The Vector
Editorial Team
Karen Bulaklak, PhD – Editor, The Vector
Jon Brudvig, PhD – Associate Editor, The Vector
Jessica Schneller, PhD – Junior Editor, The Vector
Inside This Issue
Leadership Message
Breaking Through
From Molecular Therapy
Society News
Career Center
Public Policy
Industry News
Leadership Message
Fast, Clutter-Free Membership Renewal
Hello ASGCT Members,
It’s hard to believe we’re nearing the end of the year already. As you all know, though, we aren’t slowing down at ASGCT; our monthly series are going strong and planning for the 26th Annual Meeting is progressing. Most importantly, we’re officially in renewal season! I hope you’ll take some time to renew your ASGCT membership so you won’t lose access to any benefits. This year, we’re excited to share that we’re offering a brand new service to make renewals easier and faster—auto-renew for all memberships.
When you renew, you’ll be presented with the option during the checkout process to “automatically pay future renewals.” If you select the checkbox, your membership will automatically renew at the end of each year, allowing you uninterrupted access to everything that membership offers, like discounted rates for the Annual Meeting, member-rate publication in the Molecular Therapy family of journals, access to ASGCT’s archive of educational events, and more. Besides being easy, auto-renew will greatly reduce the emails in your inbox because you’ll be removed from our renewal messaging campaigns.
Your membership allows us to implement more programs and initiatives every year. We rely on our members to help shape the future of the Society, which you can do by volunteering on committees, contributing your research to our top-tier journals, and developing programs that help other members further their careers. We could not fulfill our mission without you, so please renew today and keep taking advantage of the benefits of membership.
Lastly, it’s time to start thinking about the 26th Annual Meeting! Get your research ready because next week, on Monday, Nov. 14, abstract submission begins. Send us your research through Feb. 3, 2023, for the opportunity to present your work to the largest gathering of gene and cell therapy professionals. You may also be eligible for an award or (if you’re an Associate Member) free registration to the meeting. Learn more about abstracts on this section of our website, and we can’t wait to see what you’ve been working on.
Sincerely,
Hans-Peter Kiem, MD, PhD
ASGCT President
Breaking Through
EBAG9 silencing exerts an immune checkpoint function without aggravating adverse effects
Wirges A, Bunse M, Joedicke JJ, Blanc E, Gudipati V, Moles MW, Shiku H, Beule D, Huppa JB, Höpken UE, Rehm A
DOI: https://doi.org/10.1016/j.ymthe.2022.07.009
Summary by Jessica Schneller, PhD
Chimeric antigen receptor (CAR) T cells have demonstrated clinical efficacy against a number of hematologic malignancies. Despite significant response rates and durable remissions, a large number of patients relapse. Treatment options post-CAR relapse are limited, resulting in challenges to producing a therapy with a complete response for these cancers. Cytolytic CD8+ T cells (CTLs) have been engineered to meet the need for more efficacious CAR T-cell therapies. These cells demonstrate anti-tumor activity by secreting effector molecules such as cytokines and cytotoxic granules. One strategy to improve the potency of CTLs aims to enhance the intracellular pathways responsible for transport and secretion of the effector molecules. The estrogen receptor-binding fragment-associated antigen 9 (EBAG9) negatively regulates secretion of effector molecules. Previous studies have shown that deletion of the Ebag9 gene in mice results in enhanced release of lytic granules from secretory lysosomes in CD8+ T cells. In this study, Wirges et al demonstrate that EBAG9 downregulation in murine T cells and human CAR T cells augmented the cytolytic activity of these cells against hematopoietic tumors in vitro and in vivo.
Previously, this group had identified the inhibitory effect of EBAG9 on the cytotoxic activity of T cells. To take advantage of this effect, they engineered a retroviral vector encoding GFP to express miRNAs targeting the mouse Ebag9 reading frame. After transduction with this vector in murine primary T cells, significant reduction of Ebag9 expression was observed for two of the miRNAs (miR-M1 and miR-M2) at the mRNA and protein levels. The in vivo cytotoxicity of the miRNA-modified CTLs was assessed by transducing T cells isolated from mice immunized with SV40-large T antigen (TAg) with the miR-M1 retroviral vector. GFP+ transduced cells were sorted and transplanted into immunodeficient mice also immunized with TAg and later challenged with TAg peptide-loaded splenocytes; recipients that had received the miR-M1 vector versus controls demonstrated a two-fold higher antigen specific killing rate.
To assess this strategy in a human setting, retroviral miRNA vectors targeting the human EBAG9 gene were generated and tested for their ability to achieve EBAG9 mRNA and protein knockdown in Jurkat T cells. For one of the miRNAs demonstrating activity (miR-H18), the GFP transgene of the retroviral vectors was exchanged for a B cell maturation antigen (BCMA) CAR T cell, effective against multiple myeloma. The miR-H18 BCMA CARs released higher amounts of the effector molecule granzyme A than controls in transduction experiments, and were specifically activated when cultured in the presence of multiple myeloma cells. Further killing assays identified that miRNA-mediated silencing of EBAG9 in BCMA CAR T cells resulted in more potent cytotoxicity of the CARs in BCMA+ myltiple myeloma and B cell non-Hodgkin lymphoma cell lines. The kinetics of the improved cell killing with the miR-H18 BCMA CAR T cell were characterized by microscopy and found to be universally applicable for increasing the potency of CD8+ CTLs. Studies performed in an in vitro serial transfer model demonstrated that the BCMA CAR and miRNA-edited BCMA CAR T cells maintained their effector and proliferation capacities after multiple rounds of stimulation without evidence of exhaustion or activation-induced cell death. Transcriptome profiling of the miR-H18 mediated EBAG9 silencing ultimately showed that exhaustion-related genes were downregulated, indicating that increased cytotoxic potency did not impair T-cell fitness. Finally, treatment with the BCMA CAR T cells in a xenotransplantation model showed potent suppression of tumor growth without demonstration of CAR T-cell exhaustion. In summary, the results demonstrate the improved therapeutic potency of EBAG9-silenced T cells, suggesting their clinical application as a promising option for cancer immunotherapy.
From Molecular Therapy
Call for papers: Exploiting extracellular vesicles as therapeutic agents
The editors of the Molecular Therapy family of journals are pleased to announce a concomitant series of special issues across the journal family focused on the identification, characterization, and standardization of EV technology and the exploitation of the latter as therapeutic agents and biomarkers for the treatment of the gamut of human disease. Submit by Dec. 1! Learn more.
Latest MT issues: Check out the most recent issues of these Molecular Therapy family journals:
Society News
New in 2023: Auto-Renew for Easy Membership Maintenance
We're offering a brand new auto-renewal service for the next membership year. When you renew your membership, check the box to automatically pay future renewals to guarantee uninterrupted access to all your membership benefits, including discounted Annual Meeting registration rates, member-rate publication in the Molecular Therapy family of journals, and more.
Hear From a Gene Therapy Giant on Our Podcast Network
Listen to a fascinating conversation between David Baltimore, PhD, and ASGCT President Hans-Peter Kiem, MD, PhD on Giants of Gene Therapy, the inaugural show on our new podcast network. Dr. Baltimore talks about the Nobel Prize, searching for answers on an HIV vaccine, and how gene therapy could change the course of history. Subscribe to the ASGCT Podcast Network wherever you listen to podcasts and let us know what you think.
Send Us Your Annual Meeting Abstracts by Feb. 3
We want to see your latest gene and cell therapy research! Submit an abstract and you may be able to present it at the 26th Annual Meeting, be eligible for awards, and more. Learn more about the submission process on our website. We look forward to learning more from your work and seeing you in Los Angeles, CA in May 2023.
Register for November Events
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Wednesday, Nov. 16: Neural and Cardiac Cellular Reprogramming
Discuss the progress and pitfalls of different approaches and tools for achieving cell lineage specification through reprogramming.
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Thursday, Nov. 17: Lunch & Learn: Navigating the Patient-Provider Conversation
Learn how to speak with a physician if you're a caregiver or loved one of a person with a rare disease, or if you have a disorder that may benefit from gene therapy.
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Friday, Nov. 18: Scientific Horizons and Ethical Limits of Gene and Cell Therapy
Explore foundational cases in biomedical research (related to embryo culture, biobanking, CRISPR, etc.) that have shaped approaches to defining ethical limits.
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Wednesday, Nov. 30: Immunological Responses to AAV Gene Therapy in Neurological Compartments
Receive an update on the humoral and cellular immune responses, including the impact of vector design, purity, and dose; DRG toxicity and potential immunological mechanisms; and more.
Career Center
Are you looking for a job in the field of gene and cell therapy? Check out the new ASGCT Career Center for great opportunities with industry, government, and academic organizations. Sign up to receive alerts for open jobs in your area.
If you're from a recruiting institution, advertise in the Featured Jobs section to target the 5,000+ audience of The Vector.
Featured Jobs
Public Policy
Save the Date: Free Workshop on Immune Responses to AAV Vectors
As part of FDA’s efforts to improve communications with sponsors, ASGCT is partnering with the Office of Tissues and Advanced Therapies (OTAT) for a two-day workshop on Immune Responses to AAV Vectors. This free, open to the public workshop will be held virtually Jan. 24-25 from 11a.m. to 3 p.m. (ET) each day.
AAV mediated gene therapies represent a complex treatment modality with multiple components that may impact immunogenicity. This program will address the appropriateness and utility of companion diagnostics and their relation to approval requirements – specifically their applications for assessing pre-existing immunity. Additionally, speakers will discuss requirements for immunogenicity testing as there’s often confusion around what data needs to be collected, what can be carried over from previous applications, and how to define “clinically meaningful” metrics. The agenda is currently being finalized, and speakers will consist of gene therapy researchers from academia and industry as well as FDA representatives. More info to come about speakers, session topics, and registration in the coming weeks!
ASGCT and ARM Roundtable Addresses Potency Assays
In partnership with FDA and the Alliance for Regenerative Medicine (ARM), ASGCT held an expert roundtable on potency assays for cell and gene therapies. The workshop was broken into three sessions to address stakeholders’ concerns around assay requirements and implications. The first session defined common challenges for developers and the Agency, specifically mentioning ongoing questions about the 2011 guidance Potency Tests for Cellular and Gene Therapy Products. Following this, representatives discussed some potential solutions, including sharing critical quality attributes for established modalities and other multi-stakeholder actions. This solutions conversation continued into the final session, where experts and attendees touched on optimizing the assay matrix and using appropriate assays to demonstrate the biological cascade.
While the event was not recorded, a summary is available and will be posted on ASGCT’s website. The Society is encouraged by the FDA’s continued willingness to engage with organizations like ours on these important issues. ASGCT will continue to provide updates on future partnered events in 2023, such as the OTAT workshop on AAV immunogenicity.
Apply for a Congressional Policy Fellowship
Apply for the inaugural ASGCT Congressional Policy Fellowship! In partnership with AAAS, one applicant will be selected for a year-long policy fellowship in legislative offices on Capitol Hill beginning in the fall of 2023. Fellows will provide high-quality, science-based, independent guidance to federal policy makers and elevate awareness of the Society among policymaking circles. Previous fellows describe how this opportunity helped shape their careers and created a lifelong network of contacts and mentors. Fellows must be an ASGCT member with a doctoral degree looking to learn more about the intersection of science and policy. A summary of application materials and FAQ are available, so apply today!
Attend Upcoming FDA Educational Events
In addition to events FDA is hosting this fall with ASGCT, the Agency is putting on a number of public events in Q4 which will address topics of interest to a wide variety of stakeholders in the gene and cell therapy field – researchers, patients, developers, and many others. Currently announced events include:
ASGCT deeply appreciates that FDA is offering so many opportunities for public education and engagement on these important issues.