.medscape.com/viewsarticle/495344

Keen & Taylor:Aurora Kinase Inhibitors As Anti-Cancer Agents

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Documents

Monoclonal Ab & Tyr Kinase Inhibitors