The Vector

Volume 6, Issue 4: July 2017

Editorial Team

Guohua Yi, PhD - Editor, The Vector
Phillip Doerfler, PhD - Associate Editor, The Vector

Inside This Issue

President's Message
Breaking Through  
Pressing Matters  
Meeting Center
Award Spotlight
Public Policy  
On the Horizon
Molecular Link​
InSITE

President's Message

Dear Colleagues,

The 20th Annual Meeting of ASGCT held in Washington in May 2017 featured a time line prepared by Ted Friedmann and Cindy Dunbar that showed selected events in the gene and cell therapy field since the founding of ASGT as it was initially known and the Society’s first meeting. Several slides provided a reminder of the early days of gene therapy when an NIH panel convened to assess investment in gene therapy research concluded that many clinical trials were premature and more investment in basic science was needed. Presentations at this year’s meeting illustrated how the field has advanced since then with many examples of iterative bench to bedside progress leading to late phase trials and clinical benefit for patients with both inherited genetic and acquired diseases. The 2017 annual meeting was memorable not only for the quality of the basic, translational, and clinical science but also for the spectacular venue for the ASGCT 20th Anniversary Reception held at the Library of Congress. I would like to thank Cindy Dunbar for organizing such a superb meeting and for her leadership as President over the last year. I would also like to thank the departing Board members for their contributions and welcome the newly elected Board members.

ASGCT is currently in the second year of implementing its strategic plan.  One major initiative is education and we are partnering with other organizations to deliver specialized content. On June 28th we co-hosted the second of a series of webinars with the Foundation for Accreditation of Cell Therapy (FACT) on CD19-targeted CAR T cells: Efficacy, Cytokine Release and Risk Management with presentations from Drs. Marco Davila and Marcela Maus. This webinar was well received with an attendance of more than 150. At my institution a diverse audience of scientists, clinicians, nurse practitioners, GMP staff and research trainees attended this webinar attracted by the timely topic as well as the pizza we provided. For those not able to attend in real time the webinar is available for free download to ASGCT members. A second initiative is two webinars that ASGCT is developing with the Hemophilia Federation of America (HFA) to present in August. The first webinar will explain the basics of gene therapy while the second webinar will explain how gene therapy can be used to treat hemophilia and answer patient questions.

Another strategic goal is to increase government relations/advocacy efforts and to that end we have established three pillars of our advocacy platform, defining the value of gene and cell therapy, supporting research funding, and performing education and outreach to policy-makers. Finally, the ASGCT office has been devoting considerable effort to the development of an updated website which has an expected launch in October with fresh design, new content, and more intuitive navigation.

Next year ASGCT will convene its 21st Annual Meeting which will for the first time be in Chicago located in the downtown area close to the lakefront, Millennium Park, museum district, and the Magnificent Mile. We anticipate that as the society comes of age we will also be able to celebrate the first approved gene therapy products in the United States.

Sincerely,

Helen Heslop, MD

Breaking Through

Improving Gene Therapy Efficiency through the Enrichment of Human Hematopoietic Stem Cells.

Masiuk KE, et al.

Hematopoietic stem cell (HSC) gene therapy has recently demonstrated remarkable success, with a number of phase I/II trials reporting safe and efficacious correction of genetic blood cell disorders including primary immunodeficiencies, leukodystrophies, and hemoglobinopathies. In this approach, bone marrow (BM) or mobilized peripheral blood (mPB) is collected from a patient, enriched for HSC, modified to fix the genetic defect, and transplanted back into the patient. After transplant, HSC engraft in the BM and produce mature, gene-corrected hematopoietic cells ideally throughout the patient’s lifetime.

As HSC gene therapy has become more successful and widespread, the field has encountered hurdles related to clinical scale-up. While a number of pre-clinical therapies are developed using small doses of CD34+ cells in immune-deficient NSG mice (e.g. ~1x10⁶ CD34⁺ cells), treatment of a patient at clinical scale requires modification of 1x10⁸ -1x10⁹ CD34⁺ cells. Transducing this number of cells has been particularly challenging in clinical trials for hemoglobinopathies. Due to the large size and complexity of the human β-globin gene expression cassette, β-globin vectors often have low titers and can require 20-40 L of clinical-grade lentiviral vector (LV) per patient. Due to the technical difficulty, expense, and limited manufacturing capacity for producing clinical-grade LV, this is a critical issue that must be overcome before HSC gene therapy can be broadly used for hemoglobinopathies.

In order to address these hurdles, Masiuk and colleagues demonstrate a clinically relevant strategy for purification, transduction, and transplantation of HSC that improves the overall efficiency of HSC gene therapy. Here, they employed a clinically-applicable immunomagnetic bead (IB)-based method with human BM and mPB to purify CD34⁺CD38^- cells, a population enriched for HSC beyond CD34⁺ cells. When compared to transduction of bulk CD34⁺ cells, transduction of purified CD34⁺CD38^- cells results in ~5-10-fold dose reduction in LV requirements while maintaining long-term in vivo gene marking and engraftment. They further demonstrate that co-transplantation of non-transduced CD38⁺ cells promotes both early myeloid engraftment and long-term engraftment of gene-modified HSC. These results support a safe and efficacious approach to reduce LV requirements and culture scale required for ex vivo HSC gene therapy.

To first define a “CD34⁺CD38^-“ population containing the majority of HSC, they utilized competitive transplant studies to determine the long-term repopulating activity BM CD34⁺ cells based on their level of CD38 expression. CD34-enriched BM cells were FACS-sorted into 3 fractions of cells with intervals of increasing CD38 expression. Each fraction was marked with a distinct fluorescent LV vector and competitively transplanted into NSG mice. At >16 weeks post-transplant, >90% of all hCD45⁺hCD34⁺ cells in NSG marrow were derived from CD34+ cells with the lowest ~6% of CD38 expression. Thus utilizing CD38 as a surface marker to further purify CD34⁺ cells can enrich for HSC while also retaining the majority of HSC present in a given BM sample.

They next optimized a two-step IB method to purify CD34⁺CD38^- cells. First, CD38⁺ cells were magnetically labeled and depleted. Since a number of CD34⁺ cells with long-term repopulating capacity exhibit low levels of CD38 expression, careful titration of magnetic CD38 labeling was required to retain all phenotypic HSC within the lowest 6% of CD38 expression. The resulting CD38^- fraction was then relabeled with CD34⁺ beads and selected for CD34+CD38- cells.  They added one additional “trick”. A number of granulocytes are co-isolated with the target cells using IB; these may comprise a relatively large fraction when among the more purified CD34⁺CD38^- cells than when present at equivalent absolute numbers among the more populous CD34⁺ fractions. Co-depletion of CD15⁺ cells along with the CD38⁺ cells greatly reduces the numbers of granulocytes in the final CD34⁺CD38^- fraction, further reducing the amount of vector that would be wasted transducing cells beyond target HSC. 

They next evaluated the functional HSC content of IB purified CD34⁺CD38^- cells using in vivo xenograft models. Equal portions of bone marrow (or mPB) samples from healthy donors were purified in parallel by either CD34⁺CD38^- selection or standard CD34⁺ selection. After purification, the total cell product obtained by each method was transduced with a fluorescent LV using a constant MOI (with CD34⁺CD38^- cells requiring ~10-fold less total LV) and transplanted into NSG mice. Limiting dilution analysis revealed a 12-fold enrichment of long-term HSC in CD34⁺CD38^- cells compared to CD34⁺ cells. Additionally, NSG mice engrafted with CD34⁺CD38^- or CD34⁺ cells showed equivalent levels of long-term in vivo gene marking despite the 10-fold reduction in total LV used for CD34⁺CD38^- cells.

While purifying CD34⁺CD38^- cells may provide the advantage of utilizing less LV to transduce HSC, transplanting a smaller population of quiescent, stem-enriched cells could cause delayed recovery of neutrophils and increase the risk of infection post-transplant. Indeed, xenografts of CD34⁺CD38^- cells showed lower early levels of circulating human myeloid cells at 3 weeks post-transplant compared to CD34⁺ xenografts. To address this issue, they explored a strategy of adding non-transduced CD38⁺ cells (containing CD34⁺CD38⁺ progenitor cells) back to the graft, which successfully restored early myelopoiesis. Furthermore, addition of CD38⁺ cells increased the total levels of long-term gene marked engraftment, reinforcing a critical role for the inclusion of non-transduced CD38⁺ progenitor cells in the graft.

In summary, Masiuk et al have demonstrated a clinically relevant, IB-based method for purifying CD34⁺CD38^- cells from mPB and BM. They show that LV dose can be reduced 5-10-fold through co-transplantation of modified CD34⁺CD38^- cells and non-modified CD38⁺ cells. Importantly, they demonstrate that this transplant strategy can achieve early myeloid reconstitution and long-term gene-marked engraftment comparable to traditional methods of modifying bulk CD34⁺ cells.

While a large body of prior work has investigated purification of HSC based on cell surface markers, the work by Masiuk and colleagues bridges a critical gap to clinical translation of purified HSC transplants for gene therapy. The IB-based method described here can rapidly purify large numbers of cells and can be easily adapted to a number of GMP-grade IB-based cell sorting platforms currently in use. This method may be broadly applicable to a number of current lentiviral-based HSC gene therapy applications, and may additionally benefit therapeutic use of novel gene editing technologies (e.g. CRISPR/Cas9). In summary, this work demonstrates a promising new method to improve the clinical and commercial viability of gene therapy for genetic blood cell diseases.

Pressing Matters

Read highlights from the latest issue of Molecular Therapy, the official journal of ASGCT. Also, explore the open access, online-only companion journals to Molecular Therapy:

• Molecular Therapy - Methods and Clinical Development

• Molecular Therapy - Nucleic Acids

• Molecular Therapy - Oncolytics

Click Here to visit the Molecular Therapy family of journals homepage on the Cell Press website.

Meeting Center

20^th Annual Meeting Session Summaries

Thank you to all of the attendees, faculty, exhibitors, and sponsors who helped make ASGCT's 20^th Annual Meeting the best yet! Read below for summaries of the Annual Meeting symposia:

Ethics Symposium

On May 10, the ASGCT Ethics Committee presented a symposium at the ASGCT annual meeting in Washington, DC. The underlying theme of the symposium was the need to enhance and facilitate the rapid delivery of biomedical advances to clinical application. The symposium included presentations from officials from the NIH, the Cystic Fibrosis Foundation and a prominent foundation devoted to more effective and accelerated translation of basic and pre-clinical science to the bedside. Lyric Jorgensen of the NIH Office of the Director described the background and current directions of the Cancer moonshot project as proposed by vice president Joseph Biden in the Obama administration. Martin Mense from the CF foundation summarized the foundation’s decision to establish their in-house research effort of take advantage of new therapeutic opportunities for CF. Margaret Anderson, executive director of the non-profit group "Faster Cures” described her foundation’s efforts to improve clinical application of activities in genetic, metabolic and biochemical research. Their talks were followed by a brisk give-and-take panel discussion. Overall, the presentations and panel discussion underscored the relevant and timely issue of the rapid and effective clinical application of research that constitutes the central mission of the ASGCT.

Musculo-Skeletal Symposium

Summary Submitted by Chair of Musculo-Skeletal Gene & Cell Therapy Committee, Michele Calos, Ph.D.

Progress Towards Gene Therapy for Muscular Dystrophies

Co-Chairs: Michele P. Calos, Ph.D. and Joel Chamberlain, Ph.D.

There were three talks in the session.  The first talk was presented by Richard J. Samulski Ph.D. from the University of North Carolina at Chapel Hill.  The talk was entitled “Improving AAV Gene Delivery into Muscle”.  Dr. Samulski reviewed the history of the use of AAV for gene therapy, starting with cystic fibrosis over 20 years ago and encompassing gradual improvements in the efficiency of transduction and gene expression.  He stressed the importance of the mode of vector administration and illustrated that increasing volume improved delivery.  He described the first clinical trial for DMD using AAV and intramuscular injection with Dr. Mendell.  Dr. Samulski also stressed the critical importance of production for AAV gene therapy.

The second talk was given by Louise Rodino-Klapac, Ph.D. from the Research Institute at Nationwide Children’s Hospital, Columbus, OH.  The talk was entitled “Phase I Safety Trial of AAV Dysferlin Dual Vector Delivery for LGMD2B”.  Dr. Rodino-Klapac described the development of an AAV dual-vector approach for limb girdle muscular dystrophy 2B.  LGMD2B is a rare form of muscular dystrophy due to deficiency in the gene encoding dysferlin (DYSF).  Because the DYSF coding sequence is larger than the capacity of AAV, a dual vector approach was adopted in which two AAV vectors carrying the 5’ and 3’ portions of the gene with a 1-kb area of overlap were administered, leading to recombination between the vectors in cells.  Mouse studies starting with intramuscular injection and progressing to systemic injection were carried out, demonstrating long-term expression and correction of the membrane repair defect characteristic of the disease.   DYSF overproduction was also observed by Western blot in non-human primates.  The first dual vector AAV clinical trial is now underway, seeking to demonstrate safety, gene expression, and membrane repair.

The final talk was presented by Kathryn R. Wagner, M.D., Ph.D. from the Kennedy Kreiger Institute, The Johns Hopkins School of Medicine, Baltimore, MD.  The talk was entitled “Morpholino Therapies for FSHD”.  Facioscapulohumeral dystrophy is a dominant-acting form of muscular dystrophy in which expression of the DUX4 gene is derepressed and must be suppressed.  Antisense phosphorodiamidate morpholino oligonucleotides were tested using a unique xenograft system.  In this system, a human muscle xenograft  from an FSHD patient expressed DUX4, while a xenograft from wild-type did not.  The human FSHD xenograft was transplanted into immune-deficient NRG mice, where it lasted for the lifetime of the animal. Control or anti-DUX4 morpholinos were tested for knockdown of DUX4 expression by intramuscular electroporation in the xenograft model of FSHD.  The FM10 morpholino targeting the polyadenylation signal of DUX4 was shown to be non-toxic and effective in downregulating DUX4 and DUX4 targets.

International Symposium

Gene Therapy Comes of Age in China (organized by the International Committee)

Co-Chairs: Ian E. Alexander, MBBS, PhD and Renata Stripecke, PhD

Despite an early start on the final day of the meeting the symposium was well attended, particularly by our friends and colleagues from China. The Chairs opened the session with a brief overview of the sheer size of the Chinese economy, forecast to overtake the US economy as the biggest globally by 2030, and the impressive trajectory the Chinese Biomedical Research and Development sector with a growth rate of exceeding 30% per annum. This is while expenditure in Europe and the US is declining.

The first speaker, Professor Xiaojun Huang from Peking University People’s Hospital in Beijing and the Beijing University Institute of Hematology gave an outstanding presentation on Progress in Haploidentical HSC Transplantation in China. Professor Huang outlined the development of transplantation protocols in China, particularly the unparalleled levels of experience with the Beijing protocol and further refinements that have greatly extended the utility of this approach. His key message was that the field has developed to the point where every transplantation candidate has multiple potential donors and the evolving question is now how to identify the best donor.

The second presentation was to be given by Dr Huajun Jin from the Shanghai Cell Therapy Research Institute, Shanghai,and Shanghai Cell Therapy Engineering Research Center on the subject of  PD-1 Antibody Expressing CAR-T Cells for Advanced Solid Tumors. Unfortunately Dr Jin was unable to attend and the presentation was ably given by his colleague Dr Qian. The presentation covered the generic challenges of targeting CAR-T cells to solid tumors and the challenges that must be surmounted for success. He then outlined preclinical studies aimed at enhancing the local response of CAR-T cells to tumor by circumventing the inhibitory effects exerted by tumor expression of PD-1.

The closing presentation was given by Dr Zhao Wu from Innovative Cellular Therapeutics in Shanghai on The Regulatory and Commercialization Environment in China for Gene and Cell Therapies: The example of CAR-T. This excellent presentation offered insights in to the developing regulatory environment in China. A key recent change has been elevation of the former State Food and Drug Administration to ministerial level, renamed the China food and Drug Administration and with broadening of oversight from medical devices to better encompass the food and drug sectors. A second important agency is the National Health and Family Planning commission of the PRC which plays a major role in policy formulation, ethics and implementation. Dr Wu outlined the regulatory challenges posed by novel therapies such as CAR-T cells which has become a major hotspot activity and is testing the evolving regulatory framework.

Question time was lively with great interest in the challenges of increasing global engagement with experimental medicine in China.

Genetic and Metabolic Diseases Symposium

New frontiers in gene and cell therapies for metabolic diseases, aging and tissue regeneration

Co-Chairs: Federico Mingozzi, PhD, and Dawn Blessing

The symposium aimed at discussing some of the recent applications of regenerative medicine that represent the future of the field and address complex multigenic diseases that are known to have numerous genetic pathways involved. The specific topics that were covered in this session were aging, metabolic diseases, and cardiac disease.  

The session was well attended and the discussion was also animated, demonstrating the interest for the topics discussed.

The first speaker, Professor Maria A. Blasco from the Spanish National Cancer Center in Madrid, Spain, talked about gene therapy for telomere loss disorders. Professor Blasco is one of the top experts in the field of study of telomeres and telomerase. She discussed the role of telomeres in aging and in several diseases and provided an overview of gene therapy approaches in which the enzyme telomerase is expressed systemically with AAV vectors. She discussed the early work conducted by her laboratory on the extension of lifespan of mice and she also presented more recent work on disease models, such as aplastic anemia and lung fibrosis.

The second presentation was given by Professor Fatima Bosch from the Universitat Autonoma de Barcelona, in Spain. Professor Bosch is an expert in metabolism and diabetes as well as a recognized leader in the field of gene therapy with AAV vectors. In her presentation, she discussed her work on gene therapy for diabetes, showing long-term data on the correction of the disease in dogs, eight years after induction of diabetes. She also discussed the concept of metabolism manipulation with gene therapy focusing on beta cell preservation/regeneration.

The closing presentation was given by Professor Mauro Giacca, director of the International Center for Genetic Engineering and Biotechnology in Trieste, Italy. Dr. Giacca is an expert in both cell biology and gene therapy. He presented a fascinating overview of the molecular pathways involved in cardiac regeneration following injury and discussed the identification of miRNA targets for therapy development. He then showed results on the manipulation of gene expression in vivo to induce cardiac regeneration. He closed the discussion putting the work in the perspective of developments of therapeutic approaches in humans, highlighting opportunities and challenges.

All three presentations were well received and the discussion revolved around translatability of results to humans and safety of the approaches proposed, and more specific questions for each topic were covered.

Physical Gene Therapy & Vectorology Symposium

Physical Vector Delivery for Immunotherapy

Co-Chairs: Amir S. Khan, PhD and Ernst Wagner, PhD

The Symposium on “Physical Vector Delivery for Immunotherapy” was a well-balanced selection of exciting basic cellular mechanisms such as time-lapse imaging of sonoporation (Liza Villanueva), preclinical antibody gene therapy (Kevin Hollevoet) and clinical papilloma virus DNA electrotransfer vaccine trial (Cornelia Trimble). Physical delivery was also well presented in two oral poster sessions as well as in multiple specific other ASGCT sections.

Dr. Flordeliza S. Villanueva (University of Pittsburgh) reviewed therapeutic applications and provided novel biophysical insights into mechanisms of sonoporation.[1] In particular she emphasized the most different involved time scales ultrasound-triggered microbubble dynamics and cargo release (microseconds), cell membrane disruption, local macromolecule uptake and cell membrane reorganization (seconds to many minutes). Real-time 3D microscopy provided evidence that a sonoporation event directly results in the immediate generation of membrane pores through both apical and basal cell membrane layers that reseal within about 2 min. Sonoporation indirectly initiates intercellular gaps between adjacent cells for about one hour, with favorable effects on tissue and vascular permeability.

Cornelia L. Trimble, MD (Johns Hopkins University, Baltimore) provided a follow-up on the design and encouraging clinical and immunological results of the electroporated human papilloma virus (HPV-16 and -18) E6, E7 pDNA vaccine trial. [2, 3] In a randomized, double-blind, placebo-controlled phase 2b study, patients in CIN2/3 carcinoma stage associated with HPV-16/18 were randomized to receive intramuscular VGX-3100 (Inovio) electroporation or placebo at 0, 4, and 12 weeks, before planned therapeutic resection. Strong peripheral immune responses were observed at 2 weeks, spontaneous regressions in about 50% of patients, correlating with about 40% clearance from HPV virus.

Dr. Kevin Hollevoet (Leuven University) reported on DNA-based antibody therapy via in vivo electrotransfer.[4] pDNA forms of the therapeutic anti-HER2 antibody trastuzumab were intramuscularly electroporated in mice and sheep. Analogously to the HPV pDNA electroporations reported above, efficient expression of foreign proteins resulted in immune recognition and rejection. A nice long-term expression of murine anti-HER2 antibodies p4D5 was seen, with repeated treatment possible. This treatment had antitumoral efficacy in a prophylactic tumor model. Administration of the human trastuzumab pDNA resulted in high short-term expression, but loss already at day 10 after treatment, accompanied with a strong murine anti-human antibody response. Analogously, treatment of sheep with ovinized antibody pDNA and a clinical eectroporator resulted in fast decline of expression, presumably due to remaining murine sequences in the antibody. In sum the study showed high potency for antibody expression, but also potent immune response against foreign sequences.

1. Helfield, B, Chen, X, Watkins, SC, and Villanueva, FS (2016). Biophysical insight into mechanisms of sonoporation. Proc Natl Acad Sci U S A 113: 9983-9988.
2. Trimble, CL, Morrow, MP, Kraynyak, KA, Shen, X, Dallas, M, Yan, J, et al. (2015). Safety, efficacy, and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3: a randomised, double-blind, placebo-controlled phase 2b trial. Lancet  386: 2078-2088.
3. Morrow, MP, Kraynyak, KA, Sylvester, AJ, Shen, X, Amante, D, Sakata, L, et al. (2016). Augmentation of cellular and humoral immune responses to HPV16 and HPV18 E6 and E7 antigens by VGX-3100. Mol Ther Oncolytics 3: 16025.
4. Hollevoet, K, and Declerck, PJ (2017). State of play and clinical prospects of antibody gene transfer. J Transl Medicine 15: 131.

Cancer Gene Therapy Symposium

Eva Galanis:  MV and brain tumors- Mayo Clinic

Dr Galanis provided an update on trials of MV for glioblastoma.  In a phase 1 trial of oncolytic measles virus for GBM, N=10 patients treated with IT injection of the resection cavity following tumor resection.  Treatment appeared to be well tolerated in the post resection setting.  MV and checkpoint inhibitor strategies may be attractive to test in clinical studies for GBM despite recent failure of monotherapy check point inhibitors for GBM.

Sattva Neelapu:  CART cell related CRS and treatment- MDACC

Reviewed clinical manifestations of CART cell related CRS associated with T cell expansion and engraftment.  Hypotension, capillary leak/hypoxia, and encephalopathy/cerebral edema are the most worrisome symptoms that manifest post CART cell therapy.  IL-6 identified as key to CRS development.  Use of anti-IL6 receptor or anti-IL-6 antibodies are very effective in treatment of cytokine mediated post CART cell symptoms.  Specifically, tocilizumab and new agent and siltuximab have been used successfully for CRS.  Up to ~40% and 30% of patients received anti-IL-6 and steroid therapy, respectively, in recently completed CART cell trials.  A new CTC AE grading system for CRS has been proposed as a more relevant approach to assessing CART cell and other therapies associated with CRS.  Prophylaxis with anti-IL6 antibody therapy being contemplated given high rate of CRS post CART cell therapy.

Michel Sadelain, MD, PhD. Memorial Sloan-Kettering Cancer Center, New York, NY

Dr Sadelain summarized his data on new design for CART cells utilizing CRSPR/Cas 9 sequence targeting.Directing a CD-19 specific CAR (CD19-specific 1928z) to the T-cell receptor alpha constant (TRAC) region (and thus placing it under the control of endogenous

regulatory elements) results in more uniform CAR expression and increased T-cell potency versus conventional retroviral based delivery in mouse models of ALL.T-cell differentiation and exhaustion also seems to be improved with this approach perhaps due to a reduction in tonic signaling and more effective CAR re-cycling to the cell membrane.This approach may provide an improved approach to CAR engineering for clinical application.

Award Spotlight

Outstanding New Investigator Award Winners

James Kochenderfer, MD
National Cancer Institute
Bethesda, MD

1)  Briefly describe your research interests:
Chimeric antigen T-cell receptor (CAR) therapies for hematologic malignancy.  I have a lab that does preclinical CAR projects, and I am principal investigator of multiple CAR clinical trials.

2)  Briefly describe how you reached your current position (educational background):
I am a tenure-track Investigator in the Experimental Transplantation and Immunology Branch (ETIB) of the National Cancer Institute (NCI). I received his M.D. from West Virginia University and then completed internal medicine training at Vanderbilt University.  Next, I completed a medical oncology fellowship at the M.D. Anderson Cancer Center and a hematology fellowship at Baylor College of Medicine. I then undertook a period of postdoctoral research training in T-cell immunotherapy in the laboratories of Dr. Ronald Gress and Dr. Steven Rosenberg at the National Cancer Institute. For the past 10 years, I have focused on a full range of chimeric antigen receptor (CAR) research from designing and constructing new CARs to preclinical testing of new CARs to conducting clinical trials. My work emphasizes developing CAR T-cell therapies for lymphoma and multiple myeloma.

3)  When and why did you first develop an interest in gene and cell therapies?
I have been interested in immunotherapy for cancer since early in my medical training.  I decided that genetically modifying T cells to target cancer was by far the most promising approach to cancer immunotherapy in 2006 after trying to develop cancer vaccines in the lab and having extensive experience with other types of immunotherapy clinically. 

4)  What, in your opinion, marks the greatest advance to date in the field of gene and cell therapy and why?
Development of genetically-modified T-cell therapies for cancer.  This is the area that has had the most clinical impact of all gene therapies.

5)  In your opinion, what are the greatest areas of need which must be addressed to ensure continued progress in this field?
Reduce regulatory burdens, encourage phase I clinical trials.

6)  In what ways do you feel the ASGCT has played a role in your scientific and career development?
ASGCT provided me the first forum to give an oral presentation on the first demonstration of antigen-specific activity of anti-CD19 CAR T cells at the annual meeting in 2010.  The Annual meetings have provided a great opportunity to learn about the work of others in the fields of gene and cell therapy. Myself and my postdoctoral fellows have had multiple opportunities to present our work at annual meetings of ASGCT over the years.  Finally, ASGCT has provided me with the New Investigator Award this year.

7)  How was your experience at the ASGCT 20th Annual Meeting?
It was a great meeting with a very active poster session and lots of good research in general.

8)  Where do you see yourself 10 years from now?
In academics still doing work on T-cell therapies for malignancy.

9)  How do you like to pass the time outside of work?
Spend time with my family, exercise.

Lili Yang. PhD
University of California Los Angeles
Los Angeles, CA

1)  Briefly describe your research interests:
The overall goal of my research is to decipher the cellular and molecular mechanisms responsible for successful or unsuccessful immune responses against chronic diseases, and to exploit this knowledge to develop innovative immunotherapies for treating these diseases. It bridges basic and translational immunology and has direct therapeutic applications. A main focus of my research is to genetically engineer the various components of the immune system to target chronic diseases, a concept called “Engineering Immunity”. My primary area of interest is cancer, but also extends to autoimmune diseases, allergies, and HIV/AIDS.

2)  Briefly describe how you reached your current position (educational background):
I received my B.S. degree in Biology from the University of Science & Technology of China (USTC) in 1997, my M.S. degree in Biomedical Sciences from the University of California, Riverside (UCR) in 1999, and my Ph.D. degree in Biology from the California Institute of Technology (Caltech) in 2004. I obtained my Ph.D. training at the Laboratory of David Baltimore. Post graduation, I stayed at Caltech and led a multi-institutional Engineering Immunity Program from 2004 to 2012, developing gene- and cell-based immunotherapies for cancer and HIV/AIDS. I joined the University of California, Los Angeles (UCLA) as an Assistant Professor in January of 2013.

3) When and why did you first develop an interest in gene and cell therapies?
I developed an interest in gene and cell therapies since I joined Caltech in 1999 as a Ph.D. student, studying with Dr. David Baltimore. Under Dr. Baltimore’s mentorship, I was given the freedom to explore my own interests. I became fascinated about the idea of genetically engineering the various components of immune system to treat disease. Traditionally, the Baltimore lab focuses on studying the basic molecular interactions in the immune system. Being always open-minded and supportive of his students’ novel ideas, Dr. Baltimore still gave me the “green light”. My work eventually led to the development of a new method of HSC-engineered T cell immunotherapy. With the elaboration of this idea in a thesis entitled “Towards Engineering Immunity”, I was awarded my Ph.D. degree in 2004. Meanwhile, both Dr. Baltimore and I immediately realized the enormous potential of this new direction of translational research. Instead of following the conventional academic path and moving on to another lab for postdoctoral training, I stayed at Caltech to join forces with Dr. Baltimore and other academic and industrial collaborators to explore the biomedical applications of the Engineering Immunity concept. Since then I have been leading a multi-institutional Engineering Immunity research team comprising 3 laboratories and over 20 researchers to explore treating cancer and HIV/AIDS through genetic engineering of blood stem cells, T cells, B cells/antibodies and dendritic cells. These collective efforts have resulted in over 20 peer-reviewed publications, 5 patents and 2 clinical trials.
After a dream experience at Caltech ranging from scientific exploration, innovation to large translational projects management, I set off to my independent career. In 2013, I joined UCLA as an assistant professor, and established my independent lab. A major focus of my UCLA lab is to develop novel gene- and cell-based immunotherapies for treating cancer.

4)  What, in your opinion, marks the greatest advance to date in the field of gene and cell therapy and why?
a. CAT-T therapy for treating blood cancers
b. HSC-based gene therapy for treating monogene-deficiencies
Both are great advances that represent new-generation medicine for treating the corresponding diseases.

5)  In your opinion, what are the greatest areas of need which must be addressed to ensure continued progress in this field?
a. Robust large-scale GMP quality vector production
b. Standardized and centralized cell manufacture
c. On-shelf instead of personalized therapeutic products

6) In what ways do you feel the ASGCT has played a role in your scientific and career development?
ASGCT provides a great platform for me to interact with the experts and talents in the gene & cell therapy field.

7)  How was your experience at the ASGCT 20th Annual Meeting?
Great.

8)  Where do you see yourself 10 years from now?
Likely I will still be in academia conducting research in the areas of tumor immunology and cancer immunotherapy. This is my interest, and I enjoy the academic freedom on exploring new horizons.

9)  How do you like to pass the time outside of work?
Spend time with my family and two daughters (5 & 3). Travel the world to meet friends and colleagues when my schedule allows. 

Public Policy

ASGCT Endorses Comments to IPPS Proposed Rule

On June 10, 2017, the American Society for Blood and Marrow Transplantation submitted comments to the Centers for Medicare and Medicaid Services (CMS) in response to the Proposed Rule for Hospital Inpatient Prospective Payment System. The letter, which ASGCT has since endorsed, supports the application submitted for New Technology Add-on Payment status by Kite Pharmaceuticals for Axicabtagene Ciloleucel (KTE-C19). CMS solicited feedback on therapeutics pending initial acceptance, which may warrant new technology add-on payments. In order to qualify for such status, the Agency requires that the technology be new, the existing diagnosis-related group (DRG) reimbursement rate be inadequate, and the technology demonstrate a substantial clinical improvement over other technologies. The ASBMT commentary which completely addressed all three elements of new technology consideration further urged CMS to develop a comprehensive reimbursement structure for CAR T cell therapies and create separate DRGs for such therapies.

ASGCT Co-Sponsors Capitol Hill Briefing on Sickle Cell Disease

ASGCT joined the American Society of Hematology, American Society for Blood and Marrow Transplantation, Be The Match, Sickle Cell Disease Association of America, Inc., and the Pediatric Hospital Sickle Cell Collaborative to host a briefing on Wednesday June 7 to highlight advancements in sickle cell disease (SCD) research and treatment options including gene therapy. The briefing was targeted for Congressional staffers and attracted approximately 100 attendees from both House and Senate offices on both sides of the aisle. Congressmen Bill Foster, PhD (IL-11) and Danny Davis (IL-7) made public comments during the event and expressed their gratitude and support for the research community’s efforts impacting SCD. Presenters also spoke about the significant medical discoveries and advances that would not be possible without federal investments in the National Institutes of Health (NIH). The presentations featured opening remarks from ASH President Elect Dr. Alexis Thompson, Dr. Linda Burns of NMDP, Dr. Dan Bauer, and SCD patient Constance Benson. During the question and answer period, several questions from legislative staffers focused on whether CRISPR Cas-9 provided a therapeutic option for SCD, evidencing a clear opportunity for continued education efforts from ASGCT.

Molecular Link

ASGCT Job Bank

The ASGCT Job Bank allows students, postdoctoral fellows, and experienced investigators seeking a new opportunity to search for gene and cell therapy positions and post your resume so employers can search for you.  Members can post positions and view resumes at a reduced rate.  Take advantage of this area to grow your professional development.  Below are three recent job postings to the ASGCT online job bank, your link to the latest career opportunities within gene and cell therapy.

Supervisor, Clinical Molecular Laboratory

Director/Sr. Director, Molecular and Cell Biology, Protein Expression and Purification

Molecular Technologist 

Medical Director, Pharmacovigilance, Gene Therapy

Click here to visit the ASGCT Job Bank and view the complete list of current career opportunities.

On the Horizon

21^st Annual Meeting

Save the date for the ASGCT's 21st  Annual Meeting! The meeting will be held at Chicago Hilton in Chicago, Illinois from May 16-19, 2018. Stay tuned for more details on the plenary speakers, abstract deadlines, and more.

ASGCT is partnering with the Hemophilia Federation of America for a series of two webinars on the role of gene therapy in treating hemophilia. The webinars will be live during the following times:

• Wednesday, August 9^th at 8 pm ET/ 5 pm PT
• Wednesday, August 30^th at 8 pm ET/ 5 pm PT

Other Society Meetings:

European Society of Gene and Cell Therapy
25^th Anniversary Congress
October 17-20, 2017 in Berlin, Germany

Japan Society of Gene and Cell Therapy
23^rd Annual Meeting
July 20-22, 2017 in Okayama, Japan

InSITE

Industry News

• Alnylam: Givosiran Shows Positive Clinical Results In Acute Hepatic Porphyrias
• ​Voyager Therapeutics Announces Clinical Trial Update with VY-AADC01 for Advanced Parkinson’s Disease
• Novartis-backed GenSight gets cash for gene therapy launch
• Bluebird Bio’s gene therapy for blood disorders yields some impressive results ― but also raises questions
• Bluebird bio steps up with a promising snapshot of its gene therapy upgrade
• Sarepta and Genethon Will Collaborate to Develop DMD Gene Therapy
• Novartis drug cuts cardiovascular risk in heart attack survivors
• Gene editing technique reverses Huntington's in mouse model
• Clinical development of TxCell’s new technology on track to start by end of 2018
• Genexine Receives Approval to Initiate Phase Ib/II Trial of GX-188E, HPV Therapeutic DNA Vaccine, in Combination with KEYTRUDA® (pembrolizumab)
• Intellia Therapeutics announces patent for CRISPR/Cas genome editing in China
• Intrexon Integrates Leading Adenoviral Gene Delivery Technology with Completion of GenVec Acquisition
• Newly Designed Viral Vectors Could Lead to Improved Gene Therapies
• MilliporeSigma Awarded its First CRISPR Patent by Australian Patent Office
• GenSight has announced Phase I/II data revealing that its gene therapy technology can restore sight in patients suffering from a rare mitochondrial disease.
• AveXis Announces Alignment with FDA on GMP Commercial Manufacturing Process for AVXS-101
• ACEA Biosciences Announces Successful Completion of Phase I Clinical Study of Novel Autoimmune Disease Drug
• Fibrocell Receives Rare Pediatric Disease Designation from FDA for FCX-013 for Treatment of Localized Scleroderma
• Dragonfly Therapeutics Announces Strategic Collaboration with Celgene to Discover and Develop Novel Natural Killer (NK) Cell-Based Immunotherapies using Dragonfly's TriNKET™ technology platform
• Gene Therapy Shows Long–Lasting Effects in Animal Model of Myotubular Myopathy
• Inovio Begins Phase 3 Clinical Trial of VGX-3100 for the Treatment of HPV-Related Cervical Pre-Cancer