Download Idiotype A Tumor Antigen Specific for Lymphoma

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 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 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
Two Arms of the Immune System
B cells
T cells
antibody
foreign
substance
(antigen)
Abnormal
cell
B cell
T cell
Function:
Make Antibodies
Kill abnormal cells
Lymphoma Tumors Have A Special Target
transformation
Normal B cells
B lymphoma cells
Monoclonal Antibody Therapy
Custom Made
Anti-idiotype antibody
Tumor Idiotype
Lymphoma
B cell
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
7
Monoclonal Antibody Therapy
Once Size Fits All
Anti-idiotype antibody
Tumor Idiotype
Rituximab
CD20
Lymphoma
B cell
Aren’t antibodies wholesome, natural and without side effects
FDA Approved Monoclonal Antibodies
YEAR
Product
Target
Indication
1986
Orthoclone
CD3
Transplant Rejection
1994
ReoPro
GPIIa/IIIb
Angioplasty
1997
Rituxan
CD20
B Cell Lymphoma
1998
Zenapax
IL2R
Transplant Rejection
1998
Simulect
IL2R
Transplant Rejection
1998
Remicade
TNF
Crohn’s, RA
1998
Herceptin
Her2
Breast Cancer
2000
Mylotarg
CD33
AML
2001
Campath
CD52
CLL
2002
Zevalin
CD20
B Cell Lymphoma
2003
Bexxar
CD20
B Cell Lymphoma
2003
Raptiva
CD11a
Psoriasis
2004
Avastin
VEGF
Colon Cancer
2004
Erbitux
EGFR
Colon Cancer
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
3) Antibody-dependent Cellular
Cytotoxicity (ADCC)
FcR
Dendritic Cells
4) Antigen Presentation
and Cross-priming
Response to Antibodies
Depends On Your Genes
Rituximab
Clinical Response Determined by Genetics
FcgR IIIA 158 V/F polymorphism
p=0.037
15
V/V
V/F
F/F
8/10
(80%)
12/28
(43%)
9/23
(39%)
F Carriers
21/51
(41%)
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
16
A Therapeutic Vaccine for Lymphoma
“Rescue hybridization”
Myeloma cell
+
Tumor Biopsy
Vaccine Production
3
2
1
Immunization
KLH
carrier protein
Id
Adjuvant (SAF)
Tumor Id Protein
Genitope Phase III Trial
Treatment Schedule
Enrollment
Randomize 2/1
CVP
Recovery
26 weeks
Monthly Vaccines x7
Immunization: 28 weeks
Follow for Time to Progression
Idiotype Vaccine
Can A Custom Vaccine Be Practical?
Idiotype Vaccine Production Via Recombinant DNA
Recombinant Id
proteins
Mammalian or
insect cells
Bacteria
Genetic Id Vaccines
Plants
Naked
DNA
Cell Free
Whole
Immunoglobulin
Immunoglobulin
Fragments
Recombinant
Viruses
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 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
Future Doctor
“Take some immunotherapy and call me in the morning”
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
Dendritic Cells
• Most potent “antigen-presenting cells”
• Reside in tissues to collect antigen -> travel to lymph nodes
• Co-culture with antigens -> cellular vaccine
Myeloma cell
+
1
Fusion
Tumor Biopsy
Vaccine Production
Leukapheresis
2
+
Immunization
4
Dendritic Cells
Antigen-Pulsed
Dendritic Cells
Tumor Id Protein
Co-culture
3
Idiotype-pulsed dendritic cell vaccination
Pre-vaccine
11 months post-vaccine
In situ Vaccination with DC
Chemotherapy
2
Leukapheresis
1
3
Intratumor
Injection
Dendritic Cells
Freedom From Progression
Follicular Lymphoma first remission
PROBABILITY (%)
100
80
60
Responders (n=14)
40
p<0.0001
non-Responders (n=18)
20
0
0
2
4
6
TIME (YEARS)
8
10
Rituximab Publications
180
160
Publications
140
Genentech (DNA) stock price
120
IDEC (IDPH) stock price
240
220
200
180
160
140
120
100
80
60
40
20
0
Stock price ($)
Number of publications
200
100
80
60
40
20
0
Jan/91 92
Year
30
93
94
95
1st clinical trial
96
97
98
99
00
Pivotal
FDA
approval trial results
Norman Klinman 1970
Monoclonal Antibody Imaging
111In-Labeled Zevalin™
4 hours
3 days
6 days
Abdominal SPECT
106-00-158RS
Abdominal CT
Hybridoma Technology
Making Antibodies Immortal
Antigen
Cells Fuse into a
Hybridoma
Antibody-producing
Plasma Cell
34
Monoclonial Antibodies
Cancerous
Plasma Cell