IOTF Mentors: Track 3 and Track 4

While at FDA, fellows will each be assigned a mentor who will be a senior member of FDA scientific review staff. Fellows will be matched with one of 24 mentors from the list below through a process of mutual selection. Mentors are listed in alphabetical order by last name.


Cyrus Agarabi, CDR, Pharm.D., Ph.D.

Principal Investigator, Center Drug Evaluation and Research/Office of Biotechnology Products Division of Biotechnology Review and Research

cyrus.agarabi@fda.hhs.gov

(301) 796-7569

Regulatory Science Priority Area: Application of advanced technology for the manufacturing and characterization of biologics for cancer Treatment/Therapy

Program

Emerging technologies for upstream bioprocessing and characterization of cancer biotherapeutics

The objective of this project is to explore control methods for perfusion biomanufacturing of monoclonal antibodies, a drug class that can be used for cancer therapy (e.g. Herceptin, Rituxan, et al.). The biomolecule is from CHO cell culture and improving steps to increase production and quality of antibodies over an extended time can provide scientific support for complex Emerging Technology Team (ETT) regulatory applications targeted for oncology applications. This project will expose the fellow to diverse aspects of bioprocessing and mammalian cell culture critical to oncology drug development, and the integration of cutting edge process analytical tools such as biochemical nutrient and cell viability analyzers, real-time glucose/lactate monitors, biomass monitoring probes, off-gas analyzers, and near infrared spectroscopy. The end goals of the project will be to successfully set up and run model perfusion bioreactors similar to those used commercially to produce antibody-based oncology products. These model production trains can study new strategies to monitor and control the productivity and viability of the cells, and determine the quality of anti-tumor monoclonal antibodies throughout the length of the bioreactor run using multiple orthogonal analytical tools, such as mass spectrometry, spectroscopy, liquid chromatography, and other advanced analytical tools.

Proposed Project for IOTF fellow

The IOTF fellow, depending on the candidate’s expertise, will lead a project focused on either model mammalian cell culture oncology product biomanufacturing or protein characterization using advanced analytical methods. Both aspects are critical to advancing the regulatory science of biomanufacturing this class of cancer drugs. The cell culture aspects will include bioreactor operation, perfusion cultures, continuous monitoring and feedback using on-line and in-line tools such as spectroscopy, electrochemical sensors and other orthogonal methods. The analytical methods will utilize mass spectrometry and liquid chromatography to perform in depth characterization, such as glycosylation, aggregation, and charge variance of the generated monoclonal antibodies for cancer treatment. Overall the project aims to explore the integration of cutting edge tools into upstream bioprocessing, coupled with in depth orthogonal analytics to support the development of rapid manufacturing methods. By shortening time lines for manufacturing process development of break-through therapeutics for oncology indications, more patients can be treated sooner.

Regulatory Activity

The mentor is responsible for primary and secondary review of IND’s, BLA’s, and sBLA’s. He was the primary reviewer for the first Monoclonal Antibody Biosimilar and is a member of the Emerging Technology Team (ETT) consult review cadre, which is a specialized group focused on emerging technologies for biologics related to advanced manufacturing approaches and analytics. The mentor’s team is frequently assigned consult reviews for complex submissions related to continuous biomanufacturing, mass spectrometry, advanced model building and other areas that are precedent setting for the agency. While the mentor regulates a strong portfolio of cancer drugs are regulated such as Mabs, Fabs, Antibody Drug Conjugates (ADC), and Fab-conjugates, the mentor is also assigned a wide variety of clinical products servicing hematologic, dermatologic, and other clinical divisions. The mentor is also deeply involved in the development of regulatory policy including guidance documents, Code of Federal Regulations, and has participated in 6 Advisory Committee Meetings. The IOTF fellow will be fully integrated into an existing team and will be provided with opportunities to participate in training and regulatory review activities related to regulatory submissions. The fellow will spend up to 50% of their time reviewing manufacturing, production, and quality of biotechnology product submissions related to the treatment of cancer and other indications. The fellow will also be exposed to regulatory policy and support working group activities from both a technical and regulatory perspective to gain expertise in the development of regulatory policy. The fellow will also attend lab, branch, divisional, and office level meetings, and may join the mentor at CDER or FDA level meetings to support regulatory or policy decision making, which is often germane to oncology drug products.


Steven R. Bauer, Ph.D.

Biologist, Laboratory of Stem Cell Biology, Division of Cell and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration

steven.bauer@fda.hhs.gov

301-827-0684

Program

Safety and efficacy of ex-vivo cell and gene therapy

Project Summary

We have established a model system to study the multipstep process of virally mediated tumorigenesis 1 with the ultimate goal of assuring safer combination cellular and gene therapies. The combination of cell plus gene therapies holds tremendous potential for the treatment or cure of cancer. Many cell therapies rely on ex vivo gene transduction followed by selection and expansion to achieve the desired number of cells with the desired therapeutic properties. Unfortunately, three out of eleven patients in a SCID gene therapy trial received retrovirally-transduced hematopoietic stem cells and subsequently came down with T cell leukemia. This illustrates the importance of understanding mechanisms of tumorigenesis when considering risks and benefits of combined cellular and gene therapy.

Proposed Project for IOTF Fellow

In this lab, fellows would utilize a model system that we have established to increase our understanding of the multistep transformation1 process with the ultimate goal of assuring safer combination cellular and gene therapies. Our lab uses normal mouse precursor B-cells cultured with recombinant IL-7 and bone-marrow stroma. These cells are normal but proliferate indefinitely in the presence of IL-7 and the stromal cells. We have demonstrated that these pre-B cells can be infected and transformed in vitro by dual oncogene retroviruses carrying c-myc with either v-abl or v-raf1. We have used this model to study some of the important steps that lead to leukemia including mechanisms that lead to constitutive activation of growth factor signal transduction pathways1 and mechanisms that lead to loss of sensitivity to growth inhibition factors, specifically TGF-beta. However, many questions remain and more global approaches such as micro array and proteomics techniques could be used by IOTF fellows to compare and contrast the effects of different oncogenes introduced into normal cells using oncogenic retroviruses. We expect that knowledge gained will ultimately enhance our ability to safely use vector-transduced precursor cell populations for use in treatment of a variety of human diseases. We also expect that a better understanding of oncogenic subversion of growth pathway signaling will lead to safer and a greater range of therapeutic approaches to lymphoid lineage pathologies and tumors in general.

Regulatory Activity

The PI has extensive experience in regulation of cellular and gene therapies (since 1991) and will mentor the fellow in the investigational new drug (IND) review process in the areas of cell and gene therapies, especially those related to cancer (e.g., gene-transduced stem cells, allogeneic stem cells for hematopoietic reconstitution). The fellow will gradually accumulate experience and spend up to 50% of their time in reviewing manufacturing, production, and characterization of cell or gene therapy products. M.D.s can also spend a portion of their time learning and performing clinical reviews within the clinical/pharmacology/toxicology review division.


Serge L. Beaucage, Ph.D.

Chief, Laboratory of Biological Chemistry (LBC), Division of Biotechnology Research and Review IV (DBRR IV), Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research

serge.beaucage@fda.hhs.gov

240-402-9387

Program

Chemical synthesis of oligonucleotides for therapeutic and synthetic biology applications.

Project Summary

This project has important implications for both the detection and treatment of infectious diseases and cancers. Indeed, antisense DNA oligonucleotides, aptamers, and small interfering RNA oligonucleotides (siRNA) have been used in vivo to treat certain types of cancers by altering the expression of cancer-related genes. Although our research group has engineered a novel class of heat-sensitive DNA therapeutic oligonucleotides that are activated in vivo through the heat-induced loss of thermolabile protecting groups, our research program has also been focused on the development of technologies that will enable the chemical synthesis and solid-phase purification of ultra-long DNA and RNA sequence (>1 kb). First and foremost, the aim of this project is to fulfill the high demand for synthetic genes, which will be used in a variety of therapeutic and synthetic biology applications including genetic engineering and chromosome construction.

Proposed Project for IOTF Fellow

The main objectives of the project are to carry out the automated synthesis an assembly of an edited form of an oncogene using a new technology developed in our laboratory. Basic organic chemistry skills are required for this project given that modification of standard nucleic acid protecting groups may be necessary to overcome solubility problems and DNA/RNA chain extension kinetic issues. Molecular cloning skills will also be required to assemble ultra-long DNA sequences into the edited oncogene of interest. If successful, the outcomes of this project should have far-reaching implications in gene therapy applications and chromosomal manipulations. An optional project, the IOTF fellow might consider working on, is the development of reagents designed to enhance the cellular delivery of therapeutic DNA and/or RNA sequences targeting the expression of oncogenic proteins in vitro and in vivo.

Regulatory Activity

The review of incoming pre-Investigational New Drugs (pINDS) and Investigational New Drugs (INDS) submissions, and of the amendments of the currently active INDs, is the responsibility of the LBC. More than 400 active INDs are under review in the LBC; these INDs relate to a plethora of enzymes including pancreatic, PEGylated and unPEGylated enzymes. In addition, PEGylated and unPEGylated growth factors, erythropoetin-derived products, immunoconjugates, fibroblast and epidermal growth factors, thrombolytic and toxin-fusion proteins are among the active INDs under the jurisdiction of the LBC. The fellow will participate in the regulatory review of pIND and IND submissions. These activities will provide the fellow with a solid regulatory training under the tutelage of review teams dedicated to assess the quality attributes of therapeutic proteins and enzymes, through a science-based approach.


Nirjal Bhattarai, Ph.D.

Principal Investigator, Gene Transfer and Immunogenicity Branch, Division of Cellular and Gene Therapies, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration

nirjal.bhattarai@fda.hhs.gov

240-402-6834

Program

Assessing Immunogenicity of Products for Gene Therapy and T cell Therapy

Project Summary

Although T cell based cancer immunotherapy has shown a remarkable promise to treat various cancers, patients treated with therapeutic T cells can develop severe inflammatory disease notably cytokine release syndrome (CRS) in part due to activation of bystander immune cells. Furthermore, inflammation has become a critical risk factor in the clinical application of T cell immunotherapy. Immunosuppressive drugs that are used to manage the inflammation associated with T cell therapy also suppress the efficacy of therapeutic T cells. Thus, novel strategies to manage inflammation during T cell immunotherapy are required for their wide spread use against various cancers. The goal of this project is to develop strategies to reduce inflammation associated with T cell immunotherapy for cancer.

Proposed Project for IOTF Fellow

In this lab, fellow will utilize our established model to examine activation of therapeutic T cells in response to cancer antigens, and assess the intracellular signaling of cancer-specific T cells. Previous studies have shown that activated T cells secrete exosomes that induce bystander immune cell activation; however, the mechanism for this remains largely unknown. The IOTF fellow will study the role of exosomes secreted by CAR-T cells in bystander immune cell activation and inflammation associated with T cell immunotherapies. We expect that the knowledge gained from these studies will enhance our understanding of the role of exosomes in inflammation associated with T cell immunotherapy and aid to design safer and more effective cancer specific T cell therapies for future.

Regulatory Activity

The IOTF fellow will participate in the regulatory review of investigational new drug (IND) applications for cell and gene therapy products. Many of these investigational new drug products are for the treatment of cancer. The fellow will also attend office and divisional regulatory meetings, and seminars. All of these activities will provide the fellow with a regulatory training to assess safety and efficacy of cell and gene therapy products.


Rosalie K. Elespuru, Ph.D.

Principal Investigator, Genetic Toxicology Lab, OSEL, Division of Biology, Chemistry and Materials Science (DBCMS) CDRH

rosalie.elespuru@fda.hhs.gov

301-796-0237

Program

Genetic Alterations, Cancer Risk, and Translational Diagnostics

Project Summary

Genetic alterations are implicated in the causation of cancer and recently have been used as biomarkers for diagnosis of cancer, stratification of patients into treatment groups, and monitors of therapy outcome. In the area of safety assessment (cancer prevention), we assess the capability for DNA interactions of new drugs, device materials, and food additives. In the area of cancer diagnosis and therapy, CDRH regulates genetic and genomic diagnostic devices, expected to be developed for the advent of "personalized medicine". Early diagnosis is a central goal in the prevention of metastatic tumor development (cf. “Moonshot”). In both aspects a central theme is the analytical capability for detection of rare mutant DNA within a background of normal DNA.

Proposed Project for IOTF Fellow

Diagnostics for early cancer detection and therapy monitoring. Detection of mutant DNA in blood and/or exosome RNA in urine or saliva would be the focus. K-RAS codon 12 mutations are a common biomarker for lung and pancreas cancers, and a good model for assessment of diagnostic tools, limits of detection, and human application. Exosomes are a new source of stable nucleic acid biomarkers and can be resourced from less invasive human compartments such as urine and saliva. The fellow would experiment with a choice of molecular diagnostic techniques and instruments (lab equipment or a battery operated PCR instrument), depending on his/her particular interests and goals. Experiments would be designed with spiked-in surrogate nucleic acids to determine limits of detection. Adequate systems development would be followed by acquisition of human or more relevant and realistic samples for analysis. Adaption of a diagnostic system to the battery operated instrument could be used for point of care diagnostics assessment. As a corollary, this project would define the technical factors affecting detection of rare mutant DNA and/or RNA biomarkers in blood and other tissues, relevant to review standards for genetically based diagnostic tests.

Regulatory Activity

The PI has 20 years of FDA experience in the application of genetic analyses to cancer risk assessment of regulated products and is involved in the broader scientific community as past President of the US society of genetic toxicologists. The fellow would follow product reviews relative to cancer risk (device safety assessment) or nucleic acid-based (NAAT) diagnostics, involving the Office of Device Evaluation or the Office of InVitro Diagnostics, respectively. The latter group also reviews genetic tests used in personalized medicine.


David Frucht, M.D.

Principal Investigator, Director, Division of Biotechnology Review and Research II, Office of Biotechnology Products, Office of Product Quality, Center for Drugs, US Food and Drug Administration

david.frucht@fda.hhs.gov

240-402-9533

Program

Using anthrax lethal toxin as a tool to dissect the regulation of the oncoprotein, c-Jun

Project Summary

One of the primary research goals of our laboratory has been to understand the mechanisms of action of anthrax toxins, which underlie the pathogenesis of anthrax infection. We recently discovered that one of the downstream targets of anthrax lethal toxin is c-Jun, a known oncogene involved in cancer biology. Last year we published that exposure to anthrax lethal toxin (LT) leads to the rapid degradation of c-Jun protein, in a manner that is dependent upon the toxin’s proteolytic effect on mitogen activated protein kinase kinases 1 and 2 (MKK1 and MKK2). Moreover, we have shown that cell lines overexpressing toxin-resistant MKK2 are resistant to c-Jun degradation and to the anti-proliferative effect induced by anthrax LT. We believe that understanding the effects of anthrax LT on c-Jun might not only have relevance to pathogenesis of anthrax infection, but could be leveraged to understand the biochemical pathways that underlie the regulation of the levels of c-Jun protein, a critical oncoprotein underlying tumor biology. To this end, we have identified the E2 ubiquitin ligase, COP-1, as a critical component in anthrax LT-dependent c-Jun degradation. We are currently using a variety of molecular tools to identify additional proteins the regulate this pathway.

Proposed  Project for IOTF Fellow

Based on his/her experience and interest, the fellow will have the opportunity to select one or more projects derived from the research program previously described with the goal of using anthrax LT as a tool to dissect the biochemical pathways that regulate c-Jun protein levels. These data will ultimately be leveraged to predict new molecular targets for therapeutic intervention in cancer patients.

Regulatory Activity

As a team member of OBP/Division 2, the fellow will gain experience in diverse aspects of the regulatory review of therapeutic biologics to assess their efficacy and safety. The fellow will have access to formal regulatory training sessions and will participate in the office and division regulatory activities.


Brandon D. Gallas, Ph.D.

Mathematician, Division of Imaging, Diagnostics, and Software Reliability (DIDSR), Office of Science and Engineering Laboratories (OSEL), Center for Devices and Radiological Health (CDRH), FDA

brandon.gallas@fda.hhs.gov

301-796-2531

Program

Improving Clinical Trials for Imaging Devices

Project Summary

Imaging devices, image processing tools, artificial intelligence algorithms, visualization packages, and display devices represent a large regulatory portfolio in CDRH that is continuing to expand.  CDRH is in perpetual need of new paradigms for the evaluation of these products using reader studies, standardized databases, and modeling. These evaluations must be statistically interpretable, relevant for their intended use, and at reasonable cost. This project will investigate new, improved clinical trial designs and statistical methods, as well as develop and validate data analysis tools, which will lead to more powerful clinical studies of the efficacy of imaging devices for fewer resources.

Proposed Project for IOTF Fellow

Depending on the skills and interests of the fellow, a project will be developed in any of the following areas

  • developing mathematical and simulation demonstrations of potential to increase statistical power with new clinical trial designs and analysis methods
  • writing software interface for image display and reader interpretation
  • designing reader study protocols and analyses and executing them with novice readers and simulated images to demonstrate proof-of-concept under a controlled setting
  • designing and executing reader studies with expert readers to tailor methods to the clinical environment

Regulatory Activity

Training courses will be offered to the Fellow on the premarket and postmarket functions of CDRH, the importance of risk management in evaluating the safety of new medical products, how to conduct meetings, technical writing, and writing for sponsors. The Fellow will gain experience with the device approval process used in CDRH through exposure to actual submissions of imaging devices, computer-aided diagnostic (CAD) devices, and others. The fellow will assist in all aspects: the planning of trials, the review process, meeting with sponsors, writing letters to sponsors, and preparing/attending panel meetings.


Indira Hewlett, Ph.D.

Chief, Laboratory of Molecular Virology, Division of Emerging and Transfusion Transmitted Diseases, Office of Blood Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration

indira.hewlett@fda.hhs.gov

240-402-9587

Program

Nanotechnology diagnostics — Point-of-care and Benchtop assays

Project Summary

A primary goal of FDA is to bring new technologies including better methods that are rapid, more accurate, and less expensive to disease screening and diagnosis. We have used nanomaterials to improve the performance of assays for detection of proteins and nucleic acids. Our lab has successfully developed highly sensitive antigen /antibody and nucleic acid assays for the detection of HIV and influenza viruses as well as for the major biodefense pathogens using fluorescent Europium particles for protein and metal gold/silver nanoparticles for nucleic acid detection. With additional funding we have initiated development of microfluidics based point-of-care platforms. We intend to extend this technique to other pathogens of relevance to FDA's public health mission including West Nile virus (WNV), Hepatitis B virus (HBV), hepatitis C virus (HCV), Ebola, a biodefense pathogen and M. tuberculosis, a significant co-infection in AIDS. The technology can be used to detect cancer biomarkers. We will evaluate the feasibility of developing a multiplex assay to simultaneously detect these pathogens in a single sample. The proposed project will benefit FDA in the following ways: 1) it will give FDA scientists involved in regulating diagnostics hands-on expertise and knowledge of how to regulate related products 2) laboratory experience with the nanoscale technology to develop review criteria and standards for effective regulation of product applications of future nano-scale assays for detection of biomarkers of diseases.

Proposed Project for IOTF Fellow

The fellow will be involved with development and optimization of the nanoparticle-based assays for detection of biomarkers of HIV and other pathogens. In addition, the nanoparticle-based assay technology will be extended to detection of serum biomarkers using single and multiplexed diagnostic assays for early detection of AIDS related pathogens.

Regulatory Activity

Review of in vitro diagnostics for retroviral agents and blood borne/biodefense pathogens.


Deborah A. Hursh, Ph.D.

Principal Investigator, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research (CBER), FDA

deborah.hursh@fda.hhs.gov

240-402-9597

Program

Developing markers to assess genome stability of stem cell-based medical products

Project Summary

Cell-based medical products represent therapeutic source material with tremendous promise for the treatment of degenerative disorders as well as cancer. However, deriving and manufacturing cellular products for clinical use often requires expansion and manipulation in vitro, which may introduce risk factors for genome instability and subsequent tumor formation. These risk factors remain incompletely understood and current research is limited by inadequate tools to identify and investigate the sources of genomic instability in culture. The Hursh lab is investigating potential epigenetic markers for genome stability in cell-based products. Our goal is to further develop effective tools to identify cell culture-related risk factors for genome stability and identify potential genomic regions susceptible to damage during cellular manufacturing. In recent years, evidence has emerged linking specialized chromatin structures to DNA replication as well as DNA damage response (DDR). These structures include histone variants and unique post-translational modifications (PTM) of histones, which facilitate faithful replication of the genome and repair of damaged DNA resulting from replication errors or spontaneous double-strand breaks. In response to double-strand breaks, the histone variant H2A.X is phosphorylated around the break site to generate gamma-H2A.X, which marks the damage location and coordinates the DDR. Notably, evidence in yeast and mammalian cells suggests genomic gamma-H2A.X preferentially occurs at proposed fragile sites in the genome, which may be vulnerable to damage during cellular manufacturing processes. Additionally, other histone PTMs have been identified that mark damage locations and influence their resolution. We are actively investigating the utility of these structures as leading indicators of genome instability in cell-based products with the potential to serve as markers of quality assurance in cell-based medical products.

Proposed Project for IOTF Fellow

An IOTF fellow will investigate the effect of culture conditions, including chemical differentiation, of human multipotent and pluripotent stem cells in vitro on epigenomic and genomic stability. The fellow will be responsible for developing appropriate cell culture protocols to explore potential dynamic chromatin structures associated with DNA damage events upon in vitro manipulation. Available tools for this project include spectral karyotyping, confocal microscopy, flow cytometry, chromatin immunoprecipitation, and quantitative real-time PCR.

Regulatory Activity

At the FDA, Dr. Hursh is a product reviewer who regulates clinical trials in cell therapy, gene therapy, and devices. Many of these are for the treatment of cancer. Under the mentorship of Dr. Hursh, fellows will undertake research on human stem cells, and receive mentorship in the review of investigational new drug applications for cell and gene therapy medical products.


Kathryn E. King, Ph.D.

Staff Scientist, Laboratory of Molecular Oncology, Division of Biotechnology Products Review and Research 1, Office of Biotechnology Products (OBP), Center for Drug Evaluation and Research (CDER), FDA

kathryn.kingk@fda.hhs.gov

240-402-9634

Program

Molecular mechanisms of epithelial neoplasia

Project Summary

The development of monoclonal antibodies for the targeted treatment of solid tumors is a major focus of efforts in the pharmaceutical arena as is evidenced by recent product approvals.  An understanding of the molecular mechanisms underlying cancer pathogenesis is critical for the development and regulatory review of such therapies. In the Weinberg laboratory it is our aim to understand the molecular mechanisms involved in cancer pathogenesis by using the murine epidermis as a model system for the study of epithelial cancers. In particular the lab is focused on the p53 family, comprised of p53/p63/p73, which are expressed as multiple protein isoforms. These isoforms can mimic or interfere with one another, and their balance ultimately determines biological outcome in a context-dependent manner. Unlike p53 which is commonly mutated in human tumors, p63, and in particular the deltaNp63 subclass, is often overexpressed in human squamous cell cancers. However, normal levels of p63 expression are critical for normal epidermal development and homeostasis. The aim of the research is to understand the biological impact of dysregulated p63 expression and the molecular mechanisms of action underlying this impact using murine squamous epithelium in both in vitro and in vivo models.

Proposed Project for IOTF Fellow

Fellow will work on a project relating to the characterization of upstream interactions between the p63 and c-Rel pathways, mediation of downstream events, or targets impacted by the overexpression of deltaNp63 that are c-Rel dependent. This work will contribute to the overall research program of the Weinberg lab, which is focused on p63 and interacting pathways in epithelial biology and neoplasia. The fellow should have a good understanding of cancer, cellular and molecular biology. Candidates must have a Ph.D. and/or a M.D. and experience in cellular/molecular biology. The position will be located on the FDA White Oak Campus in Silver Spring, MD. Opportunities to participate in journal clubs and data sharing meetings exist.

Regulatory Activity

Over nearly 30 years monoclonal antibodies have transformed from being solely a research tool to therapeutic agents for treating human disease. Today development of monoclonal antibodies is a major focus of pharmaceutical manufacturers. The Division of Monoclonal Antibodies is responsible for product quality review of antibodies, antibody conjugates, Ig-linked fusion proteins, ScFv, Fab’s and other antibody related proteins including those currently under development for the detection and treatment of solid tumors. The Fellow will be mentored to participate in regulatory responsibilities which may range from pre-IND meeting guidance to Sponsors through post-marketing manufacturing changes. The mentor has a strong interest in cell substrate characterization issues as they relate to biologics manufacturing and the use of emerging molecular methods for virus detection in biologics. Ample additional opportunities for reviewer training are available both at the divisional and office level.


Andrew M. Lewis Jr., M.D.

Research Reviewer, Laboratory of DNA Viruses, Division of Viral Products, Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, FDA 

andrew.lewis@fda.hhs.gov

301-827-0650

Program

Possible risks associated with genomic instability of neoplastic cells represented by the evolution of the neoplastic phenotype from non-tumorigenic to tumorigenic in the VERO and MDCK cell models.

Project Summary

VERO cells are known to evolve from an immortalized non-tumorigenic state to a phenotype that expresses the capacity to form tumors in nude mice. We have found that this process can be associated with in vitro correlates of cell mobility (wound healing assays) and cell invasion (Matrigel invasion) assays and the over-expression of at least 4 different microRNAs (miRNAs). Studies are underway to confirm and extend these results (using cells at intermediate passage levels to those cells studied to date) to determine the relationship of passage level to the expression of characteristics attributable to the evolution of the neoplastic processes that occurs during serial passage in tissue culture. Similar studies are underway using dog kidney cells (MDCK and other canine cell lines under development). In addition, studies are underway to evaluate the complexities of the variety of tumorigenic phenotypes that appear to be expressed by MDCK cells.

Proposed Project for IOTF Fellow

The directions that the above studies are taking indicate that there are multiple projects for an IOTF Fellow to consider. A new Fellow would be invited to participate one of the projects noted above. However, to ensure (to the extent possible) a successful Fellowship, given the vagaries of research, I prefer to have Fellows involved in several projects that are mutually agreed upon.

Regulatory Activity

Our research is directed toward understanding neoplastic processes from the perspective of addressing possible risks posed by neoplastic cells being used in the manufacture of viral vaccines. Those participating in these projects will be exposed to the variety of issues associated with neoplastic cell substrates and the vaccines being manufactured in them. In addition, our staff is involved in the regulation of papillomavirus vaccines.


Marian Major, Ph.D.

Chief, Laboratory of Hepatitis Viruses. Office of Vaccine Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration

marian.major@fda.hhs.gov

240-402-9720

Program

Studies on hepatitis virus pathogenesis and prevention

Project Summary: Our research program is focused on learning more about the way hepatitis C virus (HCV) causes disease in humans and how the immune system responds to this virus. An estimated 3.2 million Americans have chronic HCV infection and over 200 million people worldwide are infected. In addition, 85% of people infected with the virus develop persistent infections that can eventually cause severe liver problems, such as cirrhosis and liver cancer (hepatocellular carcinoma, or HCC). HCV infection is considered one of the major risk factors for primary liver cancer in the US, Europe and Japan. Furthermore, HCC is one of the few cancers that is increasing in frequency and rate of mortality in the US. There is no vaccine to prevent HCV infection. Therapy for HCV has improved over the past five years yet for most of the world daily treatment with these drugs is not an option because they are expensive and must be administered carefully due to their toxicity. Two options that hold promise for reducing the rates of infection, disease, and death due to HCV are vaccines and immunotherapy.

Proposed Project for IOTF Fellow

This work will study systems and approaches that can prevent or inhibit HCV infection in vitro using cell culture and in vivo using a mouse models for HCV infection.

Regulatory Activity

Review of all BLA and IND applications for hepatitis virus vaccines. Participation in pre-IND and pr-BLA meetings with sponsors provides guidance on potential clinical trials and licensure of hepatitis virus vaccines. 

References:

  1. Tan, W.G.; et al. Qualitative differences in cellular immunogenicity elicited by hepatitis C virus T-Cell vaccines employing prime-boost regimens (2017) PLoS ONE 12(7): e0181578.
  2. Kachko, A et al. Antibodies to an Interfering Epitope in Hepatitis C Virus E2 Can Mask Vaccine-Induced Neutralizing Activity (2015) Hepatology Dec; 62(6):1670-82
  3. Zubkova et al Hepatitis C virus clearance correlates with HLA-DR expression on proliferating CD8+ T-cells in immune-primed chimpanzees (2014) Hepatology, 59:803-813.

Kyle J. Myers, Ph.D.

Director, Division of Imaging, Diagnostics, and Software Reliability (DIDSR), Office of Science and Engineering Laboratories (OSEL), Center for Devices and Radiological Health (CDRH), FDA

kyle.myers@fda.hhs.gov

301-796-2533

Program

Quantitative Imaging and Computer-Aided Diagnosis

Project Summary

The imaging program in the Division of Imaging, Diagnostics, and Software Reliability (DIDSR), Office of Science and Engineering Laboratories (OSEL), Center for Devices and Radiological Health (CDRH), FDA, has a well-established reputation in the field of performance assessment of medical imaging systems and ancillary devices such as computer-aided diagnostic algorithms. It is also fully integrated within the Center regulatory review process for these devices. Medical images contain considerably more information than what clinicians currently use as part of their routine evaluation. Carefully-designed image acquisition/analysis techniques to better collect and extract quantitative information, and pattern recognition/statistical learning techniques to intelligently aggregate the extracted information hold the promise to enable the clinician exploit this information for improved patient care. Example areas of application include imaging biomarkers to quantify response to therapy, prognostics, and computer-aided detection/diagnosis systems such as those used in screening radiology, malignant/benign tissue discrimination in medical images, and digital pathology.

Our research program impacts the regulatory assessment of a wide variety of systems that either extract quantitative imaging biomarkers or use extracted image features in computer-aided diagnosis devices. Findings from the quantitative imaging component of our project will be helpful for recommendations for appropriate study designs and endpoints for CDRH and CDER submissions, guidance to developers, and in the process of qualification of imaging biomarkers. Findings from the computer-aided diagnosis component of our project will be helpful in evaluation of claims for devices utilizing quantitative imaging features, identifying the extent to which synthetic/blended image data may be useful in this context, and in reducing the data size/number of clinical trials for these devices.

Proposed Project for IOTF Fellow

The Fellow will collaborate with DIDSR scientists on the investigation of current barriers to quantitative imaging, including issues related to image acquisition and the development of imaging standards and/or calibration methods, image analysis methods for the extraction of quantitative information from images related to disease state, image display requirements for furthering quantitative image analysis, and methods for the assessment of quantitative tools. The project will involve collaboration with the RSNA (Radiological Society of North America) Quantitative Imaging Biomarker Alliance.

Regulatory Activity

The Fellow will gain experience with the device approval process used in CDRH and the drug approval process in CDER through exposure to imaging and computer-aided diagnosis (CAD) device applications in CDRH and drug applications in CDER. This will involve understanding how CDRH and CDER perform their premarket and postmarket functions and the importance of risk management in evaluating the safety of new medical products.


Michael O’Hara, Ph.D.

Deputy Director, Division of Radiological Health, Office of In Vitro Diagnostics and Radiological Health (OIR), Center for Devices and Radiological Health (CDRH), Food and Drug Administration (FDA)

michael.ohara@fda.hhs.gov

301-796-0294

Program

Regulatory Requirements for Radiation Oncology (RO)

Project Summary

Like all medical treatments, radiation therapy treatments present both benefits and risk. Approximately 70% of all cancer patients will receive radiation therapy in one form or another. Of these patients, 60% will be treated with curative intent. This therapeutic modality has led to improvements in the treatment of numerous types of cancer. At the same time, it exposes patients to high doses of ionizing radiation (hereafter “radiation”), which elevates a person’s lifetime risk of developing cancer and can cause substantial morbidity. A balanced public health approach seeks to support the benefits of radiation therapy while minimizing the risk.

Patients should receive an optimal radiation dose, with the desired treatment effect on the tumor and sparing of normal tissue. FDA can advance this goal by using our regulatory authority judiciously while also collaborating with the healthcare profession community. FDA and our partners will take steps to:

  • Identify weaknesses in pre-market regulatory review that affect cleared medical devices;
  • Increase the level of post-market device failure reporting;
  • Develop methods to analyze device failure databases;
  • Promote safe use of radiation therapy devices.

By coordinating these efforts, we can optimize patient exposure to radiation, prevent treatment errors, and thereby reduce radiation-related risk while maximizing the benefits of RO treatment.

Proposed Project for IOTF Fellow

Conduct scientific reviews of radiation therapy devices to determine if changes in pre-market requirements or new post-market programs are necessary to maximize the benefits of radiation therapy with as low as reasonably achievable radiation doses. These reviews will include pre-market assessment of the regulatory data currently necessary to clear radiation therapy devices for clinical markets. The project will review post-market and compliance data from marketed radiation oncology devices to determine if the post-market and compliance issues with these devices can help predict the need for changes in regulatory scrutiny during pre-market evaluation. This project will provide input and direction for the implementation of FDA’s initiative to reduce exposure to radiation through dose reduction efforts related to equipment design and labeling. Regulatory activities related to radiation therapy treatments and regulatory changes for radiopharmaceuticals or chemotherapeutic drugs at FDA’s Center for Drug Evaluation and Research (CDER) will be assessed for impact on clearance of radiation therapy devices and our dose check program. This project will involve working with a team of interdisciplinary scientists to better regulate medical devices for radiation therapy. Also, the Fellow will provide input and direction in the implementation of FDA’s goal of reducing errors in radiation therapy through efforts related to training, equipment design and labeling, and education.

Regulatory Activity

Expected 1 year accomplishments: Learn FDA’s pre-market, post-market and compliance review program for radiation therapy products. Assist in developing and guiding implementation of all aspects of FDA’s action plan for radiation therapy devices, as described above. Develop a monitoring plan and metrics to measure longer term outcomes of FDA’s action plan.


Keith Peden, Ph.D.

Chief, Laboratory of DNA Viruses, Division of Viral Products, Office of Vaccines Research and Review, CBER, FDA 

keith.peden@fda.hhs.gov

240-402-7312

Program

Evaluation of the safety of neoplastic cell substrates for viral vaccine production: Development of assays to assess tumorigenicity and oncogenicity

Project Summary

Vaccines have proven to be the best way to control infectious diseases. Vaccines are needed against such diseases as HIV/AIDS, pandemic influenza, MERS, Ebola virus, and Zika virus. Unfortunately, the current repertoire of cell substrates used to produce vaccines is inadequate and additional cells are needed. The types of cells required to manufacture these new vaccines are always immortal, some are tumorigenic, and some are derived from human tumors. The use of such cells presents regulatory hurdles such as the perceived risks of using cells that were derived from a human cancer to make preventative vaccines for infants and children. Our research attempts to address these concerns by establishing animal models capable of detecting the oncogenic activity of DNA. We have demonstrated that the animals most susceptible to the oncogenic activity of DNA are newborn rats and certain strains of newborn mice. Current work is centered on investigating whether the newborn p53-deficient mouse is as sensitive as other models and whether it has advantages over other rodents.

Proposed Project for IOTF Fellow

While specific projects change depending on progress being made, the general areas of research will be in evaluation of virus detection methodologies, understanding how cells become tumorigenic (which will involve investigating the contribution of epigenetics to tumorigenicity), and evaluating the oncogenicity of DNA in animal models.

Regulatory Activity

Our area of regulation is in viral vaccines against diseases caused by HIV, influenza virus, Ebola virus, Zika virus, and other viruses; our specific areas of responsibility are in product safety and manufacturing as well as in evaluating vaccine effectiveness.


Ashutosh Rao, R.Ph., Ph.D.

Chief, Laboratory of Applied Biochemistry, Division of Biotechnology Review and Research III, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research (CDER), FDA

ashutosh.rao@fda.hhs.gov

240-402-7338

Program

Protein oxidation and autophagy in the context of cancer chemotherapy and cardiotoxicity

Project Summary

Our goal is to understand the mechanisms of oxidative stress, protein oxidation and DNA damage in the context of drug quality, safety and efficacy, with an emphasis on cancer chemotherapy and cardiotoxicity. The anthracycline doxorubicin is a critical front-line treatment for primary breast cancer. Unfortunately, doxorubicin and other oncology agents also cause dose-limiting cardiotoxicity. The cardiac damage is thought to result from mitochondrial oxidative stress that causes free radical damage to heart muscle. Previous combination therapies aimed at cardioprotection have used non-specific antioxidants that have failed to show clinical benefit. Our previous findings on iron chelators and cancer chemotherapy have provided preliminary insight into the complex nature of these agents. We have identified specific proteins that are oxidized under cardiotoxic conditions that could serve as biomarkers of adverse events and targets for cardioprotective drug development. We validated a syngeneic, preclinical animal model for investigating the safety signals from a range of small molecule and biotechnology-derived oncology agents. Using cellular and animal models, we aim to characterize the molecular pathways by which oxidants and anti-oxidants effect cardiac and tumor biology. Towards this overall goal we have three ongoing, oncology-related projects: (1) elucidate the mechanisms of cell death and autophagy by mitochondrially-targeted redox agents, (2) the validation and applications of the syngeneic animal model for studying cardiotoxicity and antitumor efficacy, and (3) apply Next-Generation Sequencing technology to identify genomic signatures linked to drug-related adverse events.

Proposed Project for IOTF Fellow

The fellow will have the opportunity to pursue one of several research projects based on his/her interest within the context of cancer chemotherapy. Candidates must have a good understanding of cancer biology, biochemistry and molecular biology. Position is located on the main campus of the FDA at White Oak in Silver Spring, MD. The fellow will also have opportunities to interact and collaborate with oncologists and NCI laboratories on specific joint projects. The Fellow will also be expected to participate in regular research meetings and seminars.

Regulatory Activity

The Office of Biotechnology Products regulates a broad range of therapeutic agents such as monoclonal antibodies and cytokines including, but not limited to, oncology products. The fellow will actively participate in the team-based review of investigational new drug applications. The fellow will be expected to attend regulatory training sessions and participate in regulatory meetings.

Related References:

  1. Aryal B, Rao VA. Specific protein carbonylation in human breast cancer tissue compared to adjacent healthy epithelial tissue. PLoS One. 2018.
  2. Biel TG, Rao VA. Mitochondrial dysfunction activates lysosomal-dependent mitophagy selectively in cancer cells. Oncotarget. 2017.
  3. Gonzalez Y, et al. Reproductive hormone levels and differential mitochondria-related oxidative gene expression as potential mechanisms for gender differences in cardiosensitivity to Doxorubicin in tumor-bearing spontaneously hypertensive rats. Cancer Chemother Pharmacol. 2015.
  4. Aryal B, Jeong J, Rao VA. Doxorubicin-induced carbonylation and degradation of cardiac myosin binding protein C promote cardiotoxicity. Proc Natl Acad Sci U S A. 2014.

 


Jakob Reiser, Ph.D.

Principal Investigator, Division of Cellular and Gene Therapies, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration

Jakob.Reiser@fda.hhs.gov

240-402-7340

Program 

Engineering and manufacturing of gene therapy vectors

Project Summary

Lentiviral vectors provide a key tool for gene and cell therapy applications. The ability to use lentiviral vectors to genetically modify cells ex vivo and in vivo has resulted in new treatment options for a number of acquired and inherited diseases. While these vectors are promising, they pose risks in the context of in vivo applications in that the tissue tropism of the currently available lentiviral vectors is broad, potentially resulting in the transduction of off-target tissues. Also, the production of these vectors in sufficient quantities for clinical applications remains as a major hurdle. This illustrates the need for improved approaches allowing targeted vector delivery and improved vector production.

Proposed Project for IOTF Fellow

The goal of our laboratory is to improve the safety of HIV-1-based lentiviral vectors and to improve their manufacturing. The main objectives are to identify useful strategies for lentiviral vector targeting and to determine the robustness, specificity, and scalability of these approaches. Fellows will help develop strategies to target lentiviral vector transduction to specific cells in vivo in the context of mouse-based orthotopic models of human cancer using vector particles displaying cell-specific ligands. The human interleukin-13 receptor 2 (IL-13R2) will be used as a model receptor in the context of lentiviral vectors displaying human IL-13 or other ligands directed against IL-13R2. Human IL-13R2 is an appealing target because it is uniquely overexpressed in many different human tumors, making it an attractive target for tumor therapy. Fellows will also work on approaches involving genomic editing tools aimed at engineering human cell lines for improved lentiviral vector production.

Regulatory Activity

The PI has experience in reviewing gene therapy files (since 2008) and will mentor the fellow in the investigational new drug (IND) review process in the areas of gene and cell therapies, especially those related to cancer (e.g. CAR T cells). The fellow will spend up to 50% of her/his time in reviewing manufacturing, production, and characterization of gene therapy products related to cancer.

References:

  1. Ou, W., M.P. Marino, A. Suzuki, B. Joshi, S.R. Husain, A. Maisner, E. Galanis, R.K. Puri and J. Reiser. Specific targeting of human IL-13 receptor α2-positive cells with lentiviral vectors displaying IL-13. Human Gene Therapy Methods 2012, 23: 137-147.
  2. Marino, M.P., M. Panigaj, W. Ou, J. Manirarora, C.H. Wei and J. Reiser. A scalable method to concentrate lentiviral vectors pseudotyped with measles virus glycoproteins. Gene Therapy 2015, 22: 280-285.

Jan Simak, Ph.D.

Principal Investigator, Laboratory of Cellular Hematology, Division of Blood Components and Devices (DBCD), Office of Blood Research and Review (OBRR), Center for Biologics Evaluation and Research (CBER), FDA

jan.simak@fda.hhs.gov

Tel: 240-402-7393

Program

Investigation of Potential Toxic Effects of Extracellular Membrane Vesicles in Blood and Blood Products and their Biomarker Applications

Project Summary

Our research program is focused on application and development of high resolution nanoscience analytical and imaging methods for analysis of membrane micro- and nanovesicles in blood and blood products. Cell membrane extracellular vesicles (EVs), also called membrane microparticles, are phospholipid vesicles, 40 nm 1000 nm in size, released in blood from membranes of blood cells, platelets, endothelial cells, and other cell types. Different populations EVs are present in the circulating blood of healthy donors; rises in the levels of EVs in the blood are associated with various diseases, including cancer, and may serve as biomarkers. EVs are released from blood cells during processing and storage of cellular blood components, the potential for EVs to cause adverse events following the administration of blood products is also a concern. In addition, in frozen and freeze dried platelet derived hemostatic products, submicron EVs represent a major component with a marked impact on the product in vitro procoagulant potency and potentially also on safety and efficacy in vivo.

Proposed Project for IOTF Fellow

The project will focus on development of analytical assays for detection, characterization, and immunophenotyping of EVs in blood.  More than 90% of EVs present in blood and blood products are smaller than 300 nm, most are of exosome size 40 -100 nm. These nanoscale EVs are not detectable by traditional analytical methods, such as conventional flow cytometry. Thus, there is an urgent need for novel reliable methods for analysis of membrane micro- and nanovesicles in blood and blood products. 

Regulatory Activity

Laboratory of Cellular Hematology regulates cellular transfusion products, including red blood cells, platelets, and platelet substitutes. We also regulate devices and solutions used for collection, processing, storage, and pathogen reduction of these products. In addition, bacterial detection assays and leukocyte counting assays for blood product testing are regulated in our laboratory.


Carole Sourbier, Ph.D.

Principal Investigator, Division of Biotechnology Research and Review 1 (DBRR1), Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research

carole.sourbier@fda.hhs.gov

240-402-7407

Program 

Modulation of renal cell carcinoma metabolism by immune checkpoint inhibitors.

Research Project Summary

With about 120,000 deaths worldwide each year, kidney cancer is one of the most lethal urologic cancers. Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney tumors, representing 75% of cases. Patients with advanced stages of ccRCC have a 5-year survival rate of only 11.7%, underscoring the need to improve the efficacy and safety of current therapies. Advanced ccRCC present a metabolic shift toward aerobic glycolysis (TCGA, Nature 2013), consistent with the idea that metabolic flexibility is important for their survival. Therapeutic pressure could be a driver of metabolic flexibility, thus, understanding how current therapies affect ccRCC metabolism will allow for better development of biomarkers of efficacy or resistance. There are currently 95 active/recruiting clinical trials for ccRCC: 42 (44%) involve biologics, 61% of which (27) comprise immune checkpoint inhibitors (ICIs). Recent reports demonstrated the modulation of tumor metabolism by ICIs (Chang et al, Cell 2015), however little is known about ICIs’effects on ccRCC. Thus, identifying the metabolic events associated with ccRCC’s response or resistance to therapies involving ICIs is an important step toward the development of non-invasive biomarkers to improve the safety and efficacy of therapies.

Proposed Project for IOTF Fellow

Based on his/her experience and interest, the fellow will have the opportunity to select one or more projects derived from the research program previously described with the goal to understand how ICIs affect tumor metabolism and/or their micro-environment, and how this relates to efficacy and resistance to therapy.

Regulatory Activity

As a team member of OBP/Division 1, the fellow will gain experience in diverse aspects of the regulatory review of therapeutic monoclonal antibodies to assess their efficacy and safety. The fellow will have access to formal regulatory trainings and will participate in the office and division regulatory activities.


Yelizaveta Torosyan, M.D., Ph.D.

Health Scientist at the Division of Epidemiology, Center for Devices and Radiological Health (CDRH), Food and Drug Administration (FDA)

Yelizaveta.Torosyan@fda.hhs.gov

301-796-7127

Program

Discovery and validation of biomarkers are critical for developing biomarker-based diagnostic/prognostic tests and enabling predictive evaluation of medical products. Research on biomarkers aligns with the recent FDA/CDRH regulatory science priorities such as:

  • Leverage real-world evidence and employ evidence synthesis across multiple domains in regulatory decision-making
  • Leverage precision medicine and biomarkers for predicting medical device performance, disease diagnosis and progression

In silico gap analysis and assessment of cancer biomarkers

Research Project Summary

There is an enormous discrepancy between the efforts aimed at biomarker discovery and the number of clinically applicable biomarker tests, mostly due to challenges of predicting overall clinical utility and clarifying the intended use in patient subgroups. The lack of an FDA-coordinated postmarket surveillance system for biomarkers hinders the agency’s ability to effectively evaluate existing biomarkers and promote new biomarker-based products based on the unmet public health needs. To tackle the clinical and regulatory need for biomarker-related infrastructure, the project attempts to chart the overall evidentiary landscape on validated and potential cancer biomarkers by employing an in silico approach and using cancer-related knowledgebases and analytic tools. Specifically, the project is aimed to outline possible in silico methodologies for: 1) positioning clinically available cancer biomarkers in the epidemiologic and genomic context; 2) revealing putative evidence on under-utilized molecular cancer signatures which are outside of the current network of validated cancer genes and oncogenic mutations; 3) assessing new diagnostic and therapeutic targets based on the sex/race-related and other epidemiologic trends in different cancers; 4) identifying putative evidence on new candidate biomarkers that are more relevant to disease subtypes and more predictive of drug responses in patient subgroups.

Proposed Project for IOTF fellow

Conducting a review of published literature and other records, running in silico analyses, and creating a database per the project’s goals

Regulatory Activity

Addressing the biomarker infrastructure gaps and providing methodological help with the assessment of existing and potential cancer biomarkers


Wendy C. Weinberg, Ph.D.

Senior Investigator and Chief, Laboratory of Molecular Oncology, Division of Biotechnology Review and Research 1, Office of Biotechnology Products (OBP), Center for Drug Evaluation and Research (CDER), FDA

wendy.weinberg@fda.hhs.gov

240-402-7472

Program

Molecular Mechanisms Involved in Regulating Epithelial Differentiation, Neoplasia and Therapeutic Efficacy

Project Summary

Despite major advances in identifying rational targets and early promising pre-clinical findings, the majority of cancer treatments proceeding through clinical trials fail. To maximize the predictive value of pre-clinical data, the models utilized must reflect as much as possible the disease etiology. Our laboratory has established novel preclinical models that reflect the altered gene expression profiles seen in human squamous cancers, and correlate a variety of in vitro assay endpoints with in vivo phenotype to aid in defining optimal bioassays for product development and characterization. Current work focuses on elucidating the biological impact and mechanism of action of p63 gene dysregulation, as has been described in human squamous cell cancers of the head and neck (HNSCC), lung, breast, cervix and ovaries. The overall goal of our research is to identify biomarkers of tumor progression and responsiveness for cancer diagnosis, monitoring therapeutic efficacy and assessing critical product quality attributes.

Proposed Project for IOTF Fellow

A research position is available to evaluate the impact of p63 gene dysregulation, as seen in human cancers, on normal keratinocyte growth regulation, differentiation and neoplasia, and defining interacting pathways in multistep carcinogenesis. The project will utilize a variety of cellular and molecular biology methodologies, in vivo and in vitro approaches, human cancer cell lines, and novel knockout and transgenic mice to clarify the molecular pathways contributing to epithelial cell transformation, and the role of p63 in the response to cancer therapeutics. Ongoing studies address the interaction of dysregulated p63 levels with the NFkB and ras pathways, modulating cancer initiating cell populations and tumor progression, defining the tumor microenvironment in an in vivo model of HNSCC for therapeutic strategies, and bioassay development for drug repurposing. The particular project to be undertaken will reflect the specific interests of the fellow. Candidates must have a Ph.D. and/or M.D. and experience in cell/molecular biology. The position is located on FDA’s White Oak campus in Silver Spring, MD.

Regulatory Activity

The development of antibody-based therapies comprises one of the most active areas of clinical research in oncology today. Many targeted therapies based on our current molecular understanding of cancer pathogenesis are under development to optimize the treatment outcome of tumors with specific genetic alterations. The Laboratory of Molecular Oncology is responsible for product review of biotechnology products, primarily monoclonal antibodies (Mab) and Mab-based products such as antibody-drug conjugates, Ig-linked fusion proteins, ScFv, and Fab’s, including those currently under development for detection and treatment of solid cancers. The fellow will be mentored to participate in regulatory responsibilities which may range from pre-IND guidance through review of licensing applications and post-marketing manufacturing changes.


Wen Jin Wu, M.D., Ph.D.

Senior Investigator, Division of Biotechnology Research and Review 1 (DBRR1), Office of Biotechnology Products (OBP), Office of Pharmaceutical Quality (OPQ), Center for Drug Evaluation and Research (CDER), FDA

wen.wu@fda.hhs.gov

240-402-6715

Program

HER2 signaling and HER2-targeted antibody therapeutics

Research Project Summary

Three areas of research are currently being pursued in Dr. Wu’s laboratory at FDA. The first involves studies of HER2 signaling in breast cancer progression and HER2 targeted antibody therapeutics, including antibody-drug conjugates (ADC), with emphasis on therapeutic resistance and toxicity induced by trastuzumab and ado-trastuzumab emtansine (T-DM1). The second area of research focuses on antibody engineering. We generate and characterize bi-specific antibodies for the treatment of breast cancers. Our lab initiates a new area of research to investigate the therapeutic resistance to immune checkpoint inhibitors and evaluate their potential for the treatment of triple negative breast cancers. These research projects address product quality issues, mechanisms of actions/drug resistance, and adverse events associated with FDA-regulated products.

Proposed Project for IOTF Fellow

The fellow will carry out research projects concerning important current issues related to the therapeutic resistance of monoclonal antibodies and toxicity, e.g. cardiotoxicity, induced by FDA-approved HER2-targeted antibody therapeutics. The IOTF fellow may have the opportunity to work on a different research project that is currently conducted in our laboratory depending on fellow’s background and interest.

Regulatory Activity

The DBRR1 is responsible for the product quality review of monoclonal antibodies and monoclonal antibody-derived products, including antibody conjugates, bi-specific antibodies, and other antibody related proteins. Our laboratory is involved in regulating novel monoclonal antibodies for the treatment of human cancers. The fellow will participate in regulatory review of investigational new drug (IND) applications. This provides the opportunity for the fellow to work as part of regulatory team to assess the product quality of therapeutic monoclonal antibodies.”


Zhaohui Ye

Senior Staff Fellow, Gene Transfer and Immunogenicity Branch, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, FDA 

zhaohui.ye@fda.hhs.gov

240-402-7471 

Program

Efficacy and safety evaluation of stem cell engineering technologies

Project Summary

Human stem cells have great potential in both regenerative medicine and cancer immunotherapies. However, significant roadblocks exist due to inefficient differentiation of stem cells to specialized lineages such as functional T cells. We study the developmental processes required for blood cell generation and lymphocyte specification from induced pluripotent stem cells (iPSCs) using tissue culture and animal transplantation models. Advanced genetic engineering technologies are used to modulate differentiation and to enhance anti-tumor activity of the differentiated cells. A second area in our research concerns the safety of gene therapy approaches, some of which have been linked to leukemia development in clinical trials. Of particular interest are genomic abnormalities caused by genome editing endonucleases. We develop in vitro methods and xenotransplantation models to study the off-target effects of genome editing tools on genomic instability and tumor initiation.

Proposed Project for IOTF Fellow

The IOTF fellow’s research can focus on one of two areas: 1) Developing cancer immunotherapy strategies using human iPSCs. This project will examine methods for generating universal chimeric antigen receptor (CAR) T cells with enhanced safety features and more defined CAR expression levels than conventional viral vector transduced primary T cells. 2) Establishing in vitro and in vivo methods for functional evaluation of genetic mutations caused by the genome editing process in gene therapy product development. This project will focus on understanding the biological consequences of these genomic abnormalities and their roles in potential leukemic transformation.

Regulatory Activity

Dr. Ye’s main regulatory activity is chemistry, manufacturing and controls review of gene therapy products. In addition, he provides consultation to pharmacology/toxicology reviewers on issues related to pluripotent stem cells and genome editing technologies. Under Dr. Ye’s mentorship, the IOTF fellow is expected to gain regulatory experience by participating in the review of investigational new drug (IND) applications of gene and cell therapy products and by participating in relevant regulatory working group activities.


Baolin Zhang, Ph.D.

Senior Investigator, Office of Biotechnology Products, Center for Drug Evaluation and Research (CDER), Food and Drug Evaluation and Research (FDA)

Baolin.Zhang@fda.hhs.gov

240-402-6740

Program

Identify biomarkers to promote precision medicine in cancer: Linking product quality to safety and efficacy

Project Summary

Our research is focused on developing innovative tools to study mechanisms of tumor resistance or sensitivity to therapy. This includes assessing the impact of variability in critical product quality attributes - especially those resulting from glycosylation and aggregation of therapeutic monoclonal antibodies regulated by OBP. These findings are being translated to the development of novel efficacy and safety biomarkers for precision medicines in individual patients.

Proposed Project for IOTF fellow

The Fellow will join in a multi-disciplinary team of research scientists investigating cell death and cell survival pathways leading to cancer drug resistance and drug-induced cardiotoxicity.

Regulatory Activity

The Office of Biotechnology Products (OBP) regulates a broad range of biotechnology products, including recombinant proteins, monoclonal antibodies, biosimilars, and combination products. The PI has 17 years of FDA experience regulating drug product quality (CMC - chemistry, manufacturing, and control) for these products. The Fellow will participate in the quality review of biotechnology product applications submitted under Investigational Investigation New Drug Applications (INDs) and Biologics License Applications (BLAs).

References:

  1. Julianne Twomey, Su-Yuan Kim, Liqun Zhao, William Bozza, and Baolin Zhang (2015) Spatial dynamics of TRAIL death receptors in cancer cells, Drug Resistance Updates 19, 13-21.
  2. William P. Bozza, Yaqin Zhang, Kory Hallett, Leslie A. Rivera Rosado, and Baolin Zhang (2015) RhoGDI deficiency induces constitutive activation of Rho GTPases and Cox-2 pathways in association with breast cancer progression, Oncotarget 6(32), 32723-32736.
  3. Shen Luo and Baolin Zhang (2015) Dextrose-mediated aggregation of therapeutic monoclonal antibodies in human plasma: Implication of isoelectric precipitation of complement proteins, mAbs 7(6), 1094-1103.
  4. Lei Zhang, Shen Luo, and Baolin Zhang (2016) Glycan analysis of therapeutic glycoproteins, mAbs, 8(2), 205-215.
  5. William P. Bozza, Julianne D. Twomey, Su-Ryun Kim, and Baolin Zhang (2016) Detection of apoptosis: From bench side to clinical practice (Book Chapter), Apoptosis Methods in Toxicology, p13-29, Springer.
  6. Lei Zhang, Shen Luo, and Baolin Zhang (2016) The use of lectin microarray for assessing glycosylation of therapeutic proteins, mAbs, 8(3), 524-535.
  7. Julianne Twomey, Nina Brahme, and Baolin Zhang (2017) Drug-biomarker co-development in oncology - 20 years and counting, Drug Resistance Updates, 30, 48-62.
  8. Liqun Zhao and Baolin Zhang (2017) Doxorubicin induces cardiotoxicity through upregulation of death receptors mediated apoptosis in cardiomyocytes, Scientific Reports, 7:44735.
  9. William Bozza, Keisha Melodi Sweeney, and Baolin Zhang (2018) Cellular modeling of cancer therapy induced cardiotoxicity. Cancer Therapy & Oncology Int. J, 9(1), MS.ID.555751
  10. William Bozza and Baolin Zhang (2018) Cytokeratin 8/18 protects breast cancer cells from TRAIL induced apoptosis. Oncotarget, 9:23264-23273.   

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