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 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 antibody foreign substance (antigen) T cells 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 The image cannot be display ed. Your computer may not hav e enough memory to open the image, or the image may hav e been corrupted. Restart y our computer, and then open the file again. If the red x still appears, y ou may hav e to delete the image and then insert it again. Monoclonal Antibody Therapy Once Size Fits All Anti-idiotype antibody Tumor Idiotype Rituximab CD20 Lymphoma B cell The image cannot be display ed. Your computer may not hav e enough memory to open the image, or the image may hav e been corrupted. Restart y our computer, and then open the file again. If the red x still appears, y ou may hav e to delete the image and then insert it again. Aren’t antibodies wholesome, natural and without side effects FDA Approved Monoclonal Antibodies YEAR 1986 1994 1997 1998 1998 1998 1998 2000 2001 2002 2003 2003 2004 2004 Product Orthoclone ReoPro Rituxan Zenapax Simulect Remicade Herceptin Mylotarg Campath Zevalin Bexxar Raptiva Avastin Erbitux Target CD3 GPIIa/IIIb CD20 IL2R IL2R TNF Her2 CD33 CD52 CD20 CD20 CD11a VEGF EGFR Indication Transplant Rejection Angioplasty B Cell Lymphoma Transplant Rejection Transplant Rejection Crohn’s, RA Breast Cancer AML CLL B Cell Lymphoma B Cell Lymphoma Psoriasis Colon Cancer Colon Cancer Rituximab Anti-tumor Effect: Proposed Mechanisms 1) Apoptosis, Anti-proliferation 2) Complement-mediated Killing Tumor Cell T Cells FcR Natural Killler Cells Monocytes FcR Dendritic Cells CD20 or other tumor Ags 3) Antibody-dependent Cellular Cytotoxicity (ADCC) 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 V/V 8/10 (80%) p=0.037 V/F 12/28 (43%) F/F 9/23 (39%) F Carriers 21/51 (41%) 15 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 Immunization KLH carrier protein 2 1 Tumor Id Protein Id Adjuvant (SAF) Genitope Phase III Trial Treatment Schedule Enrollment Randomize 2/1 Monthly Vaccines x7 CVP Recovery 26 weeks 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 Plants Genetic Id Vaccines Naked DNA Recombinant Viruses Cell Free Whole Immunoglobulin Immunoglobulin Fragments 1. Lymphoma Biopsy Vaccine Just in Time 2. Amplify Ig V genes Insert into Vector (~ 3 Days) T7 p ca t RBS 20 0 0 Va l ph a 0 36 34 0 0 0 40 G 0GG G 360 Sx 0 t et Vb 00 a 32 80 0 30 0 0 1 00 0 2 80 0 0 Km R 3. Express Cell-Free /Purify (~ 2 days) T 7 te r 18 0 0 20 0 0 4. Vaccinate 6H m is G G G G S 16 00 22 0 0 24 0 0 Ce b t 0 26 a 12 00 1 40 0 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 The image cannot be display ed. Your computer may not hav e enough memory to open the image, or the image may hav e been corrupted. Restart y our computer, and then open the file again. If the red x still appears, y ou may hav e to delete the image and then insert it again. 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 3 Co-culture 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 100 PROBABILITY (%) 80 60 Responders (n=14) 40 20 0 non-Responders (n=18) p<0.0001 0 2 4 6 8 10 TIME (YEARS) Rituximab Publications Number of publications 200 Publications Genentech (DNA) stock price IDEC (IDPH) stock price 180 160 120 100 80 60 40 20 0 Jan/91 92 Year 30 140 240 220 200 180 160 140 120 100 80 60 40 20 0 Stock price ($) Stock price ($) 99 00 93 94 95 96 97 98 1st clinical trial Pivotal FDA approval trial results The image cannot be display ed. Your computer may not hav e enough memory to open the image, or the image may hav e been corrupted. Restart y our computer, and then open the file again. If the red x still appears, y ou may hav e to delete the image and then insert it again. Norman Klinman 1970 The image cannot be display ed. Your computer may not hav e enough memory to open the image, or the image may hav e been corrupted. Restart y our computer, and then open the file again. If the red x still appears, y ou may hav e to delete the image and then insert it again. 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 Cancerous Plasma Cell 34 Monoclonial Antibodies