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Access remains the most prevalent unmet need regarding CAR T-cell therapy, which is currently approved only for patients with late-stage relapsed or refractory multiple myeloma. Patients must wait and sometimes cannot receive the products in time.

spoke with Noopur Raje, MD, director, Center for Multiple Myeloma, Massachusets General Hospital, about these unmet needs with CAR T-cell therapy in multiple myeloma. She discussed how improving access for these patients is a vital concern.

Raje discussed the potential of moving CAR T-cell therapy into earlier stages of treatment to help improve access and expand the number of patients who could receive treatment. Ciltacabtagene autoleucel (cilta-cel; Carvykti) and idecabtagene vicleucel (ide-cel; Abecma) are currently being investigated in the up-front setting in clinical trials. Once the indication is received in earlier stages of myeloma, bridging therapies will help more patients receive CAR T-cell therapy, Raje concluded.

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The director of the Center for Multiple Myeloma and Mass Gen discussed unmet needs with CAR T-cell therapy in multiple myeloma.

Noopur Raje, MD, on Unmet Needs With CAR T-Cell Therapy in Multiple Myeloma

Weekly Rewind! We’ve compiled 5 highlights from this week’s coverage of advances in gene and cell therapies, including FDA actions, notable research, and interviews with experts across the field.

1. Gene Therapy for Knee Cartilage Lesions Receives RMAT Designation

NeoCart was originally developed by the company Histogenics.

2. EtranaDez Accepted for Priority Review in Hemophilia B

A final analysis of the pivotal HOPE-B study was presented at ASGCT 2022.

3. Developing Safer Viral Vectors for Gene Therapy

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

4. Ami J. Shah, MD, on Reaching Normalized Hemoglobin With Gene Therapy in PKD

The clinical professor of pediatrics at Stanford Medicine discussed positive interim findings from a phase 1 study of RP-L301.

5. Gene Therapy for AADC Deficiency Receives Positive CHMP Opinion

The positive opinion was based on findings from studies conducted in Taiwan.

Articles

Review top news and interview highlights from the week ending May 27, 2022. 

CGTLive’s Weekly Rewind – May 27, 2022 

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 chicken anemia virus (CAV) 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 Nelo viruses 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 CAV anellovirus?

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 Ring 46. 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 benefits 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 humansvirome. 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 cell and gene therapy sectors are growing exponentially, with new playersemerging daily and much progress being made both in and out of the lab. 

Around the Helix is your chance to catch up with the latest news in cell and gene therapies, including partnerships, pipeline updates, and more.

Ocugen has added the phase 3 cell therapy platform NeoCart to its pipeline following its Regenerative Medicine Advanced Therapy (RMAT) recognition for the repair of full-thickness lesions of the knee cartilage in adults.

uniQure's biologics license application (BLA) for etranacogene dezaparvovec (EtranaDez) has been accepted by the FDA for priority review for the treatment of hemophilia B. A final analysis of the pivotal HOPE-B study was presented at ASGCT 2022.

3. Gene Therapy for AADC Deficiency Receives Positive CHMP Opinion

The European Medicines Agency (EMA)’s Committee for Medicinal Products for Human Use (CHMP) has granted a positive opinion to PTC Therapeutics’ gene therapy eladocagene exuparvovec (PTC-AADC; Upstaza) for treating aromatic L-amino acid decarboxylase (AADC) deficiency based on findings from studies conducted in Taiwan.

4. International Partnership Aims to Improve CAR T-Cell Therapy Accessibility

University of Pennsylvania Medicine and Children’s Hospital of Philadelphia are teaming up with Costa Rica’s Caja Costarricense de Seguro Social to facilitate research with chimeric antigen receptor (CAR) T-cell therapies in the country.

Bayer has decided to end their exclusive worldwide licensing agreement with Atara Biotherapeutics for next-generation mesothelin-directed CAR T-cell therapies, which includes cell therapy programs indicated for malignant pleural mesothelioma and non-small-cell lung cancer.

6. Consortium to Accelerate Rare Disease Therapy Development

ASC Therapeutics has joined Joins the Accelerating Medicines Partnership Bespoke Gene Therapy Consortium US Consortium of Gene Therapy Partners, which includes the NIH and FDA. The consortium aims to accelerate development of therapies for rare diseases by tackling challenges in research, production, and regulations.

7. Kelonia Gets Funding for Safer CAR T-Cell Therapies

Kelonia Therapeutics, a new start-up, has designed off-the-shelf CAR T-cell therapies that are safer than traditional CAR T therapies but still personalized to patients, created with detargeted and redirected lentivirus-like particles.

8. Castle Creek Biosciences Funding Advances Gene Therapy Programs

The company has raised $112.8 million to advance the development of their phase 3 gene therapy program for recessive dystrophic epidermolysis bullosa (RDEB) as well as to submit an investigational new drug application for their in vivo gene therapy program for hereditary tyrosinemia type 1.

9. Myrtelle and Rescue Hearing to Collaborate on Hearing Loss Gene Therapy

Myrtelle has entered into a Worldwide Exclusive License Agreement with Rescue Hearing to develop a novel gene therapy for DFNB8 genetic hearing loss.

10. Ultragenyx Acquires Rights to MPSIIIA Gene Therapy

The company has acquired rights to Abeona Therapeutics' adenovirus-associated vector (AAV) gene therapy ABO-102 for the potential treatment of Sanfilippo Syndrome Type A, which is currently being evaluated in the phase 1/2 Transpher A trial (NCT02716246).

Its new platform, titled UpTempo Virtuoso, which includes optimized standard protocols for cell culture, transfection, and downstream purification, streamlines AAV manufacturing with the goal of reducing the timeline from development to clinic and to enable rapid first-in-human clinical evaluation.

12. Roche, Spark, and bluebird Settle Trademark Suit

The lawsuit by Roche, on behalf of their subsidiary Spark Therapeutics, was filed in response to bluebird’s “Be the Spark” campaign. The lawsuit has been dismissed and the campaign remains live.

Catch up on the latest news, breakthroughs, and announcements from biotechnology companies making advancements in cell and gene therapies. 

Around the Helix: Cell and Gene Therapy Company Updates – May 25, 2022 

“[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. 