Transcript The Making of a Translational Researcher

The Making of a Translational
Researcher
Lupe G. Salazar, M.D.
Tumor Vaccine Group
Division of Oncology
In the Beginning….
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Started in hematology with interest in BMT research
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Meet future mentor on oncology service
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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
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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
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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
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Take a vaccine in pre-clinical development and design
a study to test it in humans
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Designing the study and deciding what questions to ask
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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
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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
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Primary objectives
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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
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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
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Patients with stage III/IV HER2 + tumors
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Dose-escalation study: 10µg, 100µg, 1,000µg
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Most immunogenic dose
22 patients/dose
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Breast and ovarian
Sufficient to gather immune response data
Vaccinate monthly for 3 months
GM-CSF as an adjuvant
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Based on previous vaccine trials and animal data
K23 Research Questions
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K23 specific aims based on the clinical trial
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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
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Determine whether HER2 specific T cell memory occurs after
active immunization with a HER2 ICD plasmid-based DNA
vaccine
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Determine if prolonged local antigen expression is associated
with the development of a HER2 specific memory T cell
response after immunization.
Methods
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Phase I study: 22 subjects at each dose-level
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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
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Assess generation of immunologic memory
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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)
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Chronic deposition of CD1a+ cells
in vivo transfection of APC
Chronic expression of HER2 protein
Timeline
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Protocol Concept- March 2001
Protocol designed-July 2001
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Pre-IND Meeting with FDA- August 2001
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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
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(AACR/ASCO Clinical Trials Course)-
Approval from FDA/IRB/GCRC April 2004
Phase I study enrolls 1st subject-May, 2004
Some Results
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9 subjects enrolled at lowest dose (10mcg)
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Toxicity
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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
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4/5 patients have generated HER2 specific T cell responses
after the 2nd vaccine
Skin biopsies currently being evaluated (IHC)
Financing a Clinical Trial
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It takes lots of money to fund the needed resources
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NIH/NCI funding
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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
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FHCRC RTO
GCRC
Things That Can Slow Down the
Process
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Regulatory Agencies and Committees
FDA
 SRC (FHCRC Scientific Committee)
 UW HSD
 GCRC
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Things that might help
Pay attention to detail
 Pay attention to deadlines
 Quick responses from the PI
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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