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Customized Cancer Medicine. All Treatments are Customized at the point of delivery All Treatments Are Designed to Take advantage of Differences between Cancer Cells and Normal Cells

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customized cancer medicine
Customized Cancer Medicine

All Treatments are Customized at the point of delivery

All Treatments Are Designed to Take advantage of Differences between Cancer Cells and Normal Cells

Some of these differences are Generic and some are more Specific to the Type of Cancer, the Subtype, or even to the Individual Person

customized cancer medicine1
Customized Cancer Medicine

Generic Treatments

Cancer Starts from One Cell in One Place

Surgery- Early Detection

Cancer Cells Divide Faster

Chemotherapy and Radiotherapy

Cancer Type Specific Treatments

Hormone Responsive

Prostate/Breast

Tissue Type

Thyroid

Receptors

Monoclonal Antibodies

customized cancer medicine2
Customized Cancer Medicine

Personalized Treatments

Not All People Are The Same

Match The Treatment For the Person’s Inherited Genes

Pharmacogenomics

Not All Tumors Are The Same

Match The Treatment For the Tumor That Person Has

Tumor Phenotyping

Gene Expression Profiling

The Relationship between the Immune System of the Person and Their Tumor Is Variable

Re Educate the Immune System

Monoclonal Antibodies

Transplanted Immune Cells

Tumor Vaccines

slide4

B cell

T cell

Two Arms of the Immune System

B cells

T cells

foreign

substance

(antigen)

antibody

Abnormal

cell

Function:

Make Antibodies

Kill abnormal cells

slide6

Monoclonal Antibody Therapy

Custom Made

Anti-idiotype antibody

Tumor Idiotype

Lymphoma

B cell

slide7

New England Journal of Medicine, 306:517. 1982

Treatment of B Cell Lymphoma

with Monoclonal Anti Idiotype Antibody

Richard A Miller, David G. Maloney, Roger Warnke, and Ronald Levy

slide10

Monoclonal Antibody Therapy

Once Size Fits All

Anti-idiotype antibody

Tumor Idiotype

Rituximab

Lymphoma

B cell

CD20

slide13

Rituximab Anti-tumor Effect: Proposed Mechanisms

1) Apoptosis, Anti-proliferation

2) Complement-mediated Killing

Tumor Cell

T Cells

CD20 or

other tumor Ags

FcR

Natural Killler Cells

Monocytes

FcR

Dendritic Cells

3) Antibody-dependent Cellular

Cytotoxicity (ADCC)

4) Antigen Presentation

and Cross-priming

slide15

Rituximab

Clinical Response Determined by Genetics

FcgR IIIA 158 V/F polymorphism

V/V V/F F/F F Carriers

8/10 12/28 9/23 21/51

(80%) (43%) (39%) (41%)

p=0.037

monoclonal antibody conclusions
Monoclonal Antibody Conclusions

Antibodies are Effective Drugs

Improved versions will be Found

New Targets will be Found

New Disease Indications Will be Found

? Mechanisms of Action and Resistance

? Prediction of Efficacy

slide17

A Therapeutic Vaccine for Lymphoma

“Rescue hybridization”

Myeloma cell

+

Tumor Biopsy

.

Vaccine Production

3

2

1

Immunization

Tumor Id Protein

KLH

carrier protein

Id

Adjuvant (SAF)

slide18

Genitope Phase III Trial

Treatment Schedule

Enrollment

Monthly Vaccines x7

Randomize 2/1

Recovery

26 weeks

Immunization: 28 weeks

CVP

Follow for Time to Progression

idiotype vaccine
Idiotype Vaccine

Can A Custom Vaccine Be Practical?

slide20

Idiotype Vaccine Production Via Recombinant DNA

Recombinant Id proteins

Genetic Id Vaccines

Naked DNA

Recombinant Viruses

Mammalian or insect cells

Bacteria

Plants

Cell Free

Immunoglobulin Fragments

Whole Immunoglobulin

vaccine just in time

3

2

1

1. Lymphoma Biopsy

Vaccine Just in Time

2. Amplify Ig V genes

Insert into Vector

(~ 3 Days)

4. Vaccinate

3. Express Cell-Free /Purify

(~ 2 days)

customized cancer medicine3
Customized Cancer Medicine

Personalized Treatments Are Problematic

Drug Industry

Mass produced products for mass markets

High margins between cost of goods and sales price

Intellectual Property favors composition over use

Health Care Delivery Organizations

Standard Operating Procedures

Risk/Reward better for acute interventions

HMO model shifts financial risk to the provider

Regulatory Bodies

Accustomed to manufacturing issues and large scale trials

Privacy Concerns

Work against genetic testing

Work against use of medical records to develop predictive tests

slide23

Future Doctor

“Take some immunotherapy and call me in the morning”

using the immune system to treat cancer 2005
Using The Immune System To Treat Cancer: 2005

Antibodies, Antibodies and more Antibodies

Therapeutic Vaccination

Dendritic Cells

Adoptive Cellular Therapy

Allogeneic Bone Marrow Transplantation

Autologous T Cells

Inhibition of Suppressor T Cells

slide25

Dendritic Cells

  • Most potent “antigen-presenting cells”
  • Reside in tissues to collect antigen -> travel to lymph nodes
  • Co-culture with antigens -> cellular vaccine
slide26

1

2

Myeloma cell

+

Fusion

TumorBiopsy

Vaccine Production

Leukapheresis

+

Immunization

4

Dendritic Cells

Tumor Id Protein

Antigen-Pulsed Dendritic Cells

Co-culture

3

slide27

Idiotype-pulsed dendritic cell vaccination

Pre-vaccine 11 months post-vaccine

slide28

In situ Vaccination with DC

Chemotherapy

2

Leukapheresis

3

1

Intratumor

Injection

Dendritic Cells

slide29

100

80

60

PROBABILITY (%)

Responders (n=14)

p<0.0001

40

non-Responders (n=18)

20

0

0

2

4

6

8

10

TIME (YEARS)

Freedom From Progression

Follicular Lymphoma first remission

rituximab publications

240

220

200

180

160

140

120

100

80

60

40

20

0

Rituximab Publications

200

180

Publications

160

Genentech (DNA) stock price

140

Number of publications

IDEC (IDPH) stock price

120

Stock price ($)

100

80

60

40

20

0

00

93

94

Jan/91

92

97

98

99

95

96

Year

Pivotal

trial results

FDA

approval

1st clinical trial

slide33

3 days

4 hours

6 days

Abdominal SPECT

Abdominal CT

Monoclonal Antibody Imaging

111In-Labeled Zevalin™

106-00-158RS

hybridoma technology making antibodies immortal

Antigen

Cells Fuse into a Hybridoma

Cancerous

Plasma Cell

Antibody-producing

Plasma Cell

Monoclonial Antibodies

Hybridoma TechnologyMaking Antibodies Immortal