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The Making of a Translational Researcher Lupe G. Salazar, M.D. Tumor Vaccine Group Division of Oncology In the Beginning…. Started in hematology with interest in BMT research Meet future mentor on oncology service Interest dwindled after 4 months of BMT in-pt. service Panic sets in at the end of 1st clinical year Sparks my interest in tumor immunology Vaccines targeting HER2 in breast/ovarian Ca Join the Tumor Vaccine Group with specific interest in clinical development of HER2 vaccines in breast and ovarian cancer Going from Big to Small What does “clinical development of HER2 vaccines in breast and ovarian cancer” mean? Clinically oriented- I didn’t want to be under a hood or taking care of mice all day Yet I was very interested in the basic science aspects Biology of the disease (humans and mouse models) Tumorigenic and immunogenic aspects of HER2 protein Formulation of HER2 vaccines Monitoring of immune responses to HER2 vaccination A Leap of Faith and Lots of Luck Take a vaccine in pre-clinical development and design a study to test it in humans Designing the study and deciding what questions to ask DNA plasmid based vaccine encoding the intracellular domain (ICD) of HER2 The product itself- first time use in humans Current literature on DNA vaccines- malaria and HIV Mentors previous experience with peptide vaccines Based on the above Phase I study to look at safety and immunogenicity Enroll enough subjects to be able to ask scientific questions A Phase I Trial to Evaluate the Safety and Immunogenicity of a DNA Plasmid Based Vaccine Encoding the HER2 Intracellular Domain in Subjects with HER2 Overexpressing Tumors Primary objectives To determine the safety of intradermal administration of 3 doses of a DNA based HER2 vaccine administered with a fixed dose of GM-CSF To determine whether a plasmid DNA HER2 vaccine can elicit HER2 specific immune responses Secondary objectives To determine if the dose of the plasmid-based DNA vaccine effects immunologic responses To determine the persistence of DNA at the site of vaccination. Phase I Study of HER2 ICD DNA Vaccine Patients with stage III/IV HER2 + tumors Dose-escalation study: 10µg, 100µg, 1,000µg Most immunogenic dose 22 patients/dose Breast and ovarian Sufficient to gather immune response data Vaccinate monthly for 3 months GM-CSF as an adjuvant Based on previous vaccine trials and animal data K23 Research Questions K23 specific aims based on the clinical trial Evaluate the safety and measure the extent of immunogenicity of HER2 (ICD) plasmid-based DNA vaccination in patients with advanced stage HER2 overexpressing breast and ovarian cancer Determine whether HER2 specific T cell memory occurs after active immunization with a HER2 ICD plasmid-based DNA vaccine Determine if prolonged local antigen expression is associated with the development of a HER2 specific memory T cell response after immunization. Methods Phase I study: 22 subjects at each dose-level Provide adequate numbers of subjects for gathering (1) safety data, (2) statistically powered immunologic response data and (3) statistically powered data comparing the immunologic efficacy of the 3 doses of vaccine Immunologic Correlates Assess generation of immunologic memory • • Proliferation and ELIspot assays to determine HER2 specific T cell response Cytokine Flow cytometry to characterize memory T cells DTH response post- immunization Assess prolonged local antigen expression (IHC) • • • Chronic deposition of CD1a+ cells in vivo transfection of APC Chronic expression of HER2 protein Timeline Protocol Concept- March 2001 Protocol designed-July 2001 Pre-IND Meeting with FDA- August 2001 Pre-clinical testing, manufacturing, vialing of Product, multiple revisions of protocol K23 submitted June 2002 (Awarded June 2003) IND Meeting with FDA- July 2003 Final IND submission-January, 2004 (AACR/ASCO Clinical Trials Course)- Approval from FDA/IRB/GCRC April 2004 Phase I study enrolls 1st subject-May, 2004 Some Results 9 subjects enrolled at lowest dose (10mcg) Toxicity 6 Stage IIIB 3 Stage IV (2 with stable bony disease) 5 have completed 3 vaccines Grade I skin reaction at injection site Grade I Autoimmune: ANA 1:40 Grade I Myalgias No evidence of plasmid at vaccination site 1 month post Immunologic Correlates 4/5 patients have generated HER2 specific T cell responses after the 2nd vaccine Skin biopsies currently being evaluated (IHC) Financing a Clinical Trial It takes lots of money to fund the needed resources NIH/NCI funding Research Coordinators Research Nurses Lab Personnel RO1 (Nora Disis) to run the study K23 pay young investigator salary including travel and few lab supplies and 5% of lab tech Institutional resources for young investigators FHCRC RTO GCRC Things That Can Slow Down the Process Regulatory Agencies and Committees FDA SRC (FHCRC Scientific Committee) UW HSD GCRC Things that might help Pay attention to detail Pay attention to deadlines Quick responses from the PI Acknowledgements Tumor Vaccine Group Jennifer Childs, M.P.H. Yushe Dang, Ph.D. Corazon dela Rosa, BSMT Collaborators Nora Disis, M.D. Katherine Guthrie, Ph.D., FHCRC Patty Fintak, M.A. Ted Gooley, Ph.D., FHCRC Ekram Gad, Ph.D. Holden Maeker, Ph.D., BD Biosciences Vivian Goodell, M.P.H. Heidi Gray, M.D. Skip Maino, Ph.D., BD Biosciences Doreen Higgins, R.N., B.S.N. Karilynn Howard, M.S. Hailing Lu, Ph.D. Bob Schroeder, B.A. Ron Swenson, M.D. Nate Van Denend, B.S. George Vielhauer, Pharm.D./Ph.D. Wolfgang Wagner, Ph.D. Sarah Wallace, M.S. Devon Webster, M.D. www.tumorvaccinegroup.org