Leveling Up: Cell Therapy Research Expands Horizons in Autoimmune Disease

In recent years, cell therapy has begun integrating into the clinical trial landscape for autoimmune diseases. The shift, which began with an early push in lupus, has since expanded into early programs in several indications, including myasthenia gravis, multiple sclerosis, systemic sclerosis, myositis, stiff person syndrome, and others.

Thus far, no cell therapies have been approved for treating autoimmune diseases – or even entered phase 3 trials for such indications – but nonetheless, the possibility of curative-type therapies has generated great excitement in the field. Chimeric antigen receptor (CAR) T-cell therapies, for example, are able to target and eliminate B-cells, and are thus a promising mode of treatment for B-cell-driven autoimmune diseases. Years of experience with CAR-T therapy in oncology and long-term data supporting its durability and efficacy are supporting the move into autoimmune disease.

Companies leading the charge to bring cell therapy to autoimmune disease include Kyverna Therapeutics, one of the first companies to investigate CAR-T therapy for lupus; Cabaletta Bio; and Cartesian Therapeutics, all of which have cell therapies in phase 2 trials for autoimmune diseases. These programs have produced life-changing results in many patients and disappointing results in others. As a wide array of other companies have launched and continue to launch phase 1 trials, experts in the field have pointed out that while cell therapies may be curative for certain patients, they will certainly not be for all.

“[Cell therapy] generates an enormous amount of hype. Some of that is justified, but we have to see the long-term data. We’ve had similar levels of excitement in the past, and long-term data sort of tempered our expectations. I don't want to seem like a denier with this, but I think we just need to sort of take it in the context of where it is. It will probably be a very effective therapy for a small portion of treatment resistant patients. How much that's generalized across the disease, we'll see. But we'll get the answer eventually,” Jack Arnold, a clinical research fellow and clinician treating lupus at Leeds Centre of Rheumatic and Musculoskeletal Medicine told HCPLive®.

Supporting the move into autoimmune disease now are years of experience with CAR-T therapy in oncology and long-term data supporting its durability and efficacy. HCPLive and CGTLive spoke with experts, advocates, and companies engaged in the cell therapy autoimmune scene to learn more about what the field learned from hematology/oncology, continuing progress in the field, and unlocking cell therapy’s full potential for autoimmune disease in the rheumatological field.

Lessons Learned With Cell Therapy for Autoimmune Disease

Lupus, including systemic lupus erythematosus (SLE) and lupus nephritis (LN), was one of the first areas of investigation for cell therapies such as CAR-T therapy. Lupus Research Alliance and its clinical affiliate Lupus Therapeutics have helped to bring a number of cell therapies to the clinical stage through its Lupus Clinical Investigators Network (LuCIN) and partnerships with companies making progress in this area including Bristol Myers Squibb, Cabaletta, Caribou Bio, Nkarta, and others.2 As such, they are a key player in the space with a unique view on cell therapy’s potential and progress for autoimmune diseases.

Stacie Bell, PhD, executive vice president of Lupus Therapeutics, sat down with HCPLive during the American College of Rheumatology (ACR) 2024 Convergence in November to discuss the changing field of autoimmune disease.

“When the first major publication came out in November 20221, for CAR T and the involvement with the lupus community, it was like something I'd never thought I would ever see in my career, you know, to see people basically have complete disease remission, not only relief of symptoms, but actually their lived disease course,” Bell said.

Bell discussed the growth of investigations into cell therapy since their initial introduction and how groups such as Lupus Research Alliance, Lupus Therapeutics, and the FDA have worked together since then to facilitate research in the space. She emphasized the importance of taking learnings from oncological experience with cell therapy and translating them to the rheumatology field, as well as the importance of supporting patient education and informed consent.

“...Translating the love language between hematology and oncology and the things that they've experienced into the rheumatology community and how that relates to those living with autoimmune disease is an important element,” Bell said.

Bell also reminded viewers that no one therapy is 100% effective for everyone and cell therapy is no exception, although it has acted as a curative therapy for a number of patients with lupus in the follow-up done thus far.

Future Goals for CAR-T in Autoimmune Disease

The first-in-human clinical study of CAR-T in autoimmune disease began around 3 years ago. At the time, not much was known about the potential safety and efficacy of CAR-T in patients with autoimmune disease, and as such the trial was carried out in patients with severe disease who had generally exhausted other treatment in options. Notably, an autologous CAR-T product was used, with the standard lengthy manufacturing time for such products.

Since this and other early trials have shown some promising signs of long-term safety and efficacy, experts are now thinking about the next steps to optimize the safety, efficacy, and accessibility of CAR-T for autoimmune disease, as well as ways to broaden eligibility. In December 2024, CGTLive spoke with Georg Schett, MD, vice president of research and chair of internal medicine at the University of Erlangen – Nuremberg, who served as an investigator on the earliest CAR-T trial for autoimmune disease. Schett discussed what has been learned from these early efforts, pointing out that the risk of high grade cytokine release syndrome and neurotoxicity was shown to be low, thus suggesting a strong safety profile for the modality in autoimmune disease. Schett also discussed key areas of innovation that may be a focus of future clinical research for CAR-T in autoimmune disease. For example, he discussed the technically challenging process of manufacturing autologous CAR T-cells and the need to streamline and shorten this process in order to utilize fewer resources and less space. He also spoke about the potential of using hypoimmunogenic allogeneic CAR T-cells in order to further improve scalability and time-to-treatment.

Schett also noted that if CAR-T in autoimmune disease continues to demonstrate safety, it may eventually be able to be used as an earlier-line treatment in patients with severe autoimmune disease. He emphasized the potential benefits of CAR-T over other options in this scenario.
“Imagine you can abrogate the whole disease with a single infusion and do this early and prevent organ damage,” Schett told CGTLive. “I think that concept is very appealing. At the moment, I think we are not there because [earlier on] data on safety were basically not present, but now [those data] are actually coming up more and more. So at the beginning, actually, the therapy was limited to very resistant patients, but I think the concept to move earlier, if safety data look good, which they do so far, is extremely appealing to prevent organ damage.”
Schett also touched on the fact that most CAR-T trials for autoimmune disease are still in phase 1, but that in the future more CAR-T products will be brought into phase 2 and phase 3 studies. Although, he highlighted that recruiting patients for CAR-T trials poses some unique challenges compared to other modalities, and that even phase 3 trials for CAR-T in autoimmune disease may continue to include relatively lower numbers of patients compared to more conventional treatments like antibody therapies.

The Role of Established Pharmaceutical Companies in Bringing Cell Therapy to Autoimmune Disease

The earliest efforts exploring the use of CAR-T in autoimmune disease were carried out by academic institutions and small biotech companies. As the technology has shown promise, however, more and more companies have begun to show interest in launching trials for CAR-T products in autoimmune disease. Among these are large, well-established pharmaceutical companies, with previous experience developing and commercializing CAR-T in oncology and substantial resources to dedicate to new research in autoimmune disease. One such company is Bristol Myers Squibb (BMS), which already has an FDA-approved CD19-directed CAR-T product for oncology indications and is now also exploring the potential of CD19-directed CAR-T in autoimmune diseases including lupus, systemic sclerosis, idiopathic inflammatory myopathies, and multiple sclerosis. CD19 NEX-T, the company’s lead CAR-T candidate for autoimmune disease, is currently being evaluated in 2 clinical trials, data from one of which were presented at the 2024 ACR Convergence.

In the lead up to the conference, CGTLive spoke with Daniela van Eickels, MD, PhD, MPH, the vice president and head of medical affairs for BMS’s Cell Therapy Organization, about the company's plans for developing CAR-T products in autoimmune disease. Notably, BMS has formed the Autoimmunity Cell Therapy Network (ACTioN) Steering Committee in order to foster collaboration and facilitate the advancement of investigational candidates.3

“ACTioN is a BMS initiative where we are providing a platform that should enable deep connectivity and the building of a network between the different stakeholders that are involved in cellular therapies and how to bring them into the field of autoimmunity,” van Eickels previously told CGTLive. “We understand from our past that the patient journey will touch on different disciplines, and it is very important that this is a seamless connectivity along the patient journey.”

An important factor in the application of CAR-T to autoimmune disease has been the need for collaboration at the level of individuals between oncology specialists who have practical experience using CAR-T therapies in the clinic and autoimmune disease specialists who are disease area experts. Van Eickels also discussed more generally how this concept applies on the institutional level, as well.

“I think, generally speaking, we are very, very excited about the concept of deep immune reset,” van Eickels told CGTLive. “It's something that we are driving with utmost urgency, knowing that there are currently patients that are really suboptimally treated. We hope that by accelerating [this approach] we will really bring a real value to those patients. This is something that we really need to execute together with scientific experts, clinicians, and the patients that go on our studies. This is where we see the biggest value of an established player like BMS bringing that all together and also using our expertise in cellular therapies from other areas.”

Translating CAR-T Therapy from Oncology to Autoimmune Disease

Another, smaller company that has begun to integrate rheumatological targets into an oncology-focused pipeline is Allogene Therapeutics, with its ALLO-329, an allogeneic CD19/CD70 dual CAR-T. Allogene presented preclinical data from the program at the ACR Convergence that demonstrated the therapy’s dual targeting and elimination of targeted B-cells in mouse models.4

Zachary Roberts, MD, PhD, executive vice president of Research & Development and Chief Medical Officer of Allogene, spoke with HCPLive during the ACR Convergence and shared that the company plans to file an investigational new drug (IND) application for the therapy in early 2025. He also discussed Allogene’s experience developing cell therapies for oncology and now rheumatology.

“We are very good at dealing with toxicities that we expect to see with CAR-T,” Roberts said. “...We have direct clinical experience with that CAR molecule in patients with oncologic disease... we have encountered several of the same kind of toxicity profiles that others have seen with CD19 and BCMA CARTs. And so, we feel very prepared.”

Allogene’s pipeline is still comprised mostly of oncological allogeneic CAR-T therapies, with lead candidate cemacabtagene ansegedleucel currently in phase 2 trials for large B-cell lymphoma.

Roberts discussed how Allogene and other companies investigating CAR-T for autoimmune disease, most of which began their pipelines with oncologic indications, are able to take their experience developing, investigating, and managing CAR-T and its treatment in this new group of patients. Of course, there are many differences in patients with malignancies compared with autoimmune diseases, and approaches will need to be adapted and tailored to these patients.

“Rheumatologists are not oncologists, and autoimmune patients are not cancer patients. And so, you really have to come at this with a point of view that is tailored to the target audience... We plan to... further reduce the intensity of the lymphodepletion and ideally, we'll be able to get rid of it all together. So, this product design really was founded on this idea of tailoring this towards a group of physicians and a group of patients whose needs are different than oncologists and patients with malignant disease,” Roberts said.

Further commenting on the interplay between cell therapy for cancers and autoimmune diseases, Roberts mused that CAR-T's quick expansion in the rheumatological field feels the same as CAR-T's initial launch in the oncology field. He shared his excitement over what he believes will be an exciting new couple of years for the field.

The Big Picture

The field of CAR-T for autoimmune disease has made substantial progress over the past few years. Following promising early results from academic institution-led clinical research in lupus, biotech companies began jumping into the race to bring CAR-T to autoimmune diseases beginning in late 2022, with a flurry of new trials being launched by companies from that point onward and through 2023.

Now, in 2024, as this trend continues, and companies such as Cabaletta and Cartesian have begun to announce positive early efficacy and safety results from these trials, some experts are beginning to think about the longer-term future.5,6

The possibility of bringing CAR-T into earlier lines of treatment for autoimmune disease, the need to improve manufacturing processes, the potential of allogeneic approaches, and benefits of collaboration and knowledge-sharing across disciplines and would-be competitors are all relevant considerations on the horizon now. With that in mind, the need for vigilance and cautious optimism also remains, as the ultimate proportion of patients with autoimmune diseases who may actually stand to benefit from cell therapy continues to be uncertain. Regardless of how things play out, the field will likely need to make adjustments and accommodations as the landscape develops.

“We have the deep belief that this is a true innovation so it will require some adaptations in the healthcare environment,” van Eickels additionally told CGTLive. “We are trying to enable early conversations on what needs to change and what needs to happen, so that these new therapies can actually really benefit a wide array of patients if the data prove that to be beneficial.”

REFERENCES

1. Mackensen, A., Müller, F., Mougiakakos, D. et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med 28, 2124–2132 (2022). doi: 10.1038/s41591-022-02017-5
2. Current Collaborations and Initiatives. Lupus Therapeutics. 2024. Accessed December 24, 2024. https://lupustherapeutics.org/current-partner-studies/
3. Taking ACTioN. Bristol Myers Squibb. Website. Accessed December 24, 2024. https://www.bms.com/researchers-and-partners/areas-of-focus/our-research-in-immunology/taking-action.html
4. Allogene Therapeutics to Present Pre-Clinical Data Highlighting the Potential of ALLO-329, an Allogeneic CD19/CD70 Dual CAR T for the Treatment of Autoimmune Diseases, at the American College of Rheumatology (ACR) Convergence. Allogene Therapeutics. September 26, 2024. https://ir.allogene.com/news-releases/news-release-details/allogene-therapeutics-present-pre-clinical-data-highlighting
5. Cabaletta Bio presents positive clinical safety and efficacy data on CABA-201 at ACR Convergence 2024. News release. Cabaletta Bio, Inc. November 18, 2024. Accessed December 24, 2024. https://www.cabalettabio.com/news-media/press-releases/detail/119/cabaletta-bio-presents-positive-clinical-safety-and
6. Cartesian Therapeutics announces positive updated results from phase 2b trial of Descartes-08 in participants with myasthenia gravis and outlines design of planned phase 3 trial. News release. Cartesian Therapeutics, Inc. December 3, 2024. Accessed December 24, 2024. https://ir.cartesiantherapeutics.com/news-releases/news-release-details/cartesian-therapeutics-announces-positive-updated-results-phase