The 2024 European Society of Gene and Cell Therapy (ESGCT) conference in Rome, Italy showcased the latest innovations in gene and cell therapy, with a focus on the latest developments in chimeric antigen receptor (CAR) T- cell therapies, gene-editing tools, and immunotherapy strategies. Here’s a summary of some of the key themes and advancements presented.
Moving Toward Allogeneic CAR-T Cells and Multiplex Gene Editing
Dr. Waseem Qasim, professor of Cell & Gene Therapy at the Institute of Child Health, UCL and Consultant in Paediatric Immunology/BMT at Great Ormond Street Hospital, addressed the importance of developing off-the-shelf CAR-T cells to improve access to therapies for hematologic cancers. A key barrier for allogeneic CAR-T is human leukocyte antigen (HLA) mismatch, which leads to immune rejection. Gene editing technologies, such as TALENs, CRISPR, and base editing, are critical to overcoming this obstacle. For instance, knockout strategies for HLA class I and II molecules can reduce host rejection by eliminating antigens that trigger immune attacks. Knockouts of CD52 and TCRɑβ/CD3 can further enhance cell survival during treatment and reduce fratricide, where T cells inadvertently target each other.
Risk Mitigation in Multiplex Editing
Multiplex gene editing, while enabling multi-target modifications, also poses risks like chromosomal translocations. However, base editing, a technique that creates single-strand nicks instead of double-strand breaks, has shown promise in minimizing these risks while achieving similar efficacy to CRISPR-based editing.
Enhancing CAR-T Cell Persistence and Efficacy
In the pursuit of more durable CAR-T cell responses, Dr. Sara Ghorashian, of University College London Developmental Biology & Cancer Dept and UCL GOS Institute of Child Health, focused on strategies to address limitations in CAR-T persistence, particularly in pediatric leukemia. Relapse and loss of CAR-T cells due to antigen escape or T-cell exhaustion remain significant challenges. Bicistronic CAR-T designs and in-depth transcriptome analysis offer potential solutions to engineer cells with longer persistence and resilience.
Engineering CAR-T and CAR-NK Cells for Solid Tumors
Targeting solid tumors with CAR-T cells has proven challenging due to tumor microenvironment (TME) barriers and the risk of fratricide. Presenters introduced “armored” CAR-Ts that are engineered to express immune-activating molecules like IL-18, which can better survive and function within the TME. Dr. Concetta Quintarelli, of the University of Naples, highlighted CAR-NK cells as an alternative, as they show lower toxicity profiles and are effective in targeting solid tumors expressing CD123, such as AML.
Oncolytic Virus Therapy for Pediatric Brain Tumors
Dr. Marta Alonso, of Universidad de Navarra, shared promising results from oncolytic adenovirus research targeting pediatric brain cancers. These engineered viruses selectively infect and lyse cancer cells while avoiding healthy cells. The “delta-24” virus, modified for enhanced tumor selectivity, demonstrated promising survival rates in early trials and could potentially be used in combination with other therapies for a synergistic effect.
Gene Therapy Innovations for Tumor-Associated Immune Cells
Dr. Bernhard Gentner, of San Raffaele Telethon Institute for Gene Therapy, presented groundbreaking work on programming tumor-associated myeloid cells to stimulate anti-cancer immunity. By using lentiviral vectors to introduce interferon-alpha (IFN-α) genes into tumor-associated macrophages, this approach seeks to reprogram the TME in solid tumors like glioblastoma (GBM). This “Temferon” therapy is currently in Phase 1/2a trials and has shown initial efficacy, with evidence of IFN-α activity in brain tissue.
Regulatory Landscape and Safety
A dedicated regulatory session reviewed recent guidance from the European Medicines Agency (EMA) on advanced therapy medicinal products (ATMPs). Emphasis was placed on evolving standards for long-term safety monitoring, especially concerning viral vectors like AAVs, which were previously considered non-integrating but now require additional scrutiny due to potential genomic integration risks. The discussion underscored the need for therapy-specific safety assessments, particularly for gene-editing approaches.
Poster Highlights
A multi-omics analysis of CAR-T cells showcased differential vector copy number (VCN) distributions, offering insights into lineage-specific expansion patterns. Audience engagement highlighted the relevance of this data for understanding CAR-T efficacy, though questions remain on VCN distribution trends across clinical samples.
Key Takeaways
- Allogeneic CAR-T Progress: Advances in gene-editing tools and multiplex strategies offer hope for scalable off-the-shelf CAR-T therapies, though safety concerns around translocations remain.
- Base Editing as a Safer Alternative: Base editing is increasingly recognized for its precision in multiplex applications, especially in contexts where safety from chromosomal aberrations is paramount.
- Innovative Strategies for Solid Tumors: Armored CAR-T cells and oncolytic viruses represent promising approaches for overcoming the physical and immunological barriers of solid tumors.
- Improving CAR-T Persistence: Bicistronic CAR designs and persistence-engineering techniques are being explored to reduce relapse rates and improve long-term outcomes.
- Regulatory Evolution: EMA’s adaptive approach to ATMP safety reflects the dynamic nature of gene and cell therapy, with a focus on long-term data collection.
As the field of gene and cell therapy advances, ESGCT 2024 highlighted Europe’s dedication to developing novel, safer, and more effective therapies, with an eye toward making these innovations widely accessible in the near future. See you in 2025 in New Orleans!
