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American Society for Gene & Cell Therapy (ASGCT)

“[ImmTOR] induces tolerance in the presence of antigen, specific immune tolerance. Specifically, the issue we're trying to address in gene therapy is immunogenicity of AAV vectors to enable re-dosing. We have demonstrated this in a human proof-of-concept study last year and we are going into the first clinical indication in MMA in the second half of this year.”

Selecta Biosciences presented 3 posters at the 

2022 American Society of Gene and Cell Therapy Annual Meeting, May 16-19, 2022

, in Washington DCthat demonstrated the ability of their proprietary ImmTOR platform mitigate unwanted immune responses to adeno-associated virus capsids and potentially enable re-dosing of gene therapies.

Among these presenters was Takashi Kei Kishimoto, PhD, chief science officer, Selecta Biosciences, who presented the company’s findings on the immunogenicity and mitigation of immunogenicity mechanisms of the ImmTOR platform.

 spoke with Kishimoto and Carsten Brunn, PhD, president and chief executive officer, also of Selecta Biosciences, to learn more about the ImmTOR platform. They also discussed their first clinical gene therapy program in methylmalonic acidemia, SEL-302, initiating in the second half of 2022.

Selecta Biosciences announces six presentations at the upcoming 25th annual meeting of the American Society of Gene & Cell Therapy (ASGCT). News release. Selecta Biosciences. May 2, 2022. https://ir.selectabio.com/news-releases/news-release-details/selecta-biosciences-announces-six-presentations-upcoming-25th

Takashi Kei Kishimoto, PhD, and Carsten Brunn, PhD, the chief science and executive officers of Selecta Biosciences, discussed the immunogenicity-mitigating properties of ImmTOR. 

Re-Dosing With Gene Therapies in Rare Diseases

“If you wanted to treat just 25% of the patients out there with muscular dystrophy, it would take most of the bioreactors on the East Coast running Day and night for a year just to treat that. And that'sonly for one indication. So, Forge and the team came together to build more GMP suites and more bioreactors at larger volumes to try to help meet a lot of that unmet patient need.”

Forge Biologics is supporting gene therapy development with a dual approach, both as a contract development and manufacturing company as well as a developer of the Krabbe A gene therapy FBX101, which is currently being evaluated in the phase 1/2 RESKUE clinical trial (NCT04693598).

Forge also recently announced the formation of an independent scientific and manufacturing advisory board composed of gene therapy leaders to advise on the company’s pipeline development and gene therapy manufacturing offerings.

 spoke with Tim Miller, PhD, cofounder, president, and chief executive officer, Forge Biologics, to learn more about the company. He discussed Forge’s approach to manufacturing, the new scientific board, and the Krabbe A program, and touched on presentations from the 

American Society of Gene & Cell Therapy 25th Annual Meeting.

Forge Biologics Forms Independent Scientific and Manufacturing Advisory Board with Panel of Gene Therapy Leaders. News release. Forge Biologics. May 17, 2022. https://www.forgebiologics.com/2022/05/17/forge-biologics-forms-independent-scientific-and-manufacturing-advisory-board-with-panel-of-gene-therapy-leaders/

The cofounder, president, and chief executive officer of Forge Biologics discussed the company’s approach to gene therapy manufacturing. 

Tim Miller, PhD, on Supporting Gene Therapy Development 

“Our signature work was the ADA-SCID work. We had our first-generation approach, we did a trial, we saw the deficiencies, we went back to the lab, improved the vectors, improved the cell processing, did another trial. As technology continued to improve, we changed our approach. Now we have up to 50 children [who had ADA-SCID] who are alive and well because of gene therapy. That's our biggest accomplishment.”

The American Society of Gene & Cell Therapy (ASGCT) presented its highest honor, the Outstanding Achievement Award, to renowned physician scientist Donald Kohn, MD, professor of microbiology, immunology and molecular genetics; and pediatric hematology/oncology, University of California Los Angeles (UCLA), during the 25th Annual Meeting, which took place May 16-19, 2022, in Washington, DC. 

Kohn served as president of ASGCT from 2003-2004, president of the Clinical Immunology Society from 2013-2014, and was chair of the Recombinant DNA Advisory Committee for the NIH Office of Biotechnology from 2013-2015.

spoke with Kohn about his career and his achievements along the way in reflection of the award. He discussed his work at UCLA developing a lentiviral stem cell gene therapy for adenosine deaminase severe combined immunodeficiency (SCID), conducting the first trial of its kind. He also discussed the ever-evolving technology of cell and gene therapies, hurdles that remain in the field, and the importance of collaboration.

1. Congratulations to the 2022 Award Recipients! News release. ASGCT. April 11, 2022. 

https://asgct.org/research/news/april-2022/2022-annual-meeting-award-winners


2. Kohn DB, Booth C, Shaw KL, et al. Autologous ex vivo lentiviral gene therapy for adenosine deaminase deficiency. N Engl J Med. 2021; 384:2002-2013. doi: 10.1056/NEJMoa2027675

The renowned professor from University of California Los Angeles reflected on receiving the Outstanding Achievement Award from the ASGCT. 

Donald Kohn, MD, on the Trajectory of Gene Therapy 

, a gene-edited lentiviral mediated hematopoietic stem and progenitor cell (HSPC) therapy, seems to be efficacious and safe in patients with pyruvate kinase deficiency (PKD).

, which is being assessed in an ongoing phase 1 study (NCT04105166), restored normal levels of hemoglobin production, improved hemolysis and sustained transgene expression with no need for red blood cell transfusions at 1-year post infusion.

, in Washington DC, by Ami J. Shah, MD, clinical professor of pediatrics, Division of Hematology/ Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford Medicine.

“We expected some gradual improvement and we expected maybe they feel a little bit better. But we didn't really expect people to come out of this completely normal... [in terms of] side effects, they don't even feel like they had a transplant and... they can't remember this disease anymore,” 

The study has treated 2 adult, splenectomizedpatients with severe, transfusion-dependent anemia PKD as of January 2022. Investigators collected mobilized peripheral blood (PB) HSPCs via apheresis, then enriched and transduced them with PGK-coRPK-WPRE lentiviral vector before cryopreservation. Participants received myeloablative busulfan over 4 days before receiving the gene-edited cell therapy product and were then followed for up to 1 year after treatment. Investigators assessed PB and bone marrow (BM) genetic correction, transfusion need, anemia, reduction of hemolysis, and patient-reported-outcomes (PROs).

Developing Therapies for Rare Diseases: Kinnari Patel, PharmD

The participants were 31 and 47 years at enrollment. Patient 1 received a dose of 3.9x10

 CD34+ cells/kg with mean vector copy number (VCN) of 2.73 and patient 2 received a dose of 2.4x10

 CD34+ cells/kg with mean VCN of 2.08. Both patients have sustained transgene expression, normalized hemoglobin, improved hemolysis and no red blood cell transfusion requirements as of 1-year post infusion. PROs have also shown significant improvements, with increases in scores on both the Functional Assessment of Cancer Therapy-Anemia and 36-Item Short Form Survey instruments. Marked improvements were seen specifically in energy/fatigue, physical functioning, and general health domains.

“Since the transplantation and steadily afterwards, from 3months and then on, [patients] have continued to show marked improvements in energy levels, in work ability, in quality of health, in susceptibility to infections - especially considering we did this trial during the middle of a pandemic. Both adults were really healthy throughout the whole entire thing. They were around people that got sick, and they didn't get sick. It's been amazing to see just how they're living their lives,” Shah told 

Shah AJ, López Lorenzo JL, Navarro S, et al. Changing the treatment paradigm for pyruvate kinase deficiency with lentiviral mediated gene therapy: Interim results from an ongoing global phase 1 study. Presented at: ASGCT 25th Annual Meeting, May 16-19, 2022. Abstract #357

RP-L301 also improved hemolysis and eliminated the need for red blood cell transfusions for up to 1year after therapy. 

Lentiviral Cell Therapy Normalizes Hemoglobin in Pyruvate Kinase Deficiency 

The standard approach for gene therapies today consists of adenoviral or lentiviral vectors, which have shown great potential for correcting genetic diseases but also come with high levels of toxicity due to their immunogenicity within the human body. Ring Therapeutics has developed a novel anelloviral vector, coined Ring 46, which may lead to the development of an effective and safe gene therapy agent in humans.

American Society of Gene & Cell Therapy 25th Annual Meeting

 (ASGCT), held in Washington, DC, and virtually May 16-19, 2022, by Dhananjay Nawandar, PhD, associate director, Ring Therapeutics.

spoke with the chief executive officer of Ring Therapeutics, Tuyen Ong, MD, to learn more about anelloviruses. He discussed their properties and advantages including low immunogenicity, low preexisting immunity, and immune privilege in humans.

: What are some challenges with the current approach and use of viral vectors in gene therapy?

There have been a lot of conversations around challenges with delivery, as well as immunogenicity and immune response. When we typically think about traditional small molecules, it's really focused on pharmacokinetics and pharmacodynamics, which is straightforward. Gene therapy has become much more challenging. Ultimately, as the field continues to blossom, there are a number of areas that we need to address as a community. One is tropism, the second is potency, and the third piece is really relating to immunogenicity and the immune profile. Also, the ability to re-dose, if you don't have durability, or if you need to continue treating for 1 reason – growing children, for example, or insufficient expression of protein as well. Those are the challenges the gene therapy community faces and people are rising up to these challenges in different ways. For us, the optimal solution is anelloviruses, because they've really been able to evolve through millennia, and we have specific tricks that we can harness with them. We're really excited by what anelloviruses can offer.

What makes the anelloviruses an attractive option as a vector?

Anelloviruses are very interesting. They come from the human virome and the majority of the virome consists of viruses that don't cause disease. Ring has built out a whole platform to discover and then vectorize these viruses. We've discovered that they are highly diverse... this is in a publication in Cell Host & Microbe that we published a while back. Essentially, from millions of years of evolution, they've developed a huge amount of genetic diversity that's afforded them very specific properties. One is that intrinsically, they're able to be ubiquitous amongst the general population and are able to reside in different parts of our body. All of those traits have allowed them to be tissue tropic. The second piece is that they've somewhat become immune stealth, they've invaded our immune system and become immune-privileged.

Part of that publication showed that you can transfer anelloviruses between donors and recipients in blood transfusions and those viruses actually persist. In many cases, when the anelloviruses are very similar between the donor and recipient, you can almost re-dose the same virus or vector as well. So we published this exciting data showing anelloviruses as a potential basis for programmable medicines.

What observations and progress have been made with the anellovirus vectors?

About 2 to 3 weeks ago, the National Institutes of Health held a workshop on the humanvirome, and 1 of the challenges is being able to synthetically produce an anellovirus. Ring has been the first and only organization that I'm aware of to be able to synthetically produce anelloviruses. This is a huge milestone for us and it allows us to use ring 46 as a prototype, allowing us to take in another virus and vectorize it, and introduce a transgene tailored within that. What we've shown in the paper is the ability of those trans genes to target a number of different tissues, such as the muscle, retina or the heart. We’re laying the foundation of being able to take an anellovirus, vectorize it, introduce payloads within that, and then show transduction or infectivity into those tissues and ultimately having a therapeutic benefit to patients.

How does low preexisting immunity combat high levels of toxicity associated with current virus vectors?

Low preexisting immunity is the fundamental aspect of why we're so excited by anelloviruses. That pertains mainly to the data we generated with Dr. Ben Larman and the folks at Johns Hopkins that showed that the anellovirus is less antigenic than most viruses in the human virome. They scanned a library of 32,000 peptides from over 800 anelloviruses and tested the immune reactivity of these proteins. When you compare these proteins to the reference library of about 200 species of known viruses, we found that most of the anellovirus peptides were not associated with any detectable antibody responses.

That's an exciting finding for us, because it allows a number of opportunities to open up. One is the lack of preexisting neutralizing antibodies, for example. We've seen that in human intravenous immunoglobulin studies. The fact that anelloviruses are less antigenic means they are less likely to be eliminated by the immune system or mount an immune response. Further down, they have the ability to be re-dosed as well. So we've had interesting findings that are exciting for us in terms of how we can harness those properties.

What are other advantages with anellovirus vectors?

When we look at the Anellogy platform that Ring has built around the anellovirus, instead of looking at small, incremental improvements in the individual components of a platform, what we've done is take a holistic view trying to generate a new gold standard around this. We're innovating on multiple fronts, from discovery to vectorization. Manufacturing is a big bottleneck and the rate limiting step in the gene therapy world, what we've essentially done is to be able to assemble the capsules from our sequences in a recombinant way, which is very different to the traditional AAV approach. That offers us the ability to be much more scalable and modular in terms of how we look at manufacturing.

What will Ring be exploring next with anellovirus vectors?

We've got a substantial body of understanding of how they evade the immune system, which we plan to share in a future conference. We will continue to build out our dominion in the space and understanding about anelloviruses to be able to deploy them in the field of programmable medicines. Ultimately, what it boils down to in this field, is being able to innovate with the nature inside of us and being able to use that to generate therapies for patients in need.

Transcript edited for clarity. To read more coverage of ASGCT 2022, 

Nawandar D, Timpona J, Boisvert N, et al. A Novel Gene Delivery Vector with Low Pre-Existing Immunity in Humans. Presented at: ASGCT 25th Annual Meeting, May 16-19, 2022, Washington DC. Abstract #1158.

The chief executive officer of Ring Therapeutics, Tuyen Ong, MD, discussed the potential of anellovirus vectors for use in gene therapy. 

Developing Safer Viral Vectors for Gene Therapy 

“There are some advantages based on the fact that you could use a lower dose... it may also be able to evade some of the new neutralizing antibodies that we know are circulating in the in the bloodstream and target directly the CNS rather than increasing exposure in some of the peripheral organs.”

While gene and cell therapies have the potential to treat many rare, neurological diseases, efficient gene delivery to the central nervous system (CNS) remains a barrier to developing these therapies. One possible avenue of gene delivery lies in the cerebrospinal fluid; however, more work is needed to make this approach feasible for CNS disorders.

Sangamo Therapeutics’ new platform, SIFTER (Selecting In vivo for Transduction and Expression of RNA), is designed to engineer capsids with improved neuronal transduction after CSF administration. Preclinical data on this platform was presented at 

 (ASGCT), held in Washington, DC, and virtually May 16-19, 2022, by David S. Ojala, PhD, senior scientist, AAV engineering, Sangamo Therapeutics.

spoke with Amy Pooler, PhD, vice president of neuroscience, Sangamo Therapeutics, to learn more about the platform and how it combats challenges with gene delivery to the CNS. She discussed novel capsids identified with SIFTER that showed improved neuronal transduction.

Ojala DS, Andrews L, Nanjaraj A, et al. Engineered AAV capsids exhibit improved transduction of the central nervous system after CSF administration in adult cynomolgus macaques. Presented at: ASGCT 25th Annual Meeting, May 16-19, 2022, Washington DC. Abstract #441.

The vice president of neuroscience at Sangamo Therapeutics discussed identifying novel capsids with improved neuronal transduction to the CNS. 

Amy Pooler, PhD, on Improving Gene Delivery to the CNS 

“[The STEADFAST trial] has a lot of potential because there are some real problems with the systemic immune suppression used to treat most transplants. It's also the first stepping stone for using regulatory T-cells as a therapy for many other autoimmune diseases. In that way, it's a proof of concept.”

A first-in-human trial (NCT04817774) is evaluating the chimeric antigen receptor regulatory T-cell (CAR-Treg) therapy TX200-TR101 (Sangamo Therapeutics) in achieving allograft acceptance in patients with end-stage renal disease after HLA-A02-mismatched renal transplantation.

An overview of the study, which has dosed its first participant, was presented by Katharina H. Schreeb, MD, PhD, head of autoimmune and oncology, Sangamo Therapeutics, at the 

 (ASGCT), held in Washington, DC, and virtually May 16-19, 2022.

spoke with Jason Fontenot, PhD, senior vice president and chief scientific officer, Sangamo Therapeutics, to learn more about the study and the advantages of TX200-TR101 in this setting and autoimmune diseases. He discussed the next steps for the study.

Schreeb KH, Culme-Seymour E, Dumont C, Hsu B, Atkinson G. STEADFAST: A first-in-human study assessing HLA-A02-chimeric antigen receptor regulatory T cells in renal transplantation. Presented at: ASCGT 2022, May 16-19, 2022, Washington DC. Abstract #798.

The chief scientific officer of Sangamo Therapeutics discussed the first-in-human STEADFAST trial. 

Jason Fontenot, PhD, on Reducing the Need for Immunosuppression in Renal Transplantation 

The gene therapy AAV8-LSPhGAA (Asklepios Biopharmaceutical) has demonstrated safety and the potential to eliminate the need for enzyme replacement therapy (ERT) in patients with late-onset 

These results, from a phase 1/2 study (NCT03533673), were presented at the 

 (ASGCT), held in Washington, DC, and virtually May 16-19, 2022by Edward C. Smith, MD, pediatric neurologist and professor of pediatrics at Duke University School of Medicine.

“Gene therapy with an adeno-associated virus serotype 8 (AAV8) vector (AAV8-LSPhGAA) could eliminate the need for ERT by creating a liver depot for acid-alpha glucosidase (GAA) production,” Smith and colleagues wrote.

Three participants with LOPD have been dosed in the low-dose cohort of the phase 1/2 study so far, which is primarily assessing the incidence and severity of adverse events (AEs) as well as clinical laboratory abnormalities. Secondary outcomes include measures of efficacy such as 6-minute walk test distance (6MWT), forced vital capacity (FVC), serum GAA activity, and muscle GAA activity and glycogen content.

Research Needs in Pompe Disease: Barry Byrne, MD, PhD

Participants had no detectable anti-AAV8 neutralizing antibodies, had received at least 12 months of stable ERT dosing, and were able to walk at least 100 meters on the 6MWT. These participants went through ERT withdrawal at week 26 based on quantifiable serum GAA activity and the absence of clinically significant declines in FVC or 6MWT performance. They then received 60 mg per day of prednisone as immunoprophylaxis through Week 4, followed by an 11-week taper.

Investigators found that 2 weeks after treatment with AAV8-LSPhGAA, all participants demonstrated sustained serum GAA levels from 101% to 235% of baseline trough activity. All participants met criteria for ERT withdrawal at week 24 and continued to meet criteria to remain off ERT at weeks 52 and 104, although 1 participant chose to resume ERT at week 97.

Smith and colleagues evaluated muscle biopsies and found that 1 participant had around a 40% decrease in muscle GAA activity at week 24, although muscle GAA activity significantly increased from baseline in the cohort as a whole at week 52 (

<.05). One participant had a 10-fold increase from 2.8% to 28% of normal, the second increased from 19% to 44%, and the third increased from 56% to 94% of normal.

Thew gene therapy was well-tolerated, with no treatment-related serious AEs. Laboratory assessments supported the safety of AAV8-LSPhGAA, with no evidence of elevated serum alanine aminotransferase or ELISPOT signals. One participant experienced 2 headaches classified as moderate severity treatment-related AEs.

“Overall, these initial data support the safety and bioactivity of AAV8-LSPhGAA, the safety of withdrawing ERT, successful immunoprophylaxis, and justify continued clinical development of AAV8-LSPhGAA therapy in Pompe disease,” Smith and colleagues concluded.

Smith EC, Hopkins S, Case LE, et al. Phase 1 Study of Gene Therapy in Late-onset Pompe Disease: Initial 104-Week Experience. Presented at: ASGCT 25th Annual Meeting, May 16-19, 2022, Washington DC. Abstract #1211

All study participants met criteria to remain off enzyme replacement therapy through 104 weeks after treatment. 

Gene Therapy May Eliminate Need for ERT in Late-Onset Pompe Disease 

"With natural killer T-cells, or NK T cells for short, we have the ability to use a homogeneous population of effector lymphocytes that are able to effectively traffic into the tumor sites better than just conventional T cells... They can recognize cancer supportive tumor associated macrophages... and specifically target them. So that provides a big opportunity for NK T cell-based therapeutics to make a major impact in the treatment of solid tumor patients.”

Chimeric antigen receptor (CAR) natural killer (NK) T-cell therapy is well-tolerated with promising responses in patients with neuroblastoma, according to data from a phase 1 study (NCT03294954) presented by Andras Heczey, MD, Associate Professor, Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine at the 

Heczey and colleagues found that antitumor activity was associated with dosage and in vivo rate of expansion after treating 12 patients in 4 dose levels of 3x10

 following lymphodepletion. Of these patients, 5 had progressive disease, 4 had stable disease, 2 had a partial response, and 1 had a complete response. No dose limiting toxicities or serious toxicities related to treatment were observed.

spoke with Heczey to learn more about the phase 1 study and trends observed with antitumor activity. He discussed challenges with treating solid tumors and more research to be done.

Herczey A, Courtney A, Ghatwai N, et al. Anti-GD2 CAR NKT cells are safe and produce antitumor responses in patients with relapsed/refractory neuroblastoma. Presented at ASGCT 25th Annual Meeting May 16-19, 2022, Washington DC. Abstract #54

The director of the Liver Tumor Program at Texas Children’s Hospital discussed a phase 1 study of CAR NK T-cells in neuroblastoma. 

Andras Heczey, MD, on Antitumor Activity of CAR NKTs in Solid Tumors 

A gene-edited autologous cell therapy, Temferon, is well-tolerated in participants with unmethylated MGMT glioblastoma (GBM) with a promising ability to modulate the tumor microenvironment (TME).

Bernhard Gentner, MD, PhD, group leader, Translational stem cell and leukemia unit, and staff hematologist, San Raffaele Telethon Institute for Gene Therapy, presented findings from a phase 1/2a study (NCT03866109) at the 

American Society of Gene & Cell Therapy (ASGCT) 25th Annual Meeting, May 16-19, 2022

“We developed a genetically modified cell-based autologous hematopoietic stem cell platform designed to selectively deliver immunostimulatory cytokines into the TME through Tie-2 expressing monocytes. As a consequence, many tumor-associated macrophages, that are well recognized to foster cancer progression, are reprogrammed toward an immune-stimulating and tumor-suppressive phenotype,” Gentner and colleagues wrote.

Temferon is transduced with a lentiviral vector and expresses interferon-alpha2 to the TME of participants with an unmethylated MGMT promoter. As of January 2022, 15 participants with this disease have received doses of Temferon ranging from 0.5 x10

 cells/kg in 5 cohorts. Investigators observed rapid engraftment and fast recovery from the non-myeloablative conditioning.

 Improving Rare Disease Awareness: Bruce Dezube, MD

No dose-limiting toxicities have been observed and median overall survival was 14 months after surgery with a maximum follow-up of 27 months. Serious adverse events (AEs) did occur, but these were mostly attributed to conditioning chemotherapy or disease progression. Persistent Gamma-Glutamyl Transferase elevation occurred in 1 participant and was classified as a suspected unexpected serious adverse reaction.

Four of the 15 participants have undergone a second surgery and these tumors were analyzed for the presence of bone-marrow (BM) derived transduced cells as well as any immunological changes. Analyzed specimens from 3 of 4 patients demonstratedsignificant homing of transduced cells from BM to tumor site.

Vector copy number analysis revealed Temferon-derived differentiated cells in BM and peripheral blood made up to 30% of these cells at their peak and persisted up to 18 months. Single cells RNA sequencing of the TME in treated participants compared to recurrent tumors in control patients had a clear Temferon signature.

“We believe that our interim results provide initial evidence of Temferon's potential to modulate the TME, as predicted by preclinical studies, which will be confirmed with longer follow up in the higher dose cohorts,” Gentner and colleagues wrote.

Gentner B, Eoli M, Capotondo A, et al. Autologous cell & gene therapy for the therapeutic targeting of immune payloads to the solid tumor microenvironment: Preliminary results of the TEM-GBM study. Presented at ASGCT 2022, May 16-19, Washington DC. Abstract #1190.

The cell therapy was tolerated although there was a SUSAR of GGT elevations. 

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