Transforming autoimmune disease therapy: Post-ACR 2024 perspectives on cell therapies

The 2024 American College of Rheumatology (ACR) annual meeting spotlighted transformative advancements in cell therapies for autoimmune diseases, with chimeric antigen receptor (CAR)-T therapies, T-cell engagers (TCEs), and multi-specific antibodies leading the charge.

These innovations hold immense promise, but also come with challenges that demand further refinement. Here’s a closer look at some of the latest developments shared at ACR 2024.

CAR-T Therapy: A revolution in progress

Historically associated with haematologic cancers, CAR-T cell therapy is now making its way into the autoimmune landscape. At the forefront of discussions at ACR 2024 was the success of autologous CD19-directed CAR-T cell therapies in addressing B cell-mediated autoimmune diseases such as lupus and rheumatoid arthritis. Data presented by companies like FATE, Cabaletta, and BMS highlighted how CAR-T therapy is reshaping treatment paradigms, offering durable remissions in severe autoimmune cases.

However, enthusiasm is tempered by discussions about key barriers. Experts at ACR 2024 noted that the requirement for apheresis to collect patient T-cells poses logistical and clinical challenges. Patients often need to taper immunosuppressants before cell collection, increasing the risk of disease flare-ups. Moreover, the quality of T-cells from autoimmune patients – already compromised by disease burden or chronic immunosuppressive therapy – can affect treatment efficacy.

Allogeneic CAR-T therapies, highlighted by Allogene, Kyverna, and Caribou, are emerging as promising alternatives. These “off-the-shelf” solutions eliminate the need for apheresis, offer better batch control, and address some of the scalability and cost issues of autologous therapies.

Despite the hurdles, the consensus is that CAR-T therapies represent a significant leap forward. For now, they are best suited for severe cases of autoimmune diseases, but advances in technology and accessibility could expand their application in the future.

T-Cell engagers and multi-specific antibodies: Precision immunomodulation

TCEs and multi-specific antibodies have also been spotlighted as complementary or alternative strategies to CAR-T therapies. These biologics offer a non-cellular approach to modulating the immune system and can be designed to target specific pathogenic pathways.

Unlike CAR-T therapies, TCEs are off-the-shelf biologics designed to harness the cytotoxic power of T-cells to selectively eliminate pathogenic immune cells. Their flexibility and ease of administration make them an attractive option, particularly in the outpatient setting.

Among the next-generation TCEs showing promise, Cullinan's CLN-978 stood out at ACR this year. This subcutaneous CD19/CD3-directed bispecific-TCE (BiTE) demonstrated deep B-cell depletion and a favourable safety profile with weekly injections in Phase 1 trials for non-Hodgkin’s lymphoma (NHL). Cullinan has since discontinued enrolment in its NHL study and will focus CLN-978’s development in autoimmune diseases; the BiTE is currently in Phase 1b development for rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). CLN-978 could represent a major step forward in reducing treatment burdens, offering patients a less invasive option with the potential for fewer clinic visits and greater convenience.

TCE’s advantages include bypassing the need for apheresis, shorter hospitalisation times, and the possibility of outpatient administration in the future. Additionally, TCEs allow for therapy interruption if severe adverse events (AEs) arise – a critical safety advantage over CAR-T therapies.

However, questions remain about whether TCEs can match the magnitude and durability of efficacy observed with autologous CAR-T therapies.

Challenges and future directions

The enthusiasm for cell therapies is balanced by an acknowledgment of their current limitations:

• Cost and accessibility: Autologous CAR-T therapies remain prohibitively expensive, limiting patient access and raising concerns about payer dynamics. Allogeneic CAR-Ts and TCEs, as scalable “off-the-shelf” solutions, could provide more affordable options.
• Safety concerns: The reliance on lymphodepletive preconditioning and the broad immune suppression of many current therapies increase the risk of infections and other adverse effects.
• Precision targeting: Most therapies, including CD19 CAR-T, indiscriminately target entire B-cell populations. The future lies in selectively targeting pathogenic cells, reducing collateral damage to the immune system.

Looking ahead, next-generation therapies that eliminate the need for lymphodepletion, improve specificity, and lower costs could expand the addressable patient population. Innovations like allogeneic CAR-T, TCEs, and bispecific antibodies represent promising steps in this direction. While not discussed at ACR 2024, Roche’s recent acquisition of Poseida Therapeutics adds another layer of optimism to the cell therapy landscape. Poseida’s gene-editing and cell therapy platforms, including their next-generation CAR-T technologies, are poised to accelerate the development of innovative treatments for both oncology and autoimmune diseases. This move underscores the pharmaceutical industry’s belief in the transformative potential of cell-based therapies.

Conclusion

ACR 2024 highlighted a pivotal moment in autoimmune disease therapy, with CAR-T, TCEs, and multi-specific antibodies offering hope for transformative treatments. As these therapies evolve, they hold the potential to not just manage, but fundamentally alter the course of autoimmune diseases, bringing hope to millions of patients worldwide.

About the authors

Paola Pinto is a consultant at Lifescience Dynamics, specialising in pharmaceutical insights and strategy, with a focused expertise and interest in autoimmune diseases, including rheumatology, dermatology, and gastroenterology. Experienced in partnering with global pharmaceutical clients throughout the drug development pipeline, from candidate selection to life cycle management, she is keen to understand and deliver insights on the dynamic treatment landscapes across therapeutic areas, including the emergence of novel modalities such as cell therapies. Before joining Lifescience Dynamics, Pinto completed a PhD in Molecular Biology and Biochemistry at the University of Vienna.

Stylianos Sarrigiannidis is a senior business analyst with Lifescience Dynamics, exercising his expertise in cutting-edge developments across autoimmune diseases like SLE and cell therapies such as CAR-Ts. He endeavors to provide strategic insights to advance innovation and study patient outcomes in these transformative fields. Before joining Lifescience Dynamics, Sarrigiannidis earned a PhD in Biomedical Engineering at the University of Glasgow, where he focused on drug delivery mechanisms, tissue regeneration, and biomaterials.

Callum McCarthy is a business analyst with Lifescience Dynamics. He is actively supporting a variety of projects across immunology indications, including autoimmune diseases such as lupus and rheumatoid arthritis, with a focus on innovative therapies like CAR-T cell therapies, and bispecific antibodies. Prior to joining Lifescience Dynamics, McCarthy earned a PhD in Clinical Medicine Research (Infectious Disease) from Imperial College London, where he investigated molecular pathways involved in inflammatory cell responses to bacterial infections. He also holds a Master's degree in Biological Science from the University of Warwick.