2023 ASGCT Annual Meeting: Showcase of Exciting New Research, with a Focus on Clinical Applications

The annual meeting of the American Society of Gene & Cell Therapy (ASGCT) is one of the premier events in the field of cell and gene therapy. The 26th edition of the ASGCT Annual Meeting was held from May 16 to 20 in Los Angeles, California, with over 6,600 professionals attending in-person and online sessions, showcasing and discussing the latest breakthroughs and developments in the field.

The event not only brought together leading scientists and researchers, but also clinicians, industry leaders, representatives from regulatory agencies, medical device manufacturers, and patient advocates. The Foundation for the National Institutes of Health (FNIH) also announced the selection of 8 rare diseases for the clinical trial portfolio of the Bespoke Gene Therapy Consortium (BGTC), with the aim of promoting gene therapy research for these rare diseases. 

GeneOnline’s editorial team has compiled some significant announcements and key research presentations from across the conference, covering new discoveries in cell and gene therapy, as well as relevant clinical applications for human diseases.

Related article: RNA Therapeutics Beyond Vaccines 

Recipient of the 2023 ASGCT Founders Award: David A. Williams, MD

On the opening day of the event, hematologist David A. Williams, MD, received the 2023 ASGCT Founders Award. Established in 2022, the award celebrates a scientist who exhibits “exceptional leadership, creativity, and innovation” in the field. Following the Award Reception, the Chief of Hematology/Oncology at Boston Children’s Hospital delivered a keynote speech with the theme “The maturation of hematopoietic stem cell (HSC) gene therapy: Of mice and men”, reviewing his four decades of work at the forefront of stem cell research and clinical gene therapy and highlighting that the integration of stem cell research and clinical medicine has progressed significantly in recent years.

In his presentation, Williams also summarized an impressive and sustained record of research excellence, including cloning interleukin-11 (the first approved drug to treat thrombocytopenia); research on chemoresistance, development of the first mouse model of X-linked chronic granulomatous disease used for preclinical development, milestones in gene transfer in mouse models for severe combined immunodeficiency (SCID), and improvements to viral vector design. Williams was also instrumental in the establishment of the Transatlantic Gene Therapy Consortium (TAGTC) in 2005.

Combining AAV Gene Therapy and Cytokine Immunotherapy for Brain Cancer Treatment

At this year’s ASGCT Annual Meeting, San Francisco-based Siren Biotechnology presented preclinical data demonstrating the effectiveness of a novel cancer treatment called “Universal AAV Immuno-Gene Therapy”, a combination of AAV gene therapy with cytokine immunotherapy that constitutes a single treatment modality. 

Adeno-associated viruses (AAV) are the most commonly used vectors for gene therapy involving viruses. However, research in oncology with AAVs has been limited because they are theoretically non-oncolytic, do not replicate or lyse host cells, and do not move between cells. Besides, A major challenge for cytokine immunotherapy in oncology is that half-lives of cytokines are usually rather short, ranging from a few minutes to a few hours even when encapsulated in nanoparticles or decorated with biochemicals. 

Nevertheless, according to Siren’s preclinical data from in-vivo mouse model studies, by combining AAV gene therapy and cytokine immunotherapy, researchers attempted to refine the cytokine payload with the hope that universal AAV immune gene therapy would become the future standard of care for a variety of solid tumors.

Siren’s team conducted experiments to assess the safety and efficacy of an immuno-gene therapy using AAV9 vectors expressing 12 different engineered immunomodulatory interferon cytokine payloads including IFNɑ1, IFNβ, IFNƔ, and combinations of these cytokines. As demonstrated in primary human high-grade glioma (HGG) organoids, the AAV immuno-gene therapy reduced tumor size rapidly and selectively. On day 7 following the treatment, it was also found that there was reproducible tumor eradication, without leaving any evidence of remnants of proliferating cells or residual expression of the engineered cytokine payload.

Benefits of Epigenetic Editing in Human T Cells for Multiplex Gene Regulation

Headquartered in Boston, Massachusetts, Chroma Medicine is a new genomic medicine company working on epigenetic editing, harnessing the cell’s innate natural mechanism for gene regulation to develop revolutionary treatments for rare genetic diseases. In the 26th ASGCT Annual Meeting, the company presented data demonstrating the advantages of epigenetic editing for multiplex gene regulation using their cutting-edge technology platform.

Chroma’s epigenetic editing platform utilizes the cell’s endogenous mechanism for regulating gene expression to durably modulate transcription without cutting or nicking the DNA, showing the potential of making simultaneous editing of several genes (multiplex editing) safer. When compared with conventional gene editing methods that involve alteration of gene expression using DNA breaks (Cas9 nuclease for example), this platform can minimize unnecessary risks including chromosomal rearrangements or genomic aberrations. 

Encouraging Breakthroughs in Allogeneic CAR T-Cell Candidate for Leukemia Treatment

Cellectis is a clinical-stage biotechnology company developing cell and gene therapies with its pioneering gene-editing platform. At the 2023 ASGCT Annual Meeting, the French biopharma presented their clinical data obtained from the AMELI-01 clinical trial, a Phase 1, first-in-human, dose-escalation study evaluating the safety and efficacy of UCART123, which is an allogeneic CAR-T cell therapy targeting CD123 (interleukin-3 receptor) in patients with relapsed/refractory acute myeloid leukemia (r/r AML). 

In the meantime, Cellectis unveiled preclinical data on multiplex engineering for superior generation of CAR T-cells with enhanced efficacy and persistence. Based on the company’s poster presentation, multiplexed engineering has shown not to compromise CAR T-cell function, but may even improve it and lead to increased anti-tumor activity. In the near future, the company is anticipated to be capable of selecting and combining a variety of gene and cell engineering approaches in order to produce armored CAR T-cells that are highly effective, overcoming the immunosuppressive barriers present in the tumor microenvironment and leading to significant advances in the fight against solid tumors.

Promoting Clinical Trials of Gene Therapies to Benefit Patients with Rare Genetic Diseases

Research and development in the field of clinical therapeutics for rare diseases has been limited by the paucity of patients and small commercial scale. It is nonetheless important to note that, given the fact that more than 80% of rare diseases are genetic in nature, ASGCT, in collaboration with NIH, the U.S. FDA, pharmaceutical and life sciences companies, as well as numerous public and private organizations, established the Bespoke Gene Therapy Consortium (BGTC) in October 2021 to address this bottleneck by streamlining the review and approval processes for first-in-human clinical trials of gene therapies, resulting in more efficient and cost-effective trials.

As a part of the Accelerating Medicines Partnership® (AMP®) program managed by the Foundation for the NIH (FNIH), BGTC aims to improve current models for developing diagnostics and therapies, thereby speeding up the delivery of customized (bespoke), life-changing gene therapies for millions of patients debilitated by rare diseases, including those being too rare to be of commercial interest. 

At this year’s ASGCT Annual Meeting, the FNIH announced that the BGTC has selected 8 rare diseases for its clinical trial portfolio. These selections were made based on rigorous scientific and technical review by a panel of gene therapy experts using the BGTC’s established criteria, such as the adequacy of the gene for insertion into an AAV vector, sufficient proof of concept and natural history data, the existence of an established disease model, a lack of available treatment, and an overall readiness for entering into a clinical trial.

According to Julie Gerberding, CEO of the FNIH, BGTC’s clinical trial portfolio represents an important milestone that can lead to more accessible treatments for people living with rare genetic diseases.

Overall, many of the presentations at the ASGCT Annual Meeting were related to the integration of pathways, including patient populations, routes of administration, and different AAV carriers, exploring the diversity of product combinations to ensure that research efforts are as broadly applicable as possible to future indications. Going forward, there is a potential trend to create multidisciplinary teams that include representatives from manufacturing expertise, regulatory agencies in preclinical settings, and patient advocacy groups for individual diseases.

Author

Richard Chau